Test Bank For The Immune System Fifth Edition Peter Parham Chapter 1-17

Test Bank For The Immune System Fifth Edition Peter Parham Chapter 1-17

CHAPTER 1: ELEMENTS OF THE IMMUNE SYSTEM AND THEIR ROLES IN DEFENSE 1–1 a. b. c. d. e.

The last cases of smallpox were reported in the _____.

1950s 1960s 1970s 1980s 1990s.

1–2 The first line of defense against microorganisms that infect the body is referred to as _____. a. opportunistic immunity b. innate immunity c. adaptive immunity d. primary immunity e. central immunity.

1–3 a. b. c. d. e.

Which of the following pairs is mismatched? innate immunity: highly specialized defenses secondary immune response: immunological memory hematopoiesis: bone marrow phagocytosis: uptake and killing of microbes lymphocyte recirculation: continuous transport between blood and lymph.

1–4 a. b. c. d. e.

All of the following are examples of chemical barriers of innate immunity except _____. lactic acid normal microbiota lysozyme fatty acids proteases.

1–5 a. b. c. d. e.

When effector lymphocytes secrete _____, an inflammatory response ensues. lysozyme defensins lymph sebum cytokines.

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1–6 The thin layer of cells that makes up the interior lining of the blood vessels is called the _____. a. mucosa b. epithelium c. endothelium d. connective tissue e. lymphoid tissue.

1–7 a. b. c. d. e.

Identify the incorrect statement regarding hematopoiesis.

Hematopoiesis is a continuous process that occurs throughout one‘s lifetime.

The location for hematopoiesis differs with age.

Self renewal is necessary to replenish the supply of hematopoietic stem cells.

Most hematopoiesis occurs in the bone marrow after birth.

Leukocytes, but not erythrocytes, must go through hematopoiesis in order to develop.

1–8 a. b. c. d. e. f.

The progenitors of macrophages are _____. megakaryocytes dendritic cells monocytes neutrophils erythrocytes M cells.

1–9 a. b. c. d. e.

_____ act as cellular messengers by delivering degraded pathogens to lymphoid organs.

Plasma cells Dendritic cells Large granular lymphocytes Mast cells Basophils.

1–10 a. b. c. d. e.

Another name for a large granular lymphocyte is a _____. plasma cell helper T cell monocyte natural killer cell eosinophil.

1–11 a. b. c. d. e. f.

Effector cells that secrete antibodies are known as _____. natural killer cells cytotoxic T cells helper T cells M cells plasma cells regulatory T cells.

2

1–12 Spherical regions in lymph nodes containing areas that are packed densely with proliferating B cells are called _____. a. efferent vessels b. germinal centers c. red pulp zones d. periarterial lymphoid sheaths e. medullary sinuses.

1–13 a. b. c. d. e.

The _____ is (are) the lymphoid organ(s) that filter(s) the blood. spleen tonsils Peyer‘s patches appendix adenoids.

1–14 a. b. c. d. e.

_____ cells persist long after an individual has been vaccinated.

Neutrophil Plasma Memory M Mast.

1–15 a. b. c. d. e.

During an infection, _____ are mobilized in large numbers from the bone marrow. dendritic cells memory cells macrophages neutrophils B cells.

1–16 In most cases, adaptive immune responses rely on the initial activation of _____ in secondary lymphoid tissue: a. macrophages b.

T cells c.

B cells d. dendritic cells e. epithelium.

1–17 All of the following statements are characteristic of secondary immune responses except _____. a.

Secondary immune responses are activated when primary immune responses fail to completely eradicate an infection. b.

Secondary immune responses are restricted to adaptive immune responses. c.

Memory cells are activated rapidly during secondary immune responses. d.

Secondary immune responses are orders of magnitude greater than primary immune responses.

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e.

During a secondary immune response to a booster vaccine, it is possible to experience a primary immune response to an unrelated vaccine component encountered for the first time.

1–18 Identify the four classes of pathogens that provoke immune responses in our bodies and give an example of each.

1–19 A bacterium that causes a common disease in a population that has been previously exposed to it is called _____. a. opportunistic b. resistant c. commensal d. endemic e. attenuated.

1–20 A. Name the parts of the body where epithelia act as barriers to infection.

B. Describe the three main ways in which epithelia carry out this barrier function, giving details of the mechanisms employed.

1–21 An example of an antimicrobial peptide that protects epithelial surfaces from pathogens is _____. a. glycoprotein b. defensin c. proteoglycan d. lysozyme e. sebum.

1–22 How can antibiotics upset the barrier function of intestinal epithelia? Give a specific example.

1–23 Describe the characteristics commonly associated with inflammation and what causes them.

1–24 a. b. c. d. e.

Which of the following are characteristics of innate immunity: inflammation improvement in recognition of the pathogen during the response fast response highly specific for a particular pathogen cytokine production.

1–25 a. b. c. d. e.

Which of the following statements regarding neutrophils is false?

Neutrophils are mobilized from the bone marrow to sites of infection when needed.

Neutrophils are active only in aerobic conditions.

Neutrophils are phagocytic.

Neutrophils form pus, which comprises dead neutrophils.

Dead neutrophils are cleared from sites of infection by macrophages.

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1–26 What are the main differences between innate immunity and adaptive immunity?

1–27 A. Identify the two major progenitor subsets of leukocytes.

B. Where do they originate in adults?

C. Name the white blood cells that differentiate from these two progenitor lineages.

1–28 Primary lymphoid tissues are the sites where lymphocytes _______, whereas secondary lymphoid tissues are the sites where lymphocytes _______. a. are stimulated; develop and mature b. encounter pathogens; undergo apoptosis c. develop and mature; become stimulated d. undergo clonal selection; differentiate from hematopoietic stem cells e. die; are phagocytosed after death.

1–29 The spleen differs from other secondary lymphoid organs in which of the following ways? a.

It does not contain T cells. b.

It filters blood as well as lymph. c.

It is populated by specialized cells called M cells. d.

It receives pathogens via afferent lymphatic vessels. e.

It has no connection with the lymphatics.

1–30 What are clonal selection and clonal expansion in the context of an adaptive immune response? Describe how they shape the adaptive immune response.

1–31 What would be the consequence of a bioterrorist attack that released smallpox virus into a city?

1–32 a. b. c. d. e.

Examples of pathogens that cause human disease include: bacteria viruses fungi parasites (protozoans and worms).

All of the above are examples of pathogens that cause human disease.

1–33 a. b. c. d. e.

Which of the following is not associated with mucosal surfaces? mucus-secreting goblet cells lysozyme M cells white pulp beating cilia.

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1–34 Phagocytosis of either microbes or microbial constituents by macrophages is followed by the activation of macrophages and the secretion of cytokines. What are the main effects of these molecules?

1–35 Identify the different anatomical locations where hematopoiesis occurs in embryonic, fetal, and adult life.

1–36 a. b. c. d. e.

Which of the following pairs is mismatched? lymphocytes: innate immune response natural killer cell: kills virus-infected cells macrophage: phagocytosis and killing of microorganisms erythrocyte: oxygen transport eosinophil: defense against parasites.

1–37 a. b. c. d. e.

A term generally used to describe all white blood cells is _____. hematopoietic cells myeloid progenitor dendritic cells monocytes leukocytes.

1–38 a. b. c. d. e.

Examples of granulocytes include all of the following except: neutrophil monocyte basophil eosinophil.

All of the above are examples of granulocytes.

1–39 a. b. c. d. e.

The most abundant type of leukocyte in human peripheral blood is the _____. eosinophil basophil neutrophil monocyte lymphocyte.

1–40 a. b. c. d. e.

Which of the following statements are correct?

Macrophages are granulocytes.

Macrophages derive from monocytes.

Macrophages are non-phagocytic.

Macrophages reside in the tissues.

All of the above statements are false.

1–41 a. b. c.

Which of the following pairs is mismatched? monocyte progenitor: macrophage erythroid progenitor: megakaryocyte myeloid progenitor: neutrophil 6

d. e.

lymphoid progenitor: natural killer cell.

None of the above is mismatched.

1–42 a. b. c. c. d.

Which of the following pairs of associations is mismatched? large granular lymphocyte: T cell megakaryocyte: platelet B cell: plasma cell monocyte: macrophage myeloid progenitor: neutrophil.

1–43 Which of the following statements is false? a.

During human development, hematopoiesis takes place at different anatomical locations. b.

The hematopoietic stem cell gives rise to white blood cells, but a different stem cell is the progenitor of red blood cells. c.

Hematopoietic stem cells are self-renewing. d.

Platelets participate in clotting reactions to prevent blood loss. e.

Megakaryocytes do not circulate and reside only in the bone marrow.

1–44 Which of the following describes the flow of lymph through a lymph node draining an infected tissue? a. efferent lymphatic vessel \rightarrow lymph node \rightarrow afferent lymphatic vessel b. venule \rightarrow lymph node \rightarrow efferent lymphatic vessel c. afferent lymphatic vessel \rightarrow lymph node \rightarrow efferent lymphatic vessel d. artery \rightarrow lymph node \rightarrow efferent lymphatic vessel e. afferent lymphatic vessel \rightarrow lymph node \rightarrow artery.

1–45 Immune cells within the lymphatic circulation are directly deposited into which of the following anatomical sites so that the cells may reenter the bloodstream? a. right aorta b. left subclavian vein c. left carotid artery d. high endothelial venule e. hepatic vein.

1–46 Which of the following is the predominant route by which pathogens are brought from a site of infection into a lymph node? a. efferent lymphatics b. artery c. vein d. afferent lymphatics e. high endothelial venule.

1–47 Why does it take approximately a week after infection for the benefits of an adaptive immune response to start to be felt?

1–48 Vaccination is best described as prevention of severe disease by _______.

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a. b. c. d. e.

the deliberate introduction of a virulent strain of an infectious agent prior exposure to an infectious agent in an attenuated or weakened form prophylactic treatment with antibiotics stimulating effective innate immune responses using effective public-health isolation regimens such as quarantine.

1–49 Describe three distinct mechanisms by which antibodies eradicate infection.

1–50 Which of the following explains why immunity to influenza may appear to be relatively short-lived? a.

Effective immunological memory fails to develop. b.

Immune responses to influenza involve innate immune mechanisms only. c.

The primary and secondary immune responses are equivalent. d.

Influenza virus targets memory cells. e.

New influenza variants able to escape previous immunity appear regularly.

ANSWERS 1–1

c

1–2

b

1–3

a

1–4

b

1–5

e

1–6

c

1–7

e

1–8

c

1–9

b

1–10 d 1–11 e 1–12 b 1–13 a 1–14 c 8

1–15 d 1–16 b 1–17 a 1–18 The four classes of pathogen are bacteria, viruses, fungi, and parasites (protozoa and worms). Examples of these pathogens are given in Figure 1.4.

1–19 d 1–20 A. Skin; mucosal epithelium of the gastrointestinal tract; mucosal epithelium of the respiratory tract; mucosal epithelium of the urinogenital tract.

B. (i) Mechanical (physical) barriers. Tight junctions between the epithelial cells prevent the penetration of pathogens between the cells to underlying tissues. In addition, there is a flow of air and fluid over epithelial surfaces, which oxygenates and flushes the surface, preventing anaerobic bacterial growth and transient adhesion. On ciliated epithelial surfaces, such as those of the respiratory tract, the formation of a layer of mucus that is kept in continual movement by the beating cilia inhibits colonization and invasion by microorganisms. (ii) Chemical barriers. The epithelium produces a variety of chemical substances that interfere with the adherence of microorganisms to epithelium and with their replication. The skin produces fatty acids in sebaceous glands, which helps to create an acid environment inhibitory to the growth of many bacteria. Lysozyme, an enzyme that inhibits cell-wall formation in bacteria, is secreted in tears, saliva, and sweat. The stomach produces strong hydrochloric acid, creating a highly acidic and formidable environment, which when combined with the stomach enzyme pepsin (an acid protease) poses one of the most inhospitable environments for microbial growth in our bodies. Defensins are antimicrobial peptides secreted by all the protective epithelia. (iii) Microbiological barriers. A microbiota of non-pathogenic commensal microorganisms colonizes many epithelial surfaces and provides an additional barrier to infection. They compete with pathogenic microbes for space and nutrients, and sometimes produce antibacterial proteins that further inhibit attachment to epithelium. For example, Escherichia coli in the large intestine produce colicins, which prevent colonization by other bacteria.

1–21 b 1–22 Antibiotics attack the microbiological barriers of intestinal epithelia. The normal microbiota sensitive to the antibiotics are killed off and the intestine can then be recolonized and overgrown by microorganisms that in normal circumstances are present in very small numbers and thus do not cause a problem. An example is a condition called pseudomembranous colitis caused by the overgrowth of Clostridium difficile. A membrane-like substance is produced in the large intestine, causing an obstruction that can block intestinal flow and usually requires surgical removal.

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1–23 The hallmarks of inflammation are heat, redness, pain, and swelling (edema). These are caused by a combination of vasodilation (causing redness and heat), increased vascular permeability and the consequent infiltration of fluid and leukocytes from the blood into the infected site (causing swelling, and also pain as a result of the increased pressure on local nerve endings).

1–24 a, c, e 1–25 b 1–26 Innate immune responses are initiated almost immediately after infection, whereas adaptive immunity takes longer to develop. Innate immunity uses generalized and invariant mechanisms to recognize pathogens. Examples of these are the receptors on phagocytes that recognize surface molecules shared by many different pathogens and stimulate phagocytosis, and serum proteins such as complement. Innate immunity is often unable to eradicate the pathogen completely, and even when it does, it does not produce immunity to reinfection. An adaptive immune response, in contrast, involves specific recognition of the particular pathogen by highly specific receptor on a subset of lymphocytes, which are selected from a pool of millions of lymphocytes each bearing receptors specific for different molecules. Adaptive immunity is often powerful enough to eradicate the infection and provides long-term protective immunity through immunological memory.

1–27 A. The two major progenitor subsets of leukocytes are the common lymphoid progenitor and the myeloid progenitor.

B. In adults, all leukocytes originate in the bone marrow and are derived from pluripotent hematopoietic stem cells.

C. The common lymphoid progenitor differentiates into three cell types: B cells, T cells, and natural killer (NK) cells. The myeloid progenitor differentiates into six main cell types: basophils, eosinophils, neutrophils, mast cells, dendritic cells, and monocytes. Monocytes are circulating leukocytes that enter tissues, where they then differentiate into macrophages.

1–28 c 1–29 e 1–30 In an adaptive immune response to a pathogen, the term clonal selection describes the fact that only those lymphocytes that can recognize that particular pathogen and respond to it are selected to participate in the immune response. Clonal expansion describes the proliferation and subsequent differentiation of these few original lymphocytes to provide large numbers of effector lymphocytes. Clonal selection ensures that the adaptive response will be tailored specifically for the particular type of pathogen involved in the infection. Clonal expansion ensures that the few original lymphocytes specific for the pathogen produce a large population of effector lymphocytes that can make an effective immune response against the pathogen.

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1–31 The last case of smallpox was reported in the 1970s. As a result, children are no longer vaccinated routinely as was the case before smallpox was eradicated. A large proportion of any given population today would be unvaccinated, and thus susceptible to smallpox infection. The mortality rate would be high (30–50%) among those not protected by vaccination.

1–32 e 1–33 d 1–34 The cytokines released by activated macrophages have three principal effects. Some cytokines act as chemoattractants and recruit other leukocytes into the infected tissue, for example neutrophils, which efficiently phagocytose and kill bacteria, forming pus. Other cytokines act on the endothelial cells of local blood vessels to increase vascular permeability and vasodilation, thus initiating inflammation of the infected tissue.

1–35 The yolk sac and the liver produce blood cells in the embryo and early fetus through the first three months of gestation. The fetal spleen takes over this function from the third to the seventh months. Once developed, the bone marrow is the site of hematopoiesis from the fourth month of gestation throughout the remainder of fetal development and into adulthood.

1–36 a 1–37 e 1–38 b 1–39 c 1–40 b, d 1–41 e 1–42 a 1–43 b 1–44 c 1–45 b 1–46 d 1–47 Before the establishment of an effector population of lymphocytes, several events must occur: (1) specific recognition of pathogen by lymphocyte receptors (clonal selection); (2) proliferation of pathogen-specific lymphocytes to expand responding populations (clonal

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expansion); and (3) differentiation into effector lymphocytes with the resulting establishment of an organized adaptive immune response.

1–48 b 1–49 (i) Neutralization. By binding to the surface of a pathogen, antibodies interfere with the ability of the pathogen to grow and replicate. Antibody binding to a pathogen or a bacterial toxin can also inhibit its binding to receptors on host cells and therefore prevent its entry into cells. (ii) Opsonization. Antibody coating the surface of a pathogen or toxin can promote phagocytosis of the antibody-covered particle. Antibodies acting in this way are known as opsonins. The antibody-bound material interacts with Fc receptors on the surface of phagocytic cells such as macrophages and neutrophils, which bind the constant region (the stem) of the antibody.

Stimulation of Fc receptors in this way stimulates the engulfment and degradation of antibodycoated material by the phagocyte. (iii) Complement activation. IgG or IgM antibody bound to a pathogen stimulates activation of the complement system, leading to the deposition of complement proteins on the surface of the pathogen. Certain of these act as opsonins and bind to complement receptors on phagocytic cells to stimulate the phagocytosis and destruction of the pathogen.

1–50 e

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CHAPTER 2: INNATE IMMUNITY: THE IMMEDIATE RESPONSE TO INFECTION 2–1 Soluble effector molecules are effective when encountering pathogens in/on _____.

(Select all that apply.) a. extracellular spaces b. cytoplasm c. epithelial surfaces d. interstitial spaces e. vesicular compartments f. lymph.

2–2 Which of the three complement pathways becomes activated soonest after an initial infection? a. the classical pathway b. the lectin pathway c. the alternative pathway.

2–3 a. b. c. d. e.

Identify the incorrectly paired molecular association. iC3: factor B CR4: iC3b properdin: C3bBb membrane cofactor protein: C3b2Bb decay-accelerating factor: C3bBb.

2–4 All of the following complement proteins help form a pore in the pathogen‘s membrane except _____. a.

C3b b.

C5b c.

C6 d.

C7 e.

C8 f.

C9.

2–5 The importance of CD59 (also known as protectin) is to _____. a. promote the speed of complement activation by protecting C3 convertase C3bBb from proteolytic degradation b. prevent the recruitment of C9 c. dissociate the components of the alternative C3 convertase d. prevent the attachment of C3b to host cell surfaces e. inhibit the anchoring of C5b, C6, and C7 to host cell surfaces.

2–6 _____ are soluble complement fragments that mediate localized and systemic inflammatory responses. a. cryptdins 13

b. c. d. e.

defensins anaphylatoxins selectins C-reactive proteins.

2–7 All of the following statements are correct regarding \alpha2-macroglobulin except _____. a. it binds covalently to its target via a thioester bond b. it possesses a bait region to lure its target c. it undergoes a conformational change that enables it to enshroud the target d. when bound to its target it is cleared from the circulation by hepatocytes, fibroblasts, and macrophages bearing receptors specific for the complex e. its target is the membrane-attack complex on human cells.

2–8 Although activation of the three different pathways of complement involves different components, the three pathways converge on a common enzymatic reaction referred to as complement fixation.

A. Describe this reaction.

B. Describe the enzyme responsible for this reaction in the alternative pathway.

C. Identify the three effector mechanisms of complement that are enabled by this common pathway.

2–9 Which of the following is the soluble form of C3 convertase of the alternative pathway of complement activation? a. iC3 b. iC3b c.

C3b d. iC3Bb e.

C3bBb. 2–10 Explain the steps that take place when a bacterium is opsonized via C3b:CR1 interaction between the bacterium and a resident macrophage in tissues.

2–11 In the early stages of the alternative pathway of complement activation there are complement control proteins that are soluble (factors H and I) and associated with the cell surface (DAF and MCP). Identify the (i) soluble and (ii) cell surface-associated complement control proteins that operate in the terminal stages of the alternative pathway of complement activation, and describe their activities.

2–12 A. Review the differences between the three pathways of complement (alternative, lectin, and classical) in terms of how they are activated.

B. Distinguish which pathway(s) are considered part of an adaptive immune response and which are considered part of innate immunity, and say why.

2–13 Which of the following does not accurately describe complement components?

14

a. b. c. d. e.

soluble proteins made by the spleen located in extracellular spaces some function as proteases once activated activated by a cascade of enzymatic reactions.

2–14 Explain why a genetic deficiency of C3 leads to a type of immunodeficiency characterized by recurrent and severe infections.

2–15 Which of the following is the membrane-bound form of C3 convertase of the alternative pathway of complement activation? a. iC3 b.

C3a c.

C3b d. iC3Bb e.

C3bBb. 2–16 Explain how the alternative C3 convertase on pathogen cell surfaces is (A) formed and (B) stabilized.

2–17 Why is it important to expose the hydrophobic sites of C7 and C8 during the formation of the membrane-attack complex?

2–18 The plasma proteins that counteract the activity of factor P by inactivating C3 convertase through the cleavage of C3b are _____. a. factor B and factor H b. factor H and factor I c. factor B and factor I d. decay-accelerating factor and factor H e. decay-accelerating factor and membrane cofactor protein.

2–19 The membrane-bound proteins on human cells that dissociate and inactivate alternative C3 convertase to avoid complement activation are _____. a. factor B and factor H b. factor H and factor I c. factor B and factor I d. decay-accelerating factor and factor H e. decay-accelerating factor and membrane cofactor protein.

2–20 Explain the similarities between membrane cofactor protein, factor H, and complement receptor 1 in terms of their complement control properties.

2–21 Explain how the anaphylatoxins C3a and C5a contribute physiologically to inflammation during complement activation.

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2–22 Which of the following complement components is an opsonin that binds to complement receptor 1 (CR1) on macrophages? a.

C3b b.

C3a c.

Bb d.

Ba e.

C3bBb. 2–23 Which of the following polymerizes to form a transmembrane channel that compromises the integrity of cell membranes? a.

C5 b.

C6 c.

C7 d.

C8 e.

C9.

2–24 Which of the following are important in anchoring the membrane-attack complex to the membrane? a.

C3 and C5 b.

C5 and C6 c.

C6 and C7 d.

C7 and C8 e.

C8 and C9.

2–25 a. b. c. d. e.

Which of the following does not contain a glycosylphosphatidylinositol (GPI) lipid tail? decay-accelerating factor (DAF) homologous restriction factor (HRF) membrane cofactor protein (MCP) protectin (CD59) all of the above contain a GPI tail.

2–26 The ligand for CR3 and CR4 formed by the cleavage of C3b by the combined action of factors H and I is called _____. a.

C3bBb b.

C3a c.

C3b2Bb d. iC3b e.

C5b.

2–27 a. b. c. d. e.

Which of the following does not describe the actions of the coagulation system? blood clot formation enhancement of dissemination of microbes into lymphatics and bloodstream decrease in blood loss and fluid into interstitial spaces in tissues release of inflammatory mediators by platelets wound healing.

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2–28 Damage to tissues triggers a cascade of plasma proteins involving bradykinin and is known as _____. a. the alternative pathway of complement b. the coagulation system c. the kinin system d. receptor-mediated endocytosis e. the acute-phase response.

2–29 a. b. c. d. e.

Which of the following does not describe defensins? highly conserved with few variants contain a large proportion of arginine residues contain three intra-chain disulfide bonds amphipathic, with hydrophobic and hydrophilic regions disrupt pathogen membranes by penetrating them and disrupting their integrity.

ANSWERS 2–1

a, c, d, f

2–2

c

2–3

d

2–4

a

2–5

b

2–6

c

2–7

e

2–8 A. The cleavage of C3 into C3a and C3b and the covalent bonding of C3b to the pathogen surface is called complement fixation, and is the reaction on which the alternative, lectin, and classical pathways of complement activation converge.

B. The enzyme responsible for cleaving C3 into C3a and C3b is called C3 convertase, and it differs in composition depending on the particular complement pathway. The classical and lectin pathways use the classical C3 convertase (C4b2a), whereas the alternative pathway uses the alternative convertase (C3bBb).

C. C3 is the most abundant complement component in the plasma and circulates as a zymogen, an inactive enzyme. When cleaved into C3a and C3b, three different effector mechanisms are armed: (1) C3b binds to and tags pathogens for destruction by phagocytes through binding to a C3b receptor, CR1; (2) C3b contributes to a multicomponent enzyme, C5 convertase, that catalyzes the assembly of the terminal complement components and the 17

formation of the membrane-attack complex; and (3) C3a is an inflammatory mediator that serves as a chemoattractant and recruits inflammatory cells to the infection site.

2–9

d

2–10 The CR1 on the macrophage can bind to C3b that is coating a bacterial surface after complement activation, and the macrophage then engulfs the bacterium through receptormediated endocytosis. The macrophage membrane invaginates and forms an intracellular vesicle called a phagosome. The phagosome fuses with a lysosome to form a phagolysosome, where toxic mediators and degradative enzymes are localized. The bacterium is destroyed.

2–11 i.

The soluble proteins include S protein, clusterin, and factor J, which all inhibit C5b, C6, and C7 from binding to cell membranes. ii.

The cell surface-associated proteins include homologous restriction factor (HRF) and CD59 (protectin), which both prevent the recruitment of C9 and thus block C9 polymerization.

2–12 A. (1) The classical pathway is activated in two ways, either by the presence of antibody bound to the surface of the microorganism (for example IgM bound to lipopolysaccharide of Gram-negative bacteria) or by the presence of C-reactive protein bound to a bacterium. (2) The lectin pathway requires the presence of mannose-binding lectin, an acutephase protein made by the liver in response to interleukin-6 (secreted by activated macrophages) and which accumulates in plasma during infection. (3) The alternative pathway requires an activating surface of a pathogen, which stabilizes complement components.

B. Only the classical pathway is considered part of the adaptive immune response because of the requirement for antibody. However, the classical pathway is also considered part of innate immunity because of the ability of C-reactive protein, an acute-phase protein, to activate it. The other two pathways are considered part of innate immunity because they are initiated independently of antibody.

2–13 b 2–14 C3 is a key element in the initiation of the complement cascade in all three pathways of complement activation, namely the alternative, lectin, and classical pathways. Its cleavage into C3a and C3b occurs early in the complement cascade. C3a acts as an inflammatory mediator and recruits inflammatory cells to the site of infection. C3b becomes fixed to the pathogen surface and facilitates the opsonization of pathogens by phagocytes and the assembly of complement components for perforation of the pathogen membrane. In the absence of C3, all three pathways of complement activation would be arrested and extracellular pathogens would escape immune detection until adaptive immune mechanisms develop fully many days later.

2–15 e 2–16 18

A. Spontaneous hydrolysis of C3 without cleavage exposes its highly reactive thioester bond, forming iC3. Factor B binds to iC3, is cleaved by factor D, and consequently releases a small fragment called Ba. The larger fragment, Bb, remains associated with iC3 to form iC3Bb, a soluble C3 convertase, which cleaves C3 into C3a and C3b. The reactive thioester bond of C3b is attacked by R–OH and R–NH2 groups on the surface of the pathogen, where it becomes anchored and binds to factor B. Factor D then cleaves factor B, releasing fragment Ba and forming C3bBb on the pathogen surface.

B. Factor P (properdin) binds to C3 convertase (C3bBb) bound to the pathogen surface, and inhibits the proteolytic degradation of C3bBb. This stabilizes the C3 convertase and enhances the rate of C3b deposition on the pathogen surface.

2–17 The hydrophobic sites of C7 and C8 enable anchoring of these two complement components into the membrane of the pathogen. Once anchored in the membrane, the hydrophobic site of C8 facilitates C9 polymerization, which completes the formation of the membrane-attack complex.

2–18 b 2–19 e 2–20 MCP, factor H, and CR1 all bind to C3b and render it susceptible to proteolytic cleavage by factor I. All three contain complement control protein (CCP) modules and are therefore considered regulators of complement activation (RCA).

2–21 G-protein-coupled receptors for the anaphylatoxins C3a and C5a are found on phagocytes, mast cells, and the endothelial cells of blood vessel walls. Anaphylatoxin bound to mast cells causes them to degranulate, releasing inflammatory mediators such as histamine and leading to increased vascular permeability. Through their action on endothelial cells, anaphylatoxins exert vasoactive effects on blood vessels, contributing to increased vascular permeability and increased blood flow, which facilitate the extravasation of plasma proteins, such as complement proteins and antibodies, and the recruitment of cells to infected tissues through increased adherence and chemotaxis. Phagocytic activity is enhanced by anaphylatoxins, which bring about increased levels of CR1 and CR3 and microbicidal activity. All these activities enhance inflammation.

2–22 a 2–23 e 2–24 d 2–25 c 2–26 d 2–27 b 19

2–28 c 2–29 a

CHAPTER 3: INNATE IMMUNITY: THE INDUCED RESPONSE TO INFECTION 3–1 C-type lectins are so called because of the role of _____ in facilitating receptor:ligand interactions. a. carbohydrate b.

CR1 c. calcium d. chemokines e. caspases.

3–2 a. b. c. d. e.

Lectins recognize microbial _____. phosphate-containing lipoteichoic acids nucleic acids carbohydrates flagellin sulfated polysaccharides.

3–3 a. b. c. d. e.

Scavenger receptor SR-B recognizes _____. lipopolysaccharides teichoic acid filamentous hemagglutinin CpG-rich bacterial DNA lipids.

3–4 Macrophages bear on their surface receptors for all of the following except _____. (Select all that apply). a. mannose b. glucans c.

C3b d. muramyl dipeptide e. lipopolysaccharide f. lipoteichoic acid g.

CpG-rich bacterial DNA. 3–5 a. b. c.

_____ is a soluble protein. (Select all that apply.)

TLR4 CD14 lipopolysaccharide-binding protein (LBP) 20

d. e.

CXCR1 mannose-binding lectin.

3–6 _____ are structurally similar membrane-bound proteins that aid in the adhesion between various types of human cell. a.

Interferons b.

Integrins c.

GTP-binding proteins d.

Pyrogens e.

Pentraxins.

3–7 a. b. c. d.

All of the following induce fever except _____.

IL-12 IL-6 IL-1 TNF-\alpha.

3–8

Match the term in column A with its description in column B.

Column A ___a. interferon response ___b. apoptosis ___c. extravasation ___d. respiratory burst ___e. acute-phase response

Column B 1. a notable rise or reduction of plasma proteins in response to IL-6 2. stimulates inhibition of viral replication 3. temporary rise in oxygen consumption and toxic oxygen species production 4. cellular suicide characterized by DNA fragmentation 5. migration of neutrophils into inflamed tissues

3–9 Which of the following is not associated with mobilization of neutrophils to infected tissue? a.

TNF-\alpha production by macrophages b. upregulation of selectins on blood vessel endothelium c. interferon response d. generation of a CXCL8 gradient e. extravasation across endothelium f. proteolysis of basement membrane of blood vessels.

3–10 a. b. c. d. e.

Which of the following pairs is mismatched? primary granules: azurophilic granules secondary granules: unsaturated lactoferrin azurophilic granules: myeloperoxidase gelatinase: iron sequestration tertiary granules: natural killer cells.

21

3–11 The pH of the phagosome increases following phagocytosis because _____. a. the microbe delivers a significant number of hydroxyl ions in its cytosol that are released upon membrane disruption b. hydrogen ions are eliminated by the activity of NADPH oxidase and superoxide dismutase c. azurophilic granules deliver alkaline substances d. catalase consumes hydrogen ions once activated.

3–12 a. b. c. d. e.

C-reactive protein binds to _____. phosphorylcholine mannose-containing carbohydrates lipoteichoic acid flagellin MASP-1/MASP-2.

3–13 The C3 convertase that functions in the lectin pathway of complement activation consists of _____. a.

C3bBb b.

C3b2a c.

C4b2a d.

C4b2b e.

C3b2Bb. 3–14 a. b. c. d. e.

Which of the following cleaves C2? (Select all that apply.)

Factor B C1r MASP-2 C1s C4b.

3–15 a. b. c. d. e.

With which of the following complement proteins does C-reactive protein interact? factor D C1 factor P C4 C2.

3–16 All of the following are true of MyD88 except _____. a.

It binds to the TIR domains of all Toll-like receptors except TLR3. b.

It binds to IRAK4, a protein kinase, causing the kinase to phosphorylate itself. c.

It is an adaptor protein with similar function to TRIF. d.

A genetic deficiency of MyD88 causes the disease X-linked ectodermal dysplasia and immunodeficiency.

3–17 The name given to cytokines that recruit cells to move towards areas of inflammation is _____.

22

a. b. c. d. e.

chemokines caspase-recruitment domains (CARDs) inflammakines adhesion molecules pyrogens.

3–18 In common with Toll-like receptors, NOD-like receptors also contain _____ that is/are used for pathogen-recognition of microbial ligands. a. caspase-recruitment domains (CARD) b.

Toll interleukin 1 receptor (TIR) domain c. variable extracellular domain d. leucine-rich repeat regions (LRRs) e.

C-type lectin domain (CTLD).

3–19 Identify which of the following receptors does not lead to nuclear translocation of NF\kappaB through an activated IKK intermediate. a.

TLR4 b.

IL-1 receptor c.

NOD1 d.

NOD2 e.

All of the above receptors culminate in nuclear translocation of NF\kappaB through an activated IKK intermediate.

3–20 a. b. c. d. e.

Which of the following is most similar in its activity to that of IRF3?

IRAK4 NF\kappaB TRAF6 I\kappa\kappa GTP-binding (G) protein.

3–21 _____ help to prevent systemic bacterial dissemination by producing chromatin structures loaded with antimicrobial substances. a.

Inflammasomes b.

Neutrophil extracellular traps c.

RIG-1-like helicases d.

Granulomas e.

Plasmacytoid dendritic cells.

3–22 Match the condition/disease in column A with its description in column B. Use each answer only once.

Column A ___a. X-linked hypohidrotic ectodermal dysplasia and immunodeficiency (NEMO deficiency) ___b. septic shock

Column B 1. insufficient superoxide production in neutrophils compromises the respiratory burst 2. failure to translocate NF\kappaB and 23

___c. chronic granulomatous disease

activate macrophages due to deficiency in IKK\gamma subunit 3. allelic polymorphism of TLR4 with glycine at position 299 causing reduced responsiveness to LPS of Gram-negative bacteria

3–23 _____ is/are needed to minimize the damaging effects to neighboring host cells during a respiratory burst. a.

Catalase activity b.

Complement control proteins c.

NADPH oxidase activity d.

Neutrophil mobilization e.

Superoxide dismutase activity.

3–24 Measurement of which of the following is commonly used when monitoring patients with autoimmune diseases as an indicator of inflammatory relapse? a.

IL-1RA b. cryopyrin c.

C-reactive protein d. proIL-1\beta e.

IL-15.

3–25 a. b. c. d. e.

All of the following characterize serum amyloid protein except _____. it contains approximately 100 amino acids it interacts with CD36 scavenger receptor it increases in concentration by 25% or more in response to infection it associates with high-density lipoprotein particles it activates the classical pathway of complement activation.

3–26 a. b. c. d. e.

_____ is not an opsonin.

Mannose-binding lectin IFN-\alpha C-reactive protein surfactant protein-A (SP-A) surfactant protein-D (SP-D).

3–27 a. b. c. d. e.

Toll-like receptors are located _____. only on the plasma membrane on the plasma membrane and the mitochondrial outer membrane on the plasma membrane and endosomal membranes only in the cytoplasm inside inflammasomes.

3–28 Toll-like receptors differ from scavenger receptors in that they _____. a. bind to common repetitive arrays on microbial surfaces 24

b. c. d.

stimulate a pathway that causes enzymatic degradation of the microbe to which they bind are soluble receptors that bind to microbes in extracellular spaces mediate signal transduction pathways, causing cytokine production.

3–29 The Toll-like receptor that is able to signal through both the TRIF and MyD88 pathways is _____. a.

TLR3 b.

TLR4 c.

TLR5 d.

TLR7 e.

TLR8 f.

TLR9.

3–30 a. b. c. d. e.

Unlike inflammatory cytokines, Toll-like receptors _____. are never secreted participate only in adaptive immune responses are expressed only by dendritic cells stimulate the production of acute-phase proteins induce fever.

3–31 All of the following statements regarding Toll-like receptors are true except _____. a.

They exist as either transmembrane homodimers or heterodimers. b.

The extracellular domain detects the microbial component. c.

They facilitate changes in gene expression. d.

They sense molecules not found in or on human cells. e.

The cytoplasmic signaling domain contains a variable number of leucine-rich repeat regions (LRRs).

3–32 a. b. c. d. e.

_____ binds to and retains NF\kappaB in the cytosol.

MyD88 TRAF6 I\kappaB I\kappa\kappa IRAK4.

3–33 a. b. c. d. e.

Plasmacytoid dendritic cells _____. (Select all that apply.) detect viral infection by using TLR4 produce large amounts of the type I interferons when activated are found exclusively in the blood make up 10% of circulating leukocytes have a cytoplasmic morphology resembling that of antibody-producing plasma cells.

3–34 All of the following are correct in reference to type I interferons except _____. a.

Type I interferons inhibit the replication of viruses. b.

In the presence of type I interferons, virus-infected cells undergo cell-surface changes that render them more susceptible to attack by NK cells.

25

c. d. e. f.

Not only can most cells synthesize type I interferons, but they can also respond to them.

The receptor for type I interferons is abundant in the cytosol.

Type I interferons function in autocrine and paracrine fashions.

Type I interferons promote NK-cell proliferation and differentiation into cytotoxic cells.

3–35 Match the term in column A with its description in column B. Column A ___a. oligoadenylate synthetase ___b. plasmacytoid dendritic cell (PDC)

___c. RIG-I-like helicase ___d. protein kinase R (PKR) ___e. NK-cell synapse

Column B 1. activates endoribonucleases that degrade viral RNA 2. facilitates adhesion and information exchange between cells undergoing surveillance via activating and inhibitory receptors 3. synthesizes 1000 times more interferon than do other cells 4. inhibits protein synthesis by phosphorylating eIF-2 5. contains domains that bind to viral RNA and mitochondrial-associated adaptor proteins

3–36 The following cytokines activate NK cells early in the course of a viral infection with the exception of _____. a.

IFN-\alpha b.

IFN-\beta c.

IFN-\gamma d.

IL-12 e.

IL-15.

3–37 A. Describe the different functions performed by the two subpopulations of NK cells in the blood and how they are distinguished.

B. How does this compare with NK-cell subpopulations in other tissues?

3–38 The function of uterine NK cells (uNK) is to _____. a. kill virus-infected cells b. secrete growth factors that promote blood vessel growth to supply the placenta c. activate resident macrophages by secreting inflammatory cytokines d. secrete 1000 times more type I interferon than other cells to protect the fetus from viral infection.

3–39 NK cells express all of the following proteins either on endosome membranes or on their cell surface with the exception of _____. (Select all that apply) a.

CD3 b. type I interferon receptor 26

c. d. e. f. g. h. i. j.

CR3 CD56 LFA-1 activating receptors inhibitory receptors TLR3 TLR4 IL-12R\beta1 and IL-12R\beta2.

3–40 Which of the following does not describe a safety mechanism to ensure that only infected cells are attacked by NK cells? a.

The default state is one of active inhibition, which must be overcome by activating signals before killing occurs. b.

Intimate contact with target cells is required. c.

Activating receptors are induced only after encountering an infected cell. d.

No single receptor–ligand interaction induces cytotoxicity, but instead many combinations of receptor–ligand interactions influence the decision to kill or not to kill a target cell.

3–41 Which of the following does not describe a feature observed when a target cell is induced to commit apoptosis by an NK cell? a.

DNA fragmentation by target cell nucleases b. target cell shrinkage c. shedding of membrane-enclosed vesicles by the target cell d. chromatin extrusion in the form of decondensed DNA by the target cell e. macrophage disposal of apoptotic remains of the target cell.

3–42 Which of the following Toll-like receptors are expressed exclusively in NK cells? (Select all that apply.) a.

TLR3 b.

TLR4 c.

TLR7 d.

TLR8 e.

TLR9.

3–43 a. b. c. d. e.

Immediately after engagement of NK-cell Toll-like receptors, the NK cell _____. discharges cytotoxic granules ligates IL-12R\beta1 and IL-12R\beta 2 synthesizes and secretes IL-15 synthesizes and secretes IL-12 synthesizes and secretes type I interferons.

3–44 a. b. c.

Stimulation of NK cells by IL-12 _____. enhances their cytotoxic potential skews their differentiation into effector NK cells induces the synthesis and secretion of IL-15 by NK cells 27

d. e.

turns off type I interferon production by NK cells induces the NK cell to undergo programmed cell death.

3–45 _____ is a cytokine produced by both macrophages and dendritic cells that promotes the proliferation, differentiation, and survival of NK cells. a.

IL-15 b.

IL-1\beta c.

CXCL8 d.

TNF-\alpha e.

IL-6.

3–46 On the basis of laboratory experiments, a possible scenario for the activation of an adaptive immune response would involve _____ within an infected tissue. (Select all that apply.) a. a balanced number of myeloid dendritic cells and NK cells b. an abundance of NK cells compared with myeloid dendritic cells c. a shortage of NK cells compared with myeloid dendritic cells d. migration of myeloid dendritic cells to secondary lymphoid tissue e. migration of NK cells to secondary lymphoid tissue.

3–47 After recognizing its ligand, a NOD receptor interacts with a signaling protein called _____, which is a serine–threonine kinase that phosphorylates TAKI. a.

CARD b.

NLRP3 c.

RIPK2 d.

MARCO e.

SR-A. 3–48 An adaptor protein in the inflammasome is required to link _____ to the NOD-like receptor NLRP3. a.

MyD88 b. procaspase-1 c.

RIPK2 d.

TAKI e.

IKK. 3–49 a. b. c. d. e.

Chemokine receptors form complexes with _____ after binding to their ligands. inflammasome components pro-IL-1\beta potassium channels GTP-binding proteins tertiary granules.

3–50 All of the following acute-phase proteins increase in concentration in the plasma during inflammation with the exception of _____. a. albumin b. serum amyloid A protein 28

c. d. e.

fibrinogen C3 mannose-binding lectin.

3–51 a. b. c. d. e.

The ligands of endosomal Toll-like receptors are _____. lipids of Gram-negative bacteria flagellin proteins of bacteria lipids of Gram-positive bacteria zymosan of fungi nucleic acids of viruses and bacteria.

3–52 Of the following Toll-like receptors, which is the most highly conserved and displays the smallest amount of allelic polymorphism? a.

TLR1 b.

TLR8 c.

TLR10 d.

TLR6 e.

TLR4.

3–53 Sensors for viral nucleic acid in the cytoplasm, called RLRs, possess domains that bind to _____. (Select all that apply.) a.

GTP-binding proteins b. type 1 interferons c.

5\prime-triphosphate of uncapped RNA d. oligomerized procaspase-1 e.

CARD domains of MAVS. 3–54 Match the innate immune receptor in column A with its ligand(s) in column B. More than one ligand may be used for each immune receptor.

___a. ___b. ___c. ___d. ___e. ___f.

Column A lectin receptor scavenger receptor CR3 CR4 CR1 TLR4:TLR4

___g. TLR5 ___h. TLR3

Column B 1. iC3b 2. lipophosphoglycan 3. carbohydrates (for example mannose or glucan) 4. filamentous hemagglutinin 5. lipopolysaccharide (LPS) 6. negatively charged ligands (for example sulfated polysaccharides and nucleic acids) 7.

C3b 8. flagellin 9.

RNA

3–55 Other than their ligand specificity, what is a key difference between TLR5, TLR4, TLR1:TLR2, and TLR2:TLR6 compared to TLRs 3, 7, 8, and 9?

29

3–56 Explain why TLRs can detect many different species of microbes despite the limited number of different TLR proteins.

3–57 What is NF\kappaB and what is its role in mediating signals through TLRs? 3–58 What is the name given to the earliest intracellular vesicle that contains material opsonized by macrophages? a. opsonome b. membrane-attack complex c. lysosome d. phagosome e. phagolysosome.

3–59 A. What induces the production of type I interferon by virus-infected cells?

B. Do normal cells produce this inducer? Why, or why not?

C. Discuss the mechanisms by which type I interferons exert their antiviral effects.

3–60 a. b. c. d. e.

Which of the following activities are most closely associated with natural killer cells? production of TNF-\alpha lysis of virus-infected cells phagocytosis of bacteria release of reactive oxygen intermediates production of IFN-\gamma.

3–61 a. b. c. d. e.

The lectin pathway of complement activation is induced by _____.

C-reactive protein antibodies bound to pathogens mannose-binding lectin iC3Bb terminal components of the complement pathway.

3–62 a. b. c. d. e.

Which of the following is not a characteristic of mannose-binding lectin? acts as an opsonin by binding to mannose-containing carbohydrates of pathogens synthesized by hepatocytes induced by elevated IL-6 levels a member of the pentraxin family triggers the alternative pathway of complement activation.

3–63 a. b. c. d. e.

Which of the following is not a characteristic of C-reactive protein? acts as an opsonin by binding to phosphorylcholine of pathogens synthesized by spleen induced by elevated IL-6 levels a member of the pentraxin family triggers the classical pathway of complement activation.

30

3–64 Describe the two different domains of TLRs and their respective functions.

3–65 Explain the consequence of engagement of the TLR4, CD14, and MD2 complex with LPS in macrophages.

3–66 Which of the following TLRs do not use a signal transduction cascade involving MyD88? a.

TLR1:TLR2 b.

TLR3 c.

TLR4 d.

TLR2:TLR6 e.

TRL7.

3–67 Which of the following adaptor proteins participates in the activation pathway induced through either TLR3 or TLR4 that culminates in the synthesis of type I interferons? a.

C-reactive protein b.

MyD88 c.

LPS-binding protein d.

TRIF e.

NF\kappaB. 3–68 Which of the following properties is common to macrophages and neutrophils in an uninfected individual? a. life-span b. anatomical location c. ability to phagocytose d. morphology e. formation of pus.

3–69 a. b. c. d. e.

Which of the following best describes an endogenous pyrogen? cytokines made by pathogens that decrease body temperature pathogen products that decrease body temperature pathogen products that increase body temperature cytokines made by the host that decrease body temperature cytokines made by the host that increase body temperature.

3–70 a. b. c. d. e.

Which of the following is an acute-phase protein that enhances complement fixation?

TNF-\alpha mannose-binding lectin fibrinogen LFA-1 CXCL8.

3–71 During inflammation, host tissue may be damaged owing to the release of toxic oxygen derivatives produced by activated macrophages and neutrophils. Explain what cellular mechanisms limit these damaging bystander effects.

31

ANSWERS 3–1

c

3–2

c

3–3

e

3–4

d, g

3–5

c, e

3–6

b

3–7

a

3–8

a—2; b—4; c—5; d—3; e—1

3–9

c

3–10

e

3–11

b

3–12

a

3–13

c

3–14

c, d

3–15

b

3–16

d

3–17

a

3–18

d

3–19 3–20

e b

3–21

b

3–22

a—2; b—3; c—1

3–23

a

32

3–24

c

3–25

e

3–26

b

3–27

c

3–28

d

3–29

b

3–30

a

3–31

e

3–32

c

3–33

b, e

3–34

d

3–35

a—1; b—3; c—5; d—4; e—2

3–36 A. (i) One subpopulation of NK cells is committed to killing virus-infected cells so as to interfere with virus replication and intercellular spread. They are the most abundant subpopulation in the blood, making up 90% of circulating NK cells, and express fewer CD56 molecules on their cell surface (CD56dim) than does the other circulating subpopulation. (ii) The other subpopulation serves to maintain and exacerbate the inflammatory state in infected tissue by secreting inflammatory cytokines that activate resident macrophages. They comprise the remaining ~10% of circulating NK cells, and express higher numbers of CD56 molecules on their cell surface (CD56bright).

B. In other tissues, the situation is reversed, with CD56bright cells predominating. In addition, in the uterus there exists a specialized subpopulation of NK cells called uterine NK cells (uNK), which comprise the predominant leukocytes in this tissue. They are essential to the provision of growth factors needed for expansion of maternal blood vessels to ensure that the placenta and fetus are supplied adequately with oxygen during pregnancy.

3–37

b

3–38

a, i

3–39

c

3–40

d

3–41

a, d

3–42

e

33

3–43

b

3–44

a

3–45

c, d

3–46

c

3–47

b

3–48

d

3–49

a

3–50

e

3–51

b

3–52

c, e

3–53

a—3; b—6; c—1, 2, 3, 4, 5; d—1, 2, 3, 4, 5; e—7; f—5; g—8; h—9.

3–54 TLR-4, TLR1:TLR2, and TLR2:TLR6 are transmembrane receptors anchored on the plasma membrane surface of human cells and interact with pathogens located in extracellular locations. In contrast, TLR3, 7, 8, and 9 are anchored in endosomal membranes located in the cytosol, where the intracellular degradation of pathogens takes place.

3–56 Because many pathogens possess features that are common to different groups of pathogens, for example LPS in Gram-negative bacteria, only a small number of TLRs are required to act as sensors of molecular patterns shared by pathogens.

3–57 NF\kappaB is a transcription factor, and some TLRs signal through an intracellular pathway that involves the activation of NF\kappaB. In the absence of stimulation of the TLR, NF\kappaB is found in an inactive form in the cytoplasm. Signaling through the TLR results in a phosphorylation cascade that converts NF\kappaB to its active form, which is then able to translocate into the nucleus and direct the transcription of specific genes that promote the cell‘s response to the infection.

3–58

d

3–59 A. Type I interferon genes (for interferons-\alpha and -\beta) are transcribed as a result of the presence of double-stranded RNA. B. Normal cells not infected with virus do not contain double-stranded RNA; however, cells infected with virus often do. Some viruses either have double-stranded RNA genomes or use doublestranded RNA as an intermediate in the replication cycle.

C. Type I interferons (IFN-\alpha and -\beta) block virus replication in infected cells and protect uninfected cells nearby from becoming infected. This is accomplished by: (1) inducing cellular genes that destroy viral RNA through endonuclease attack; and (2) inhibiting protein synthesis of viral mRNA by modifying the initiation factors required for protein synthesis. In addition, IFN-\alpha and -\beta activate natural killer (NK) cells. NK cells kill virus-infected cells by releasing cytotoxic granules through a mechanism that involves the engagement of activating and inhibitory receptors; if inhibitory signals

34

predominate, the target cell is not killed; however, if activating signals predominate, the target cell is killed.

3–60

b, e

3–61

c

3–62

e

3–63

b

3–64 The first domain of the TLR is an extracellular domain, also known as the pathogen-recognition domain, which contains a hydrophobic, leucine-rich repeat region (LRR) forming a horseshoe-shaped structure that binds specifically to arrays on microbial surfaces. The second domain of the TLR is the cytoplasmic signaling domain, also known as the Toll interleukin receptor (TIR) domain, which facilitates the transmission of information to the interior of the cell.

3–65 When TLR4 on the surface of macrophages is bound to its LPS ligand, a signal transduction cascade is initiated that mediates signaling between the cell surface and the nucleus. The macrophage in turn begins to express particular genes encoding cytokines and adhesion molecules that are needed to induce a state of inflammation in the infected tissue.

3–66

b

3–67

d

3–68

c

3–69

e

3–70

b

3–71 Toxic oxygen species including superoxide, hydrogen peroxide, singlet oxygen, hydroxyl radical, hypohalite, and nitric oxide are produced during the respiratory burst in macrophages and neutrophils.

Simultaneous extraphagosomal production of enzymes that neutralize these compounds occurs.

Specifically, superoxide dismutase metabolizes superoxide to hydrogen peroxide, which is further metabolized by catalase to innocuous water and molecular oxygen.

CHAPTER 4: ANTIBODY STRUCTURE AND THE GENERATION OF B-CELL DIVERSITY 4–1 The five classes (isotypes) of immunoglobulins comprise a.

IgA, IgD, IgE, IgG, IgM b.

IgA, IgC, IgD, IgE, IgG c.

IgA, IgD, IgE, IgH, IgM d.

IgA, IgD, IgE, IgG, IgK 35

e.

IgA, IgD, IgE, IgG, IgS.

4–2 The name given to a fully activated and differentiated B cell that secretes antibody is a.

T cell b. antigen-presenting cell c. hematopoietic cell d. secretory cell e. plasma cell.

4–3 Describe the structure of an antibody molecule and how this structure enables it to bind to a specific antigen. Include the following terms in your description: heavy chain (H chain), light chain (L chain), variable region, constant region, Fab, Fc, antigen-binding site, hypervariable region, and framework region.

4–4

Match the antibody term in Column A with its correct description in Column B. Column A

___a. hinge region ___b. κ ___c. Fab ___d. α ___e. Fc

Column B 1. the stem that carries out effector function of antibodies through interaction with cell-bound receptors and serum proteins 2. provides flexibility to permit binding to different antigenic arrangements 3. a heavy-chain isotype 4. the arms of the antibody that bind antigen 5. a light-chain isotype

4–5 a. b. c. d. e.

All of the following comprise heavy-chain isotypes of immunoglobulin except α β γ δ ε

4–6 a. b. c. d. e.

Which of the following statements regarding immunoglobulin light chains is correct? κ associates with only particular heavy-chain isotypes.

There is no functional difference between κ and λ.

A given antibody may contain just κ, or just λ, or both.

Most antibodies in humans contain λ light chains.

Light chains possess only framework regions, not hypervariable regions.

4–7 _____, _____, and _____ are the three most abundant antibodies in blood: a.

IgA, IgD, and IgE b.

IgA, IgE, and IgG 36

c. d. e.

IgA, IgG, and IgM IgE, IgG, and IgM IgD, IgE, and IgM.

4–8 The five isotypes of immunoglobulin differ from each other in their _____: a. light-chain constant regions b. heavy-chain constant regions c. light-chain variable regions d. heavy-chain variable regions e. heavy-chain variable and constant regions.

4–9 Which one of the following features renders all IgG antibodies less susceptible to proteolysis than the other antibody classes? a. length of the hinge region b. ability to exchange chains with other IgG antibodies c. presence of additional disulfide bonds d. capacity to activate complement e. degree of accessibility for binding to C1.

4–10 Which of the following is mismatched? a.

100–110-amino-acid motif: immunoglobulin domain b. discontinuous epitope: amino acids that are separated in the protein chain but come together in the folded protein c. heavy-chain classes: IgG, IgA, IgM, IgE, IgD d. multivalent antigen: antigen that carries several epitopes of the same or different specificity e. four C domains: IgM and IgD. 4–11 The _______ contribute to antigen specificity of immunoglobulins, and _______ make up the more conservative flanking regions. a. hypervariable loops; framework regions b. constant domains; variable domains c. heavy chains; light chains d. variable gene segments; joining gene segments e. antigenic determinants; complementarity determining regions.

4–12 The immunoglobulin heavy-chain gene consists of _______ segments, whereas the immunoglobulin light-chain gene consists of _______ segments. a. κ; λ b.

VDJ; VJ c.

VJ; VDJ d.

P; N e.

RAG-1; RAG-2.

37

4–13 On the heavy-chain immunoglobulin gene locus, recombination signal sequences flank _______ of the V segment, _______ of the D segment, and _______ of the J segment. a. the 5′ side; both sides; the 3′ side b. the 5′ side; the 5′ side, the 5′ side c. the 3′ side; both sides; the 3′ side d. both sides; both sides; both sides e. the 3′ side; both sides; the 5′ side.

4–14 Which of the following describes two recombination signal sequences required for a permitted somatic recombination event? a.

VH 7-12-9::9-23-7 JH b.

Vλ7-23-9::9-23-7 Jλ c.

DH 7-12-9::9-23-7 JH d.

Vκ7-12-9::7-23-9 Jκ e.

VH 9-23-7::7-12-9 DH. 4–15 The enzyme responsible for recombining V, D, and J segments during somatic recombination is called a.

V(D)J recombinase b. terminal deoxynucleotidyl transferase c. exonuclease d.

DNA polymerase e.

DNA ligase.

4–16 a. b. c. d. e.

Which of the following is not a component of V(D)J recombinase?

Artemis Terminal deoxynucleotidyl transferase RAG-1/RAG-2 DNA ligase IV DNA-dependent protein kinase and the associated Ku protein.

4–17 a. b. c. d. e.

Which of the following corresponds to the antigen-binding site of immunoglobulins?

VH:CH VH:VL VL:CL CH:CL VH:CL.

4–18 a. b. c. d. e.

Another term commonly used to describe hypervariable loops is multivalency framework regions hinge region complementarity-determining regions signal joint.

38

4–19 Which of the following is not a term used to describe the molecules or components of molecules to which antibodies bind? (Select all that apply.) a.

CDR loops b. antigen c. hypervariable region d. antigenic determinant e. conformational epitope.

4–20 a. b. c. d. e.

All of the following are utilized in the binding of antibodies to antigens except interchain disulfide bonds hydrogen bonding hydrophobic interactions electrostatic forces (salt bridges) van der Waals interactions.

4–21 A. B. C. D.

What is an epitope?

Define the term multivalent antigen.

How does a linear epitope differ from a conformational epitope?

Do antibodies bind their antigens via noncovalent bonding or via covalent bonding?

4–22 A. What is the basic structural difference between the immunoglobulins produced by B cells and their descendants before antigen encounter and after antigen encounter?

B. Say which cell type(s) produce each form.

C. In which way do these different molecular forms resemble each other?

4–23 A _____ antibody is one that facilitates a chemical reaction involving the antigen to which it binds and interacts. a. conformational b. multivalent c. catalytic d. hypervariable e. monoclonal.

4–24 A. Explain why catalytic antibodies are attracting attention in the medical field.

B. Provide two potential examples.

4–25 Match the term in Column A with its description in Column B. Column A ___a. hybridoma ___b. myeloma

Column B 1. derived from blood following vaccination with an antigen 2. a pure type of antibody synthesized by a single clone of cells 39

___c. monoclonal antibody ___d. antiserum ___e. chimeric monoclonal antibody

3. immortalized cell line generated by fusing a B cell with a tumor cell 4. a tumor of plasma cells 5. engineered antibody containing mouse V regions and human C regions

4–26 Production by the patient of antibodies against therapeutic mouse monoclonal antibodies is the major limitation for their use in humans. These human anti-antibodies are directed against the _____ of the mouse antibody. a.

V regions b.

D regions c.

C regions d.

J regions e.

MC regions.

4–27 Identify the incorrect statement regarding flow cytometry. a.

Samples must be incubated with fluorescent molecules (such as fluorescent antibodies) before analysis. b.

It is possible to label samples with two fluorescent tags and determine whether cells are negative or positive for either one tag or the other, or both. c.

A one-dimensional histogram measures the amount of fluorescence versus cell number. d.

Samples must consist of a single cell type and not be composed of multiple cell types. e.

A laser is used to detect labeled cells. f.

A stream of cells in single file is generated by a nozzle.

4–28 in the a. b. c. d. e.

With the exception of B cells, all other cells of the body have the immunoglobulin genes germline configuration monoclonal form recombined configuration expressed configuration chimeric form.

4–29 Indicate which of the following statements is false. (Select all that apply.) a.

Immunoglobulin heavy- and light-chain loci are encoded on the same chromosome. b.

Light chains contain V and J segments, whereas heavy chains contain V, D, and J segments. c.

The Vκ gene segments are duplicated in about 50% of the human population. d.

All immunoglobulin loci include a leader sequence. e.

On the heavy-chain locus, V rearranges to D first, and then J joins the combined VD sequence. f.

Immunoglobulin heavy-chain loci undergo two rounds of somatic recombination, whereas light-chain loci undergo only one.

40

4–30 Which of the following statements is correct concerning membrane-coding (MC) exons of immunoglobulin genes? a.

MC exons are located upstream (5′) of the constant-domain exons. b.

MC exons code for amino acids that anchor and stabilize the light chain to the membrane of B cells. c.

MC exons specify transmembrane hydrophobic amino acids that associate with the B-cell membrane. d.

MC exons are removed from primary RNA transcripts as a consequence of alternative mRNA splicing when secreted antibodies are produced by plasma cells. e.

Somatic hypermutation causes alteration in the coding sequence of MC exons.

4–31 a. b. c. d. e.

In what way does the κ light chain differ from the λ light chain? κ performs a different function from λ when bound to the immunoglobulin heavy chain. κ, but not λ, is encoded on the same chromosome as the heavy-chain locus. κ contains a VJ region, whereas λ contains a VDJ region.

The κ locus encodes a single C segment, whereas the λ locus has more than one. κ contains a transmembrane domain but lambda does not.

4–32 In contrast with leader peptides and the C regions, the V regions in immunoglobulin heavy-chain genes a. encode hydrophobic amino acids that anchor the immunoglobulin chains to B-cell membranes b. comprise the smallest number of gene segments in the human immunoglobulin loci c. are composed of V, D, and J gene segments that must undergo gene rearrangement to generate a transcribable exon d. do not undergo somatic hypermutation e. are not subject to allelic exclusion.

4–33 a. b. c. d. e.

Which of the following is matched incorrectly? κ light-chain locus: chromosome 2 coding joint: nonhomologous end-joining of V and J gene segments λ light-chain locus: four or five C gene segments affinity maturation: addition of P and N nucleotides recombination signal sequence: heptamer–spacer–nonamer.

4–34 a. b. c. d. e.

The enzyme responsible for adding N nucleotides is V(D)J recombinase terminal deoxynucleotidyl transferase uracil-DNA-glycosylase (UNG) DNA ligase activation-induced cytidine deaminase (AID).

4–35 a. b. c.

Which of the following enzymes facilitates the process of affinity maturation?

DNA ligase V(D)J recombinase terminal deoxynucleotidyl transferase 41

d. e.

activation-induced cytidine deaminase (AID) exonuclease.

4–36 a. b. c. d. e.

The process of gene rearrangement in immunoglobulin and T-cell receptor genes is called somatic hypermutation isotype switching somatic recombination apoptosis clonal selection.

4–37 A. Explain briefly how a vast number of immunoglobulins of different antigen specificities can be produced from the relatively small number of immunoglobulin genes present in the genome. Include the following terms in your explanation: somatic recombination; germline configuration; V, D, and J segments.

B. What is the final arrangement of gene segments in the rearranged immunoglobulin heavychain gene V region, and in what order do these gene segment rearrangements occur?

C. In what order do the various immunoglobulin loci rearrange?

4–38 a. b. c. d. e.

Junctional diversity during gene rearrangement results from the addition of switch region nucleotides P and N nucleotides V, D, and J nucleotides recombination signal sequences mutations in complementarity-determining regions.

4–39 What would be the effect of a genetic defect that resulted in a lack of somatic recombination between V, D, and J segments?

3–40 A circulating B cell that has never before encountered antigen expresses _____ on the cell surface: a.

IgM and IgD b.

IgM c.

IgD d.

IgM and IgG e.

IgG f.

IgE. 4–41 a. b. c. d. e.

All of the following processes occur in mature B cells after antigen encounter except alternative splicing affinity maturation proliferation somatic recombination isotype switching.

42

4–42 How do recombination signal sequences ensure that gene segment rearrangement occurs in the right order?

4–43 How is additional diversity introduced into the variable region by the molecular mechanism of somatic recombination? Include the following terms in your answer: junctional diversity, P nucleotides, N nucleotides, terminal deoxynucleotidyl transferase (TdT).

4–44 The third hypervariable region (CDR3) is the most variable site in an immunoglobulin V region. It differs in its composition between the light-chain and heavy-chain V regions. Explain what this difference is and how the diversity in CDR3 is generated.

4–45 cell. a. b. c. d. e.

Identify the correct order of gene segments in a rearranged heavy-chain gene in a naive B

4–46 a. b. c. d. e.

Which of the following does not describe B-cell receptors?

B-cell receptors are membrane-bound and secreted.

B-cell receptors consist of a variable region and a constant region.

B-cell receptors lack specificity and can bind to a number of different antigens.

B-cell receptors possess specificity and can therefore bind only to unique epitopes.

B cell receptors undergo affinity maturation as a consequence of somatic hypermutation.

L–VDJ–Cμ–Cδ VDJ–Cμ–Cδ–L L–VDJ–Cδ–Cμ VDJ–L–Cμ–Cα1 L–VDJ–Cμ–Cα1.

4–47 Explain how mature, naive B cells co-express IgM and IgD. 4–48 Describe the process responsible for altering the expression of membrane-bound immunoglobulin to secreted antibody.

4–49 a. b. c. d. e.

Which of the following determines the isotype of an immunoglobulin? the composition of the hypervariable regions whether the immunoglobulin is membrane-bound or secreted its light chain its heavy chain the composition of the cytoplasmic tails of Igα and Igβ

4–50 Naive B cells are recognized by their expression of a. no immunoglobulins on the cell surface because somatic recombination has not yet commenced b. both membrane-bound and secreted forms of immunoglobulin c. both IgM and IgD on the cell surface d.

V(D)J recombinase e. uracil-DNA-glycosylase (UNG).

43

4–51 Which of the following statements regarding Igα and Igβ proteins are correct? (Select all that apply.) a.

They associate with all isotypes of antibodies on the cell membrane. b.

They are not required to form the fully functional B-cell receptor. c.

They facilitate signal transduction through their long cytoplasmic tails. d.

They are linked to one another by disulfide linkages. e.

They are made by somatic rearrangement.

4–52 A. What are the functions of the Igα and Igβ proteins?

B. Explain why it is desirable that they do not vary in sequence from cell to cell in the same way that immunoglobulins do.

4–53 The highest degree of diversity resulting from somatic recombination is concentrated ____________ of the VH and VL domains, whereas the point mutations caused by somatic hypermutation are found ____________. a. in CDR3; throughout the V region b. in CDR3; in CDR1 and CDR2 of VH and VL domains c. in CDR1 and CDR2; in CDR3 d. in CDR1 and CDR2; throughout the V region e. in all three CDRs; in C regions.

4–54 As an adaptive immune response progresses, the production of variant antibodies that compete more effectively for antigen occurs, and B cells producing these antibodies are preferentially selected on the basis of their improved binding to antigen. This phenomenon is referred to as _______. a. isotype switching b. neutralization c. allelic exclusion d. affinity maturation e. somatic rearrangement.

4–55 a. b. c. d. e.

All of the following are required for isotype switching except switch-region recombination J chain activation-induced cytidine deaminase (AID) B-cell proliferation uracil-DNA glycosylase (UNG).

4–56 a. b. c. d. e.

Which of the following does not activate complement? (Select all that apply.)

IgG1 IgG2 IgG3 IgG4 IgA 44

f. g. h.

IgE IgM IgD.

4–57 a. b. c. d. e.

Which of the following can be found in serum in a monovalent form?

IgG4 IgD IgA1 antibodies made up of four C domains IgG3.

4–58 a. b. c. d. e.

Neutralizing antibodies interfere with antigen degradation facilitate uptake of antigen through Fc regions stimulate complement activation inhibit interaction of antigen with human cell surfaces sensitize mast cells and basophils.

4–59 a. b. c. d. e.

Which of the following statements regarding immunoglobulins is correct?

Immunoglobulins make up five classes (or isotypes) called IgA, IgD, IgE, IgG, and IgM. Regardless of their isotype, immunoglobulins all have the same effector function.

Antibodies consist of four identical heavy chains and four identical light chains.

Peptide bonds hold the heavy and light chains together.

The constant regions make up the antigen-binding site.

4–60 Indicate which of the following statements are true (T) or and which are false (F) with reference to immunoglobulin structure. a. __The antibody secreted by a plasma cell has a different specificity for antigen than the immunoglobulin expressed by its B-cell precursor. b. __The amino-terminal regions of heavy and light chains of different immunoglobulins all differ in amino acid sequence. c. __A flexible hinge region holds the heavy chain and light chain together. d. __The heavy-chain constant region is responsible for the effector function of immunoglobulins. e. __λ and κ light chains have different functions.

4–61 a. b. c. d. e.

Which of the following is mismatched? surface immunoglobulin: B-cell antigen receptor affinity maturation: isotype switching constant region of antibodies: binding to complement proteins activation-induced cytidine deaminase: somatic hypermutation switch sequences: class switching.

4–62 Which of the following statements about the production and use of monoclonal antibodies is incorrect? a.

Production of monoclonal antibodies requires a purified form of antigen.

45

b.

A monoclonal antibody has specificity for only one epitope of an antigen. c.

B cells are fused with a tumor cell called a myeloma, to immortalize the resulting hybridoma. d.

Monoclonal antibodies made in mice have limited therapeutic potential. e.

Humanized monoclonal antibodies reduce complications associated with using mouse monoclonal antibodies.

4–63 The mutational mechanism that results in the production of antibodies that bind antigen with higher affinity is called _____: a. somatic recombination b. isotype switching c. somatic hypermutation d. clonal selection e. antigen processing.

4–64 The process of _____ results in change in the constant region of the heavy-chain of antibodies, causing a change in the effector function and transport properties of antibodies: a. complement fixation b. neutralization c. isotype switching d. somatic hypermutation e. somatic recombination.

4–65 The process used to produce either surface or secreted forms of the immunoglobulin heavy chain is called a. alternative RNA processing b. isotype switching c. somatic recombination d. somatic hypermutation e. opsonization.

4–66 A. What is affinity maturation and what molecular process enables it to occur?

B. Describe this process and its consequences.

4–67 A. What is isotype switching?

B. Explain the molecular mechanism of isotype switching.

C. Why is isotype switching important?

4–68 Which immunoglobulin isotypes (out of IgM, IgG1, IgG2, IgG3, IgG4, IgA, IgE, and IgD) participate in (a) neutralization; (b) opsonization; (c) sensitization for killing by NK cells; (d) sensitization of mast cells; (e) activation of complement? Which isotypes (f) are transported across epithelium; (g) are transported across the placenta; (h) diffuse into extravascular sites?

46

4–69 Isotype switching and immunoglobulin gene rearrangement by somatic recombination are both recombinational processes but have very different outcomes. Give four ways in which they differ from each other.

4–70 Monoclonal antibodies are used for a wide range of applications including serological assays and diagnostics probes in the laboratory, and as therapeutic reagents in the clinic. Discuss why ‗humanizing‘ monoclonal antibodies is necessary for use as therapeutic reagents but is not necessary when monoclonal antibodies are used as serological or diagnostic reagents.

4–71 What would be the effect of a genetic defect that resulted in a lack of recombination between the switch regions in the immunoglobulin C-region genes?

4–72 Influenza virus contains two proteins, called hemagglutinin and neuraminidase, exposed on the surface of the virion. Two additional proteins, located on the interior of the virion, are called matrix protein and nucleoprotein. Which of these four proteins will generate a better antibody response and why?

4–73 A. Identify the four types of antibody used for therapeutic purposes.

B. How is each produced?

C. (i) Which is most desirable for the treatment of chronic conditions? (ii) Why? (iii) Provide an example.

4–74 A. What is the difference between polyclonal antibodies and monoclonal antibodies?

B. How is each produced?

4–75 Match the term in Column A with its description in Column B Column A Column B ___a. monoclonal antibody production 1. the rearrangement of V, D, and J segments to form an immunoglobulin ___b. isotype switching

___c. opsonization ___d. somatic hypermutation

___e. somatic recombination.

2. the derivation of antibodies from a single clone of B lymphocytes that have identical antigen specificity 3. change of immunoglobulin class but preservation of antigen specificity 4. nucleotide changes in variable regions of immunoglobulin genes affecting affinity for antigen 5. enhancement of receptor-mediated phagocytosis of immunoglobulin-coated antigen

4–76 IgM and IgD are co-expressed on naive B cells by a process called a. isotype switching 47

b. c. d. e.

somatic recombination somatic hypermutation alternative mRNA splicing affinity maturation.

4–77 a. b. c. d. e.

Which immunoglobulin‘s main function is to mediate sensitization of mast cells?

IgA IgD IgE IgG IgM.

4–78 a. b. c. d. e.

Which immunoglobulin is transported most efficiently across mucosal epithelium?

IgA IgD IgE IgG IgM.

4–79 a. b. c. d. e.

_______ forms dimers, whereas _______ forms pentamers.

IgG; IgD IgE; IgM IgD; IgM IgA; IgM IgM; IgG.

4–80 A newborn derives passive immunity from its mother as a result of placental transfer of _____ during pregnancy. a.

IgA b.

IgD c.

IgE d.

IgG e.

IgM. 4–81 _____ is secreted into the bloodstream, whereas _____ is secreted into mucus such as gastrointestinal fluid, colostrum, saliva, tears, and sweat. a. monomeric IgM: pentameric IgM b. monomeric IgA: dimeric IgA c. monomeric IgA: dimeric IgG d. monomeric IgA: monomeric IgM e. dimeric IgA: pentameric IgM. 4–82 Identify which of the following is not associated with activation-induced cytidine deaminase (AID) activity. a. diversification of the VH domain but not the VL domain b. synthesized in proliferating B cells during active immune responses 48

c. d. e.

somatic hypermutation isotype switching conversion of cytosine to uracil.

4–83 The process of _____ results in the amplification of particular B cells with specificity for antigen: a. germline recombination b. somatic recombination c. clonal selection d. antigen processing e. antigen presentation.

4–84 a. b. c. d. e.

The antibody transported across mucosal epithelia is _____: IgA IgD IgE IgG IgM.

ANSWERS 4–1

a

4–2

e

4–3 An antibody molecule is made of four polypeptide chains—two identical heavy chains and two identical and smaller light chains, with a total molecular weight of approximately 150 kDa. Each chain is made up of a series of structurally similar domains known as immunoglobulin domains. The amino-terminal portion of each H chain combines with one L chain, and the two carboxy-terminal portions of the H chains combine with each other, forming a Y-shaped quaternary structure. Disulfide bonds hold the H and L chains together, hold the two H chains together (interchain disulfide bonds), and stabilize the domain structure of the chains (intrachain disulfide bonds). The arms of the antibody molecule are called Fab (fragment antigen binding) and interact with antigen. The stalk is called Fc (fragment crystallizable) and is made up of H chains only. The amino-terminal domains of an H and an L chain together make up a site that binds directly to antigen and varies greatly between different antibodies. These domains are referred to as the variable region, and each antibody has two identical antigen-binding sites. The remaining domains of both H and L chains are the same in all antibodies of a given class (isotype). These domains are referred to as the constant region. The variable region of each chain includes hypervariable regions of amino acid sequences that differ the most between different antibodies. These are nested within less variable sequences known as the framework regions.

The hypervariable regions make loops at one end of the domain structure and are also known as complementarity-determining regions because they confer specificity on the antigen-binding site.

4–4

a—2; b—5; c—4; d—3; e—1

4–5

b 49

4–6

b

4–7

c

4–8

b

4–9

c

4–10 e 4–11 a 4–12 b 4–13 e 4–14 c 4–15 a 4–16 b 4–17 b 4–18 d 4–19 a, c 4–20 a 4–21 A. An epitope is the specific part of the antigen that is recognized by an antibody and binds to the complementarity-determining regions in the antibody variable domains. Epitopes are sometimes referred to as antigenic determinants. Epitopes can be part of a protein or can be carbohydrate or lipid structures present in the glycoproteins, polysaccharides, glycolipids, and proteoglycans of pathogens.

B. Multivalent antigens are complex macromolecules that contain more than one epitope.

C. Linear epitopes are epitopes in proteins that comprise a contiguous amino acid sequence.

They are also called continuous epitopes. In contrast, a conformational epitope is formed by amino acids that are brought together as a result of protein folding and are not adjacent in the protein sequence. Conformational epitopes are also known as discontinuous epitopes.

D. Antibodies bind antigens via noncovalent bonding such as hydrogen bonds, hydrophobic interactions, van der Waals forces, and electrostatic attraction.

4–22 50

A. Before antigen encounter, antibodies are produced in a membrane-bound form. After antigen encounter, antibodies are secreted in a soluble form.

B. Immature, mature, and memory B cells produce membrane-bound antibodies. Plasma cells secrete soluble antibodies.

C. The membrane-bound and soluble forms of antibody produced by a particular B cell possess the same antigen specificity.

4–23 c 4–24 A. Catalytic antibodies bind with a high degree of specificity to the target antigen and facilitate a chemical conversion of that antigen in a similar manner to the action of enzymes. If this reaction results in the alteration of that antigen so that it is no longer able to carry out its undesirable effect in the body, the catalytic antibody has therapeutic value.

B. Examples would include: (1) converting toxic substances to less harmful molecules, and (2) converting addictive drugs to derivatives that no longer possess psychostimulating effects.

4–25 a—3; b—4; c—2; d—1; e—5 4–26 c 4–27 d 4–28 a 4–29 a, e 4–30 c 4–31 d 4–32 c 4–33 d 4–34 b 4–35 d 4–36 c 4–37 A. In developing B cells, gene rearrangements within the genetic loci for immunoglobulin light and heavy chains can produce an almost unlimited variety of different variable regions, and thus produce the huge repertoire of antibodies with different specificities for many types of antigen. This gene rearrangement mechanism is called somatic recombination. In the germline 51

configuration, before gene rearrangement, the immunoglobulin loci in progenitor B cells are composed of sequences encoding the constant regions and families of gene segments encoding different portions of the variable region. Heavy-chain loci contain a series of gene segments called variable (V), diversity (D), and joining (J). Light-chain loci contain only V and J gene segments. In somatic recombination in developing B cells, one of each family of gene segments is randomly selected and joined together to give a complete variable-region sequence, which is subsequently expressed as an immunoglobulin heavy or light chain. Immunoglobulin gene rearrangement is irreversible, leading to permanent alteration of the chromosome; it occurs exclusively in B cells.

B. A D gene segment first joins to a J to form DJ, followed by a V becoming joined to DJ to form VDJ, which encodes a complete variable region.

C. The heavy-chain locus rearranges before the light-chain loci. For light chains in humans, the κ locus rearranges first and is followed by the λ locus only if both κ loci fail to produce a successful rearrangement.

4–38 b 4–39 An individual with this genetic defect would be unable to rearrange either immunoglobulin or T-cell receptor genes somatically. There would be a severe combined immunodeficiency (SCID) owing to the absence of mature B cells and T cells.

4–40 a 4–41 d 4–42 Gene rearrangement by somatic recombination involves recombination signal sequences (RSSs) that flank V, D, and J segments and are recognized by the enzymes involved in cutting and rejoining the gene segments. An RSS is composed of a conserved nonamer sequence and heptamer sequence separated by a spacer region. There are two types of RSS, one with a spacer of 12 bp and one with a spacer of 23 bp. To ensure that segments are brought together in the right order, an RSS with a 12-bp spacer is always brought together with one with a 23-bp spacer.

This is called the 12/23 rule. This ensures that in the heavy-chain locus, V rearranges to DJ and not directly to J or another V, and in the light-chain locus, V rearranges to J and not to another V. 4–43 The rejoining and repair of DNA during the recombination process leads to additional variation in sequence at the junctions between the rearranged gene segments. This is called junctional diversity and contributes considerably to the final diversity of immunoglobulin specificities. Two sources of junctional diversity are introduced: P (palindromic) and N (nontemplated) nucleotides. P nucleotides are generated through endonuclease activity and repair around a hairpin loop at the ends of the gene segments to be joined. N nucleotides are nucleotides added at random at the junctions by terminal deoxynucleotidyl transferase (TdT) activity.

4–44 CDR3 of the light chain is composed mainly of the coding joint between the V and J segments, which is formed during somatic recombination, with junctional diversity being generated by the addition of P and N nucleotides. CDR3 of the heavy chain is composed mainly 52

of the D gene segment plus its coding joints with a V gene segment on one side and a J gene segment on the other. P and N nucleotides are also added to these joints during recombination. In addition, the D gene segment sequences differ between immunoglobulins.

4–45 a 4–46 c 4–47 Naive B cells express IgM and IgD simultaneously through a mechanism involving alternative ways of processing the RNA transcript before translation. A primary transcript containing leader (L), V, D, J, Cμ, and Cδ is produced first. This transcript contains two distinct polyadenylation signal sequences, one following the Cμ exons (pA1) and the other following the Cδ exons (pA2). Processing results in the removal of either Cμ or Cδ exons (plus introns) through alternative splicing. The resulting mRNAs, which encode either Cμ or Cδ, are polyadenylated at the pA1 or pA2 site, respectively.

4–48 Whether immunoglobulin is expressed as a transmembrane-anchored protein or a secreted protein is determined by alternative processing of the heavy-chain RNA transcript. All the heavy-chain C genes contain MC (membrane-coding) exons, which encode the transmembrane region and cytoplasmic tail, and an SC (secretion-coding) exon, which encodes the carboxy terminus of the secreted antibody. The primary RNA transcript contains the MC and SC exons. In naive resting B cells or memory B cells, cleavage and polyadenylation of the transcript at a site (pAm) following the MC exons and deletion of the SC exon by RNA splicing produces the membrane-bound immunoglobulin. On B-cell activation and differentiation into plasma cells, the SC exon is retained in the transcript, and a polyadenylation signal sequence, pAs, immediately following it is used to produce an mRNA encoding the secreted form of the heavy chain.

4–49 d 4–50 c 4–51 a, c, d 4–52 A. Igα and Igβ are essential for escorting immunoglobulins from the endoplasmic reticulum membrane to the cell membrane, where they remain associated with the immunoglobulin to form the functional B-cell antigen receptor. The long cytoplasmic tails of Igα and Igβ contain amino acid motifs that interact with intracellular signaling proteins after the receptor has been activated by the binding of antigen to the immunoglobulin.

B. Igα and Igβ proteins have no need to be variable, because they do not interact directly with antigen. Igα and Igβ perform specific signaling functions, which require particular amino acid sequences and also have evolved a sequence and structure that enable them to interact with all the different immunoglobulin isotypes. Extensive variation in Igα and/or Igβ could therefore compromise their interaction with immunoglobulins and their signal transduction capabilities.

53

4–53 a 4–54 d 4–55 b 4–56 d, f, h 4–57 a 4–58 d 4–59 a 4–60 a—F; b—T; c—F; d—T; e—F 4–61 b 4–62 a 4–63 c 4–64 c 4–65 a 4–66 A. Affinity maturation is the phenomenon observed during a B-cell response in which antibodies with increasing affinity for the antigen are produced as the response proceeds. This occurs as a result of the process known as somatic hypermutation.

B. In somatic hypermutation, which occurs only in activated B cells, random point mutations are introduced into the rearranged V regions of H-chain and L-chain genes at a rate six orders of magnitude higher than spontaneous mutation. Some of these mutations give rise to immunoglobulin with higher affinity for the antigen than the original immunoglobulin. Those B cells producing higher-affinity surface immunoglobulin will be preferentially selected for activation by the antigen and will come to dominate the response, differentiating into plasma cells producing high-affinity antibodies.

4–67 A. Isotype switching is the process by which antibodies change their heavy-chain constant regions so as to acquire different effector functions, while preserving the variable region and antigen specificity. The light chain is unaffected.

B. The molecular mechanism involves a recombination between sequences, called switch regions, which lie upstream (on the 5′ side) of heavy-chain C genes. All heavy-chain C genes except Cδ have a switch region. Recombination between two switch regions results in the excision of DNA (as a circular DNA molecule) between the two and the movement of the new 54

heavy-chain C gene next to the preserved V region. Transcription will produce an mRNA encoding the same V-region sequence and the new C region. Switching can occur between the first switch region and any other switch region that lies downstream (on the 3′ side). Isotype switching is not random but is influenced by T-cell cytokines.

C. Isotype switching is important because the different antibody isotypes have different effector functions, and efficient immune responses rely upon the production of the most appropriate effector function to combat the particular pathogen.

4–68 A. B. C. D. E. F. G. H.

Neutralization: IgM, IgG1, IgG2, IgG3, IgG4, IgA Opsonization: IgG1, IgG2, IgG3, IgG4, IgA Sensitization for killing by NK cells: IgG1, IgG3 Sensitization of mast cells: IgG1, IgG3, IgE Activation of complement: IgM, IgG1, IgG2, IgG3, IgA Transport across epithelium: IgM, IgA (dimer) Transport across placenta: IgG1, IgG2, IgG3, IgG4 Diffusion into extravascular sites: IgM, IgG1, IgG2, IgG3, IgG4, IgA (monomer), IgE

4–69 (1) Gene rearrangements affect the variable region of immunoglobulins, whereas isotype switching affects the constant region. (2) Different recombination-signal sequences and enzymes are used for the two processes. (3) Isotype switching occurs only after antigen stimulation, whereas gene rearrangement occurs only during B-cell maturation in the bone marrow. (4) All isotype switch recombinations are productive, but not all gene rearrangements are. (5) Only heavy chains are involved in isotype switching, whereas both heavy-chain and light-chain genes are involved in somatic recombination.

4–70 Mice are used routinely to generate monoclonal antibodies. The constant regions of mouse antibodies are sufficiently different from the constant regions of human antibodies in amino acid composition that, if mouse antibodies are infused into a patient, an immune response will be stimulated and directed against the mouse constant-region epitopes. This immune response neutralizes the monoclonal antibody and in practice limits its intended use to one effective dose. When monoclonal antibodies are used for serological or diagnostic purposes in the laboratory, the monoclonal antibodies do not need to be humanized because laboratory assays are performed in vitro.

4–71 The B cells in a person carrying such a defect would be unable to switch antibody isotype and would be unable to produce any antibody other than IgM. Because IgM antibodies can implement fewer effector functions than IgG antibodies, which constitute the main class of antibody produced in an adaptive immune response, one would expect that immunity would be impaired. In addition, no IgA antibodies could be produced, leaving the person highly vulnerable to infection through mucosal surfaces. There are, in fact, rare inherited genetic deficiencies that result in an inability to switch isotype. They are called hyper IgM immunodeficiencies because the patient is unable to produce any antibody other than IgM. The most frequent one affects the expression of a cell-surface molecule called CD40 ligand in T cells, which is required for the interaction between T cells and B cells that stimulates isotype switching, as we shall learn later in this book.

55

4–72 Hemagglutinin and neuraminidase epitopes, because epitopes exposed on the surface of pathogens stimulate antibodies.

4–73 A. The four types of therapeutic antibody include (i) mouse monoclonal antibodies, (ii) chimeric monoclonal antibodies, (iii) humanized monoclonal antibodies, and (iv) fully human monoclonal antibodies.

B. (i) Mouse monoclonal antibodies are produced from hybridoma cell lines obtained by immortalizing mouse B cells by fusing them with a tumor cell. Hybridomas secreting antibody with the appropriate specificity for antigen are cloned and propagated. (ii) Chimeric monoclonal antibodies are produced by fusing the coding regions of the variable regions of mouse monoclonal antibodies, known to have specificity for a particular antigen, with the coding regions of human constant regions. (iii) Humanized monoclonal antibodies retain only the complementarity-determining regions of mouse monoclonal antibodies, and all remaining regions are replaced with human-derived regions. (iv) Fully human monoclonal antibodies are made either by using human hybridoma cell lines or by using transgenic mice whose immunoglobulin genes have been replaced by human immunoglobulin genes.

C. (i) Fully human monoclonal antibodies are the most desirable, because (ii) they will not stimulate an anti-constant region antibody response in the recipient and can therefore be used for repeated treatment in chronic diseases without complications and without reducing therapeutic efficacy. (iii) Adalimumab is an example of a fully human monoclonal antibody used to treat rheumatoid arthritis. It neutralizes the inflammatory cytokine TNF-α to decrease inflammation of the joints.

4–74 A. Polyclonal antibodies are a mixture of antibodies of different specificities and affinities for a particular antigen. They are the product of numerous different B cells. Monoclonal antibodies have a single specificity and affinity for a given antigen. They derive from a single B cell.

B. Polyclonal antibodies are produced in vivo by immunizing an animal with antigen, allowing sufficient time for an immune response to occur and then preparing antiserum containing the antibodies from the blood. Monoclonal antibodies are made in vitro from individual cell lines derived from single B cells. This is achieved by producing a hybrid immortalized cell line through the fusion of an antibody-producing B cell with a myeloma tumor cell to produce an antibody-producing ‗hybridoma.‘ A hybridoma producing the desired antibody can then be cloned and grown on to produce unlimited amounts of monoclonal antibody.

4–75 a—2; b—3; c—5; d—4; e—1 4–76 d 4–77 c 4–78 a

56

4–79 d 4–80 d 4–81 b 4–82 a 4–83 c 4–84 a

CHAPTER 5: ANTIGEN RECOGNITION BY T 5–1 T cells recognize antigen when the antigen a. forms a complex with membrane-bound MHC molecules on another host-derived cell b. is internalized by T cells via phagocytosis and subsequently binds to T-cell receptors in the endoplasmic reticulum c. is presented on the surface of a B cell on membrane-bound immunoglobulins d. forms a complex with membrane-bound MHC molecules on the T cell e. bears epitopes derived from proteins, carbohydrates, and lipids.

5–2 a. b. c. d. e.

T-cell receptors structurally resemble the Fc portion of immunoglobulins MHC class I molecules secreted antibodies a single Fab of immunoglobulins CD3 ε chains.

5–3 If viewing the three-dimensional structure of a T-cell receptor from the side, with the Tcell membrane at the bottom and the receptor pointing upwards, which of the following is inconsistent with experimental data? a.

The highly variable CDR loops are located across the top surface. b.

The membrane-proximal domains consist of Cα and Cβ. c.

The portion that makes physical contact with the ligand comprises Vβ and Cβ, the domains farthest from the T-cell membrane. d.

The transmembrane regions span the plasma membrane of the T cell. e.

The cytoplasmic tails of the T-cell receptor α and β chains are very short.

5–4 a. b. c. d.

Unlike B cells, T cells do not engage in any of the following processes except alternative splicing to produce a secreted form of the T-cell receptor alternative splicing to produce different isoforms of the T-cell receptor isotype switching somatic hypermutation 57

e.

somatic recombination

5–5 When comparing the T-cell receptor α-chain locus with the immunoglobulin heavy-chain locus, all of the following are correct except a. the T-cell receptor α locus differs because it has embedded within its sequence another locus that encodes a different type of T-cell receptor chain b. both are encoded on chromosome 14 c. the T-cell receptor α-chain locus does not contain D segments d. the T-cell receptor α-chain locus contains more V and J regions e. the T-cell receptor α-chain locus contains more C regions f. they both contain exons encoding a leader peptide.

5–6 Unlike the C regions of immunoglobulin heavy-chain loci, the C regions of the T-cell receptor β-chain loci a. are functionally similar b. do not contain D segments c. are more numerous d. are encoded on a different chromosome from the variable β-chain gene segments of the T-cell receptor e. do not encode a transmembrane region f. possess non-templated P and N nucleotides.

5–7 Which of the following statements regarding Omenn syndrome is incorrect? a.

A bright red, scaly rash is due to a chronic inflammatory condition. b.

Affected individuals are susceptible to infections with opportunistic pathogens. c.

It is invariably fatal unless the immune system is rendered competent through a bone marrow transplant. d.

It is the consequence of complete loss of RAG function. e.

There is a deficiency of functional B and T cells. f.

It is associated with missense mutations of RAG genes.

5–8 A. Identify which features of the RAG genes have similarity to the transposase gene of transposons.

B. Explain how the mechanisms for immunoglobulin and T-cell receptor rearrangement may have evolved in humans.

5–9 All of the following statements regarding γ:δ T cells are correct except a. they are more abundant in tissue than in the circulation b. the δ chain is the counterpart to the β chain in α:β T-cell receptors because it contains V, D, and J segments in the variable region c. they share some properties with NK cells d. activation is not always dependent on recognition of a peptide:MHC molecule complex e. expression on the cell surface is not dependent on the CD3 complex.

5–10 Match the term in Column A with its complement in Column B. 58

Column A ___a. T-cell receptor δ-chain gene

Column B 1. positioned in the T-cell receptor αchain locus between Vα and Jα gene segments

___b. CD3 complex

2.

___c. T-cell receptor β-chain gene ___d. CD4

3. located on chromosome 7 4. counterpart to the T-cell receptor αchain gene 5. four extracellular domains

___e. T-cell receptor γ-chain gene

made up of γ, δ and ε components

5–11 During T-cell receptor _____-gene rearrangement, two D segments may be used in the final rearranged gene sequence, thereby increasing overall variability of this chain. a. α b. β c. γ d. δ e. ε.

5–12 The degradation of pathogen proteins into smaller fragments called peptides is a process commonly referred to as a. endocytosis b. promiscuous processing c. antigen processing d. antigen presentation e. peptide loading.

5–13 All of the following are primarily associated with CD4 T-cell function except a. improve phagocytic mechanisms of tissue macrophages b. assist B cells in the production of high-affinity antibodies c. kill virus-infected cells d. facilitate responses of other immune-system cells during infection e. assist macrophages in sustaining adaptive immune responses through their secretion of cytokines and chemokines.

5–14 The primary reason for transplant rejections is due to differences in _____ between donor and recipient. a.

CD3 b.

MHC molecules c.

T-cell receptor α chains d. γ:δ T cells e. β2-microblobulin.

5–15 Explain the importance of promiscuous binding specificity exhibited by MHC class I and class II molecules.

59

5–16 When describing the various components of the vesicular system, which of the following is not included? a. nucleus b.

Golgi apparatus c. endoplasmic reticulum d. exocytic vesicles e. lysosomes.

5–17 Which of the following is not a characteristic of immunoproteasomes? a.

They make up about 1% of cellular protein. b.

They consist of four rings of seven polypeptide subunits that exist in alternative forms. c.

They are produced in response to IFN-γ produced during innate immune responses. d.

They produce a higher proportion of peptides containing acidic amino acids at the carboxy terminus compared with constitutive proteasomes. e.

They contain 20S proteasome-activation complexes on the caps.

5–18 Identify which of the following statements is true regarding the transporter associated with antigen processing (TAP). a.

TAP is a homodimer composed of two identical subunits. b.

TAP transports proteasome-derived peptides from the cytosol directly to the lumen of the Golgi apparatus. c.

TAP is an ATP-dependent, membrane-bound transporter. d.

Peptides transported by TAP bind preferentially to MHC class II molecules. e.

TAP deficiency causes a type of bare lymphocytes syndrome resulting in severely depleted levels of MHC class II molecules on the surface of antigen-presenting cells.

5–19 a. b. c. d. e.

All of the following are included in the peptide-loading complex except tapasin calnexin calreticulin ERp57 β2-microglobulin.

5–20 Which of the following best describes the function of tapasin? a.

Tapasin is an antagonist of HLA-DM and causes more significant increases in MHC class I than MHC class II on the cell surface. b.

Tapasin is a lectin that binds to sugar residues on MHC class I molecules, T-cell receptors, and immunoglobulins and retains them in the ER until their subunits have adopted the correct conformation. c.

Tapasin is a thiol-reductase that protects the disulfide bonds of MHC class I molecules. d.

Tapasin participates in peptide editing by trimming the amino terminus of peptides to ensure that the fit between peptide and MHC class II molecules is appropriate. e.

Tapasin is a bridging protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules.

60

5–21 The mechanisms contributing to peptide editing include which of the following? (Select all that apply.) a. removal of amino acids from the amino-terminal end by endoplasmic reticulum aminopeptidase (ERAP) b. cathepsin S-mediated cleavage of invariant chain c. the participation of tapasin in finding a ‗good fit‘ for class I heterodimers d. recycling an MHC class I heterodimer if the peptide falls out of its peptide-binding groove e. upregulation of HLA-DM by interferon-γ.

5–22 Match the term in Column A with its description or function in Column B. Column A Column B ___a. cathepsin S 1. a chaperone that directs empty MHC class I molecules to the inside of the cell ___b. HLA-DM 2. activated by acidification in phagolysosomes ___c. endoplasmic reticulum aminopeptidase 3. a thiol-reductase in the peptide-loading (ERAP) complex ___d. receptor-mediated endocytosis 4. removes class II-associated invariantchain peptide (CLIP) ___e. ERp57 5. internalization of immunoglobulin:antigen complexes by B cells ___f. HLA-G ___g. HLA-F

6. expressed only by extravillous trophoblasts 7. trims peptides to fit MHC class I molecules

5–23 Explain how mycobacteria avoid immune recognition by T cells during infection.

5–24 Identify the three functions of the invariant chain.

5–25 Explain specifically how interferon-γ produced during an infection enhances (A) antigen processing in the MHC class I pathway, and (B) antigen presentation in the MHC class II pathway.

5–26 Discuss how T-cell receptors differ from immunoglobulins in the way that they recognize antigen. Use the following terms in your answer: peptides, antigen-presenting cells, MHC molecules, and antigen-binding sites.

5–27 Pathogens that infect the human body replicate either inside cells (such as viruses) or extracellularly, in the blood or in the extracellular spaces in tissues.

A. Identify (i) the class of T cells that are stimulated by intracellular pathogens, (ii) their coreceptor, (iii) the MHC molecule used for recognition of antigen and (iv) the T-cell effector function.

61

B. Repeat this for the classes of T cells that are stimulated by extracellular pathogens. For the purposes of this question, count those pathogens (such as mycobacteria) that can survive and live inside intracellular vesicles after being taken up by macrophages as extracellular pathogens.

5–28 In contrast to immunoglobulins, α:β T-cell receptors recognize epitopes present on _______ antigens: a. carbohydrate b. lipid c. protein d. carbohydrate and lipid e. carbohydrate, lipid, and protein.

5–29 Indicate whether each of the following statements regarding T cells is true (T) or false (F). a. __ T cells and B cells recognize the same types of antigen. b. __ T cells and B cells require MHC molecules for the recognition of peptide antigens. c. __ T cells require an accessory cell called an antigen-presenting cell, which bears MHC molecules on its surface. d. __ T-cell receptor and immunoglobulin genes are encoded on the MHC. e. __ The T-cell receptor has structural similarity to an immunoglobulin Fab fragment.

5–30 Which of the following characteristics is common to both T-cell receptors and immunoglobulins? a.

Somatic recombination of V, D, and J segments is responsible for the diversity of antigen-binding sites. b.

Somatic hypermutation changes the affinity of antigen-binding sites and contributes to further diversification. c.

Class switching enables a change in effector function. d.

The antigen receptor is composed of two identical heavy chains and two identical light chains. e.

Carbohydrate, lipid, and protein antigens are recognized and stimulate a response.

5–31 The antigen-recognition site of T-cell receptors is formed by the association of which of the following domains? a.

Vα and Cα b.

Vβ and Cβ c.

Cα and Cβ d.

Vα and Cβ e.

Vα and Vβ.

5–32 a. b. c. d. e.

The most variable parts of the T-cell receptor are Vα and Cα Vβ and Cβ Cα and Cβ Vα and Cβ Vα and Vβ.

62

5–33 How many complementarity-determining regions contribute to the antigen-binding site in an intact T-cell receptor? a.

2 b.

3 c.

4 d.

6 e.

12.

5–34 IgG possesses _______ binding sites for antigen, and the T-cell receptor possesses _______ binding sites for antigen: a.

1; 1 b.

2; 1 c.

1; 2 d.

2; 2 e.

2; 4.

5–35 In terms of V, D, and J segment arrangement, the T-cell receptor α-chain locus resembles the immunoglobulin _______ locus, whereas the T-cell receptor β-chain locus resembles the immunoglobulin _______ locus: a. λ light chain; κ light chain b. heavy chain; λ light chain c. κ light chain; heavy chain d. λ light chain; heavy chain e. κ light chain; λ light chain.

5–36 In B cells, transport of immunoglobulin to the membrane is dependent on association with two invariant proteins, Igα and Igβ. Which of the following invariant proteins provide this function for the T-cell receptor in T cells? a.

CD3γ b.

CD3δ c.

CD3ε d. δ e.

All of the above.

5–37 Owing to the location of the δ-chain locus of the T-cell receptor on chromosome 14, if the _______-chain locus rearranges by somatic recombination, then the δ-chain locus is _______: a. α; also rearranged b. α; deleted c. α; transcribed d. β; deleted e. γ; also rearranged.

63

5–38 Explain how professional antigen-presenting cells optimize antigen presentation to T cells despite the relatively limited capacity of any particular MHC molecule to bind different pathogen-derived peptides.

5–39 Which of the following is not a characteristic of native antigen recognized by T cells? a. peptides ranging between 8 and 25 amino acids in length b. not requiring degradation for recognition c. amino acid sequences not found in host proteins d. primary, and not secondary, structure of protein e. binding to major histocompatibility complex molecules on the surface of antigenpresenting cells.

5–40 a. b. c. d. e.

Which of the following statements regarding CD8 T cells is incorrect?

When activated, CD8 T cells in turn activate B cells.

CD8 is also known as the CD8 T-cell co-receptor.

CD8 binds to MHC molecules at a site distinct from that bound by the T-cell receptor.

CD8 T cells kill pathogen-infected cells by inducing apoptosis.

CD8 T cells are MHC class I-restricted.

5–41 Antigen processing involves the breakdown of protein antigens and the subsequent association of peptide fragments on the surface of antigen-presenting cells with a. immunoglobulins b.

T-cell receptors c. complement proteins d.

MHC class I or class II molecules e.

CD4.

5–42 Which of the following statements regarding T-cell receptor recognition of antigen is correct? a. α:β T-cell receptors recognize antigen only as a peptide bound to an MHC molecule. b. αβ T-cell receptors recognize antigens in their native form. c. α:β T-cell receptors, like B-cell immunoglobulins, can recognize carbohydrate, lipid, and protein antigens. d.

Antigen processing occurs in extracellular spaces. e.

Like α:β T cells, γ:δ T cells are also restricted to the recognition of antigens presented by MHC molecules.

5–43 a. b. c. d. e.

Which of the following describes a ligand for an α:β T-cell receptor? carbohydrate:MHC complex lipid:MHC complex peptide:MHC complex all of the above none of the above.

5–44 MHC class II molecules are made up of two chains called _______, whose function is to bind peptides and present them to _______ T cells: 64

a. b. c. d. e.

alpha (α) and beta (β); CD4 alpha (α) and beta2-microglobulin (β2m); CD4 alpha (α) and beta (β); CD8 alpha (α) and beta2-microglobulin β2m); CD8 alpha (α) and beta (β); γ:δ T cells.

5–45 The complementarity-determining region (CDR) 1 and CDR2 loops of the T-cell receptor contact the _______: a. side chains of amino acids in the middle of the peptide b. co-receptors CD4 or CD8 c. membrane-proximal domains of the MHC molecule d. constant regions of antibody molecules e. α helices of the MHC molecule.

5–46 a. b. c. d. e.

The CDR3 loops of the T-cell receptor contact the _______: side chains of amino acids in the middle of the peptide co-receptors CD4 or CD8 membrane-proximal domains of the MHC molecule constant regions of antibody molecules α helices of the MHC molecule.

5–47 The peptide-binding groove of MHC class I molecules is composed of the following extracellular domains: a. α1:β1 b. β1:β2 c. α2:β2 d. α2:α3 e. α1:α2.

5–48 a. b. c. d. e.

To which domain of MHC class II does CD4 bind? α1 β1 α2 β2 α3.

5–49 a. b. c. d. e.

To which domain of MHC class I does CD8 bind? α1 β1 α2 β2 α3.

5–50 MHC molecules have promiscuous binding specificity. This means that a. a particular MHC molecule has the potential to bind to different peptides b. when MHC molecules bind to peptides, they are degraded 65

c. d.

peptides bind with low affinity to MHC molecules none of the above describes promiscuous binding specificity.

5–51 T-cell receptors interact not only with peptide anchored in the peptide-binding groove of MHC molecules, but also with a. anchor residues b. peptide-binding motif c. variable amino acid residues on α helices of the MHC molecule d. β2-microglobulin e. invariant chain.

5–52 Cross-priming of the immune response occurs when _____. (Select all that apply.) a. viral antigens are presented by MHC class I molecules on the surface of a cell that is not actually infected by that particular virus b. cytosol-derived peptides enter the endoplasmic reticulum and bind to MHC class II molecules c. phagolysosome-derived peptides bind to MHC class II molecules d. peptides of nuclear or cytosolic proteins are presented by MHC class II molecules.

5–53 In reference to the interaction between T-cell receptors and their corresponding ligands, which of the following statements is correct? a.

The organization of the T-cell receptor antigen-binding site is distinct from the antigenbinding site of immunoglobulins. b.

The orientation between T-cell receptors and MHC class I molecules is different from that of MHC class II molecules. c.

The CDR3 loops of the T-cell receptor α and β chains form the periphery of the binding site making contact with the α helices of the MHC molecule. d.

The most variable part of the T-cell receptor is composed of the CD3 loops of both the α and β chains. e.

All of the above statements are correct.

5–54 a. b. c. d. e.

The diversity of MHC class I and II genes is due to _____. (Select all that apply.) gene rearrangements similar to those observed in T-cell receptor genes the existence of many similar genes encoding MHC molecules in the genome somatic hypermutation extensive polymorphism at many of the alleles isotype switching.

5–55 The combination of all HLA class I and class II allotypes that an individual expresses is referred to as their a. haplotype b. allotype c. isotype d. autotype e.

HLA type.

66

5–56 a. b. c. d. e.

All of the following are oligomorphic except HLA-G α chain HLA-DO β chain HLA-DQ β chain HLA-A α chain HLA-DR α chain.

5–57 a. b. c. d. e.

All of the following are highly polymorphic except HLA-A α chain HLA-DO α chain HLA-B α chain HLA-DR β chain HLA-C α chain.

5–58 Of the following HLA α-chain loci, which one exhibits the highest degree of polymorphism? a.

HLA-A b.

HLA-B c.

HLA-C d.

HLA-DP e.

HLA-DR. 5–59 Which of the following are not encoded on chromosome 6 in the HLA complex? (Select all that apply.) a. β2-microglobulin b.

HLA-G α chain c.

TAP-1 d. invariant chain e. tapasin f.

HLA-DR α chain.

5–60 The _____ refers to the complete set of HLA alleles that a person possesses on a particular chromosome 6. a. isoform b. isotype c. oligomorph d. allotype e. haplotype.

5–61 Peptides that bind to a particular MHC isoform usually have either the same or chemically similar amino acids at two to three key positions that hold the peptide tightly in the peptide-binding groove of the MHC molecule. These amino acids are called _____ and the combination of these key residues is known as its _____. a. alleles; allotypes b. anchor residues; peptide-binding motif c. allotype; haplotypes 67

d. e.

invariant chains; haplotypes restriction residues; MHC allotype.

5–62 Provide an explanation of why it is believed that MHC class I genes are the evolutionary ancestors of MHC class II genes.

5–63 Match the term in Column A with its description in Column B. Column A Column B ___a. MHC restriction 1. mechanism enabling extracellular antigens to bind to MHC class I molecules ___b. cross-presentation 2. evolutionary maintenance of divergent MHC molecule phenotypes ___c. heterozygote advantage 3. recognition of peptide antigen by a given T-cell receptor when bound to a particular MHC allotype ___d. balancing selection 4. mechanism used to increase polymorphisms of HLA class I and class II alleles involving homologous recombination between different alleles of the same gene ___e. interallelic conversion 5. presentation of a wider range of peptides when MHC isotypes inherited from each parent are different

5–64 Directional selection is best described as a. all polymorphic alleles preserved in a population b.

T-cell receptor interaction with peptide:MHC complexes directed to a planar interface c. a mechanism in T cells that is analogous to affinity maturation of immunoglobulins d. selected alleles increase in frequency in a population e. selection of most appropriate transplant donor directed at the identification of identical or similar combinations of HLA alleles compared with the transplant recipient.

5–65 Describe (A) five ways in which T-cell receptors are similar to immunoglobulins, and (B) five ways in which they are different (other than the way in which they recognize antigen).

5–66 Compare the organization of T-cell receptor α and β genes (the TCRα and TCRβ loci) with the organization of immunoglobulin heavy-chain and light-chain genes.

5–67 T-cell receptors do not undergo isotype switching. Suggest a possible reason for this.

5–68 a. b. c. d. e.

The role of the CD3 proteins and δ chain on the surface of the cell is to transduce signals to the interior of the T cell bind to antigen associated with MHC molecules bind to MHC molecules bind to CD4 or CD8 molecules facilitate antigen processing of antigens that bind to the surface of T cells.

68

5–69 Which of the following accurately completes this statement: ―The function of _______ T cells is to make contact with _______ and _______‖? (Select all that apply.) a.

CD8; virus-infected cells; kill virus-infected cells b.

CD8; B cells; stimulate B cells to differentiate into plasma cells c.

CD4; macrophages; enhance microbicidal powers of macrophages d.

CD4; B cells; stimulate B cells to differentiate into plasma cells e.

All of the above are accurate.

5–70 The immunological consequence of severe combined immunodeficiency disease (SCID) caused by a genetic defect in either RAG-1 or RAG-2 genes is a. lack of somatic recombination in T-cell receptor and immunoglobulin gene loci b. lack of somatic recombination in T-cell receptor loci c. lack of somatic recombination in immunoglobulin loci d. lack of somatic hypermutation in T-cell receptor and immunoglobulin loci e. lack of somatic hypermutation in T-cell receptor loci.

5–71 A. (i) Describe the structure of an MHC class I molecule, identifying the different polypeptide chains and domains. (ii) What are the names of the MHC class I molecules produced by humans? Which part of the molecule is encoded within the MHC region of the genome? (iii) Which domains or parts of domains participate in the following: antigen binding; binding the Tcell receptor; and binding the T-cell co-receptor? (iv) Which domains are the most polymorphic?

B. Repeat this for an MHC class II molecule.

5–72 What is meant by the terms (A) antigen processing and (B) antigen presentation? (C) Why are these processes required before T cells can be activated?

5–73 A. Describe in chronological order the steps of the antigen-processing and antigenpresentation pathways for intracellular, cytosolic pathogens.

B. (i) What would be the outcome if a mutant MHC class I α chain could not associate with β2-microglobulin, and (ii) what would happen if the TAP transporter were lacking as a result of mutation? Explain your answers.

5–74 a. b. c. d. e.

Which of the following removes CLIP from MHC class II molecules?

HLA-DM HLA-DO HLA-DP HLA-DQ HLA-DR.

5–75 A. Describe in chronological order the steps of the antigen-processing and antigenpresentation pathways for extracellular pathogens.

69

B. What would be the outcome (i) if invariant chain were defective or missing, or (ii) if HLA-DM were not expressed?

5–76 A. What is the difference between MHC variation due to multigene families and that due to allelic polymorphism?

B. How does MHC variation due to multigene families and allelic polymorphism influence the antigens that a person‘s T cells can recognize?

5–77 What evidence supports the proposal that MHC diversity evolved by natural selection caused by infectious pathogens rather than exclusively by random DNA mutations?

5–78 CD8 T-cell subpopulations are specialized to combat _______ pathogens, whereas CD4 T-cell subpopulations are specialized to combat _______ pathogens: a. bacterial; viral b. dead; live c. extracellular; intracellular d. intracellular; extracellular e. virulent; attenuated.

5–79 Which of the following describes the sequence of events involved in processing of peptides that will be presented as antigen with MHC class I? a. plasma membrane →TAP1/2 →proteasome →MHC class I →endoplasmic reticulum b.

TAP1/2 →proteasome →MHC class I →endoplasmic reticulum→plasma membrane c. proteasome →TAP1/2 →MHC class I →endoplasmic reticulum →plasma membrane d. proteasome →TAP1/2 →endoplasmic reticulum →MHC class I →plasma membrane e. endoplasmic reticulum →proteasome →MHC class I →TAP1/2 →plasma membrane.

5–80 One type of bare lymphocyte syndrome is caused by a genetic defect in MHC class II transactivator (CIITA), which results in the inability to synthesize MHC class II and display it on the cell surface. The consequence of this would be that a.

B cells are unable to develop b.

CD8 T cells cannot function c.

CD4 T cells cannot function d. intracellular infections cannot be eradicated e. peptides cannot be loaded onto MHC molecules in the lumen of the endoplasmic reticulum.

5–81 Which of the following describes the sequence of events involved in the processing of peptides that will be presented as antigen with MHC class II? a. protease activity →removal of CLIP from MHC class II →binding of peptide to MHC class II →endocytosis →plasma membrane b. endocytosis →protease activity →removal of CLIP from MHC class II →binding of peptide to MHC class II →plasma membrane c. removal of CLIP from MHC class II →binding of peptide to MHC class II →protease activity →endocytosis →plasma membrane 70

d. binding of peptide to MHC class II →endocytosis →removal of CLIP from MHC class II →protease activity →plasma membrane e. plasma membrane →endocytosis →protease activity →removal of CLIP from MHC class II →binding of peptide to MHC class II. 5–82 a. b. c. d. e.

Which of the following cell types does not express MHC class I? erythrocyte hepatocyte lymphocyte dendritic cell neutrophil.

5–83 cell? a. b. c. d. e.

Which of the following cell types is not considered a professional antigen-presenting macrophage neutrophil B cell dendritic cell all of the above are professional antigen-presenting cells.

5–84 Match the answer on the right that best describes the function on the left. More than one answer may be correct. ___ a. an intracellular, monomorphic 1. HLA-A, HLA-B, HLA-C MHC class I isotype whose function is unknown __ b. form ligands for receptors on NK 2. HLA-E, HLA-G cells __ c. participate in peptide loading of 3. HLA-F MHC class II molecules __ d. present antigen to CD4 T cells 4. HLA-DP, HLA-DQ, HLA-DR __ e. present antigen to CD8 T cells 5. HLA-DM, HLA-DO 5–85 Which of the following HLA-DRB genotypes is not possible in an individual? (X: X represents diploid genotype.) a.

DRB1: DRB1 b.

DRB1, DRB3: DRB1, DRB4 c.

DRB1: DRB1, DRB5 d.

DRB1, DRB4: DRB1 e.

DRB3: DRB1, DRB5.

5–86 A. How many HLA-DR α:β combinations can be made by an individual who is heterozygous at all HLA-DRβ loci, inherits the DRβ haplotype DRB1 from their mother, the DRβ haplotype DRB1, DRB4 from their father, and also inherits different allelic forms of DRA from each parent?

71

B. Repeat this exercise given the same information except that the maternal DRβ haplotype is DRB1, DRB3.

5–87 Which of the following is mismatched? a. peptide-binding motif: combination of anchor residues in a peptide capable of binding a particular MHC haplotype b.

MHC restriction: specificity of T-cell receptor for a particular peptide:MHC molecule complex c. balancing selection: maintenance of variety of MHC isoforms in a population d. directional selection: replacement of older MHC isoforms with newer variants e. interallelic conversion: recombination between two different genes in the same family.

5–88 Which is the most likely reason that HIV-infected people with heterozygous HLA loci have a delayed progression to AIDS compared with patients who are homozygous at one or more HLA loci? a.

The greater number of HLA alleles provides a wider variety of HLA molecules for presenting HIV-derived peptides to CD8 T cells even if HIV mutates during the course of infection. b.

Heterozygotes have more opportunity for interallelic conversion and can therefore express larger numbers of MHC alleles. c.

Directional selection mechanisms favor heterozygotes and provide selective advantage to pathogen exposure. d.

As heterozygosity increases, so does the concentration of alloantibodies in the serum, some of which cross-react with and neutralize HIV. 5–89 A. What is the maximum number of MHC class I and class II molecules that a heterozygous individual could theoretically express? Explain your answer. (Ignore the possibility of MHC class II molecules composed of chains from different isotypes.)

B. How does this relatively small number of MHC molecules have the potential to bind the huge number of antigenic peptides encountered in the environment, and what features of a peptide determine whether it will be bound by a given MHC molecule?

5–90 (A) Explain the difference between interallelic conversion and gene conversion, and (B) provide an example for both.

5–91 In the context of MHC isoforms, what is the difference between balancing selection and directional selection?

5–92 A. What are alloantibodies?

B. How do alloantibodies arise naturally?

C. Why are alloantibodies problematic for transplantation?

ANSWERS 72

5–1

a

5–2

d

5–3

c

5–4

e

5–5

e

5–6

a

5–7

d

5–8 A. RAG genes do not contain introns, and they function to facilitate the cleavage of doublestranded DNA. B. It has been proposed that the evolution of rearranging antigen-receptor genes began with the insertion of a transposable element into a gene encoding an innate immune receptor. This gene was not only split into two segments, but also became flanked by repetitive DNA sequences donated by the transposon. A later chromosomal rearrangement event translocated the transposase genes to a different chromosome, where they evolved into the ancestral RAG-1 and RAG-2 genes. The repetitive DNA sequences left behind at the original receptor gene location evolved into the recombination signal sequences (RSSs), and the segments of the receptor gene evolved into V and J sequences. Eventually this led to a family of rearranging genes on five chromosomes encoding the immunoglobulin heavy- and light-chain genes, and the T-cell receptor α, β, γ, and δ genes.

5–9

e

5–10 a—1; b—2; c—3; d—5; e—4 5–11 d 5–12 c 5–13 c 5–14 b 5–15 Each MHC molecule can bind to a very large number of peptides made up of different sequences of amino acids. The consequence of this promiscuity is that humans need only encode a relatively small number of MHC molecules in their genome if they are to bind to the huge number of pathogen-derived peptides encountered during a lifetime of infections. Because MHC molecules are coexpressed on the cell surface, this also ensures that an appropriate density of 73

MHC molecules populates the cell surface to ensure efficient T-cell engagement and subsequent activation.

5–16 a 5–17 d 5–18 c 5–19 b 5–20 e 5–21 a, c, d 5–22 a—2; b—4; c—7; d—5; e—3; f—6; g—1 5–23 Both the MHC class I and MHC class II pathways are subverted by mycobacteria during intracellular growth and replication. Although mycobacteria are obligate intracellular pathogens their proteins do not enter the cytosol, so proteasomes are unable to generate mycobacteriaderived peptides for the MHC class I pathway. Mycobacteria are also resistant to degradation by lysosomal enzymes because they inhibit phagolysosome formation. This interferes with the MHC class II pathway.

5–24 1.

Invariant chain protects the peptide-binding groove of MHC class II molecules from binding to endoplasmic reticulum-derived peptides.

2.

Binding of invariant chain to MHC class II molecules stabilizes their conformation so that they are eventually able to bind peptides.

3.

Invariant chain facilitates the transport of MHC class II molecules from the ER to the MIIC cellular compartment, where they can bind peptides.

5–25 A. Interferon-γ causes a shift from the production of constitutive proteasomes to that of immunoproteasomes. This is accomplished through increased expression of alternative subunits (LMP2 and LMP7) that are present in the immunoproteasome. These proteasomes exhibit modified protease activities favoring the production of peptides (antigen processing) that can bind to MHC class I molecules. Specifically, cleavage after hydrophobic residues is enhanced and cleavage after acidic residues is decreased.

B. Interferon-γ increases the expression of HLA-DM but not HLA-DO. This causes a shift in the balance of these two molecules, resulting in an overall decrease in the antagonist activity of HLA-DO. If HLA-DM is more abundant, it has the ability to catalyze the release of CLIP from MHC class II molecules and facilitate the replacement of CLIP with other peptides for presentation to CD4 T cells (antigen presentation). Another way in which interferon-γ increases antigen presentation in the MHC class II pathway is by increasing the expression levels of MHC class II molecules on both professional and non-professional antigen-presenting cells.

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5–26 First, T-cell receptors can bind to only one type of antigen, namely protein fragments called peptides. Immunoglobulins can bind to peptides, intact proteins, carbohydrates, and lipids.

Second, unlike immunoglobulins, T-cell receptors cannot bind to a free antigen directly, but instead require accessory antigen-presenting cells that present the peptide antigens in association with cell-surface glycoproteins called MHC class I and class II molecules. Third, T-cell receptors possess a single antigen-binding site; immunoglobulins have at least two binding sites for antigen, and more in the case of secreted dimeric IgA (four sites) and secreted pentameric IgM (ten sites).

5–27 A. (i) Pathogens that are propagating freely within cells (for example viruses) are eradicated by the actions of cytotoxic T cells. (ii) Cytotoxic T cells express a glycoprotein called CD8, a Tcell co-receptor that interacts with (iii) MHC class I on antigen-presenting cells. (iv) Once activated, cytotoxic T cells kill cells infected with the pathogen, which are displaying pathogen peptides on MHC class I molecules, and thereby inhibit further replication of the pathogen and infection of neighboring cells.

B. (i) Pathogens that reproduce in extracellular spaces, for example encapsulated bacteria such as Streptococcus pneumoniae, are eradicated after the activation of other cell types by helper T cells, namely the classes TH1 and TH2. (ii) TH1 and TH2 cells express a glycoprotein called CD4, a T-cell co-receptor that interacts with (iii) MHC class II molecules on antigenpresenting cells. (iv) TH1 cells activate macrophages that are displaying pathogen peptides (derived from phagocytosed pathogen) on MHC class II molecules on their surface. This stimulates increased phagocytosis by the macrophage and destruction of pathogens inside phagolysosomes. Activated macrophages also secrete inflammatory mediators that have an important part in eradicating the infection by helping to induce inflammation which recruits phagocytic cells and effector lymphocytes to the site of infection. TH1 cells also induce switching of B cells to certain antibody isotypes. TH2 cells activate B cells displaying antigen-derived peptides on MHC class II molecules, resulting in the differentiation of the B cells into plasma cells and the production of antibodies that remove the extracellular pathogen or its toxins as a result of neutralization, opsonization, and complement activation.

5–28 c 5–29 a—F; b—F; c—T; d—F; e—T 5–30 a 5–31 e 5–32 e 5–33 d 5–34 b

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5–35 c 5–36 e 5–37 b 5–38 Professional antigen-presenting cells express several different types of MHC molecule on the cell surface, and each type has the potential to bind to different peptides. In addition, MHC molecules are highly polymorphic, so that most individuals are heterozygous and encode different allelic forms at each gene locus. The variety of peptides that can bind to these MHC molecules is therefore increased.

5–39 b 5–40 a 5–41 d 5–42 a 5–43 c 5–44 a 5–45 e 5–46 a 5–47 e 5–48 d 5–49 e 5–50 a 5–51 c 5–52 a, d 5–53 d 5–54 b, d 5–55 e

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5–56 c 5–57 b 5–58 b 5–59 a, d 5–60 e 5–61 b 5–62 MHC class I molecules not only have the role of presenting antigen to T cells, but they also possess additional functions in the body not associated with MHC class II molecules. For example, they participate in iron homeostasis, IgG uptake in the gastrointestinal tract, and the regulation of NK-cell function in innate immunity. In addition, MHC class I and class I-like genes are not confined to chromosome 6, in contrast with MHC class II genes. Finally, vertebrates exist (such as Atlantic cod) that have only MHC class I genes in their genome, and lack MHC class II genes.

5–63 a—3; b—1; c—5; d—2; e—4 5–64 d 5–65 A. Similarities. (1) The T-cell receptor has a similar overall structure to the membranebound Fab fragment of immunoglobulin, containing an antigen-binding site, two variable domains, and two constant domains. (2) T-cell receptors and immunoglobulins are both generated through somatic recombination of sets of gene segments. (3) The variable region of the T-cell receptor contains three complementarity-determining regions (CDRs) encoded by the Vα domain and three CDRs encoded by the Vβ domain, analogous to the CDRs encoded by the VH and VL domains. (4) There is huge diversity in the T-cell receptor repertoire and it is generated in the same way as that in the B-cell repertoire (by combination of different gene segments, junctional diversity due to P- and N-nucleotides, and combination of two different chains). (5) Tcell receptors are not expressed at the cell surface by themselves but require association with the CD3 γ, δ, ε, and δ chains for stabilization and signal transduction, analogous to the Igα and Igβ chains required for immunoglobulin cell-surface expression and signal transduction.

B. Differences. (1) A T-cell receptor has one antigen-binding site; an immunoglobulin has at least two. (2) T-cell receptors are never secreted. (3) T-cell receptors are generated in the thymus, not the bone marrow. (4) The constant region of the T-cell receptor has no effector function and it does not switch isotype. (5) T-cell receptors do not undergo somatic hypermutation.

5–66 The organization of the TCRα locus resembles that of an immunoglobulin light-chain locus, in that both contain V and J gene segments and no D gene segments. The TCRα locus on chromosome 14 contains about 80 V gene segments, 61 J gene segments, and 1 C gene. The 77

immunoglobulin light-chain loci, λ and κ, are encoded on chromosomes 22 and 2, respectively.

The λ locus contains about 30 V gene segments and 4 J gene segments, each paired with a C gene. The κ locus contains about 35 V gene segments, 5 J segments, and 1 C gene segment. The arrangement of the κ locus more closely resembles that of the TCRα locus except that there are more J segments in the T-cell receptor locus.

The organization of the TCRβ locus resembles that of the immunoglobulin heavy-chain locus; both contain V, D, and J gene segments. The TCRβ locus contains about 52 V gene segments, 2 D gene segments, 13 J gene segments, and 2 C genes, encoded on chromosome 7.

Each C gene is associated with a set of D and J gene segments. The immunoglobulin heavychain locus on chromosome 14 contains about 40 V segments, 23 D segments, and 6 J segments, followed by 9 C genes, each specifying a different immunoglobulin isotype. The heavy-chain C genes determine the effector function of the antibody.

5–67 T-cell receptors are not made in a secreted form, and their constant regions do not contribute to T-cell effector function. Other molecules secreted by T cells are used for effector functions. There is therefore no need for isotype switching in T cells, and the T-cell receptor loci do not contain numerous alternative C genes.

5–68 a 5–69 a, c, d 5–70 a 5–71 A. (i) The complete MHC class I molecule is a heterodimer made up of one α chain and a smaller chain called β-microglobulin. The α chain consists of three extracellular domains α1, α2, and α3—a transmembrane region and a cytoplasmic tail. β2-Microglobulin is a single-domain protein noncovalently associated with the extracellular portion of the α chain, providing support and stability. (ii) The polymorphic class I molecules in humans are called HLA-A, HLA-B, and HLA-C. The α chain is encoded in the MHC region by an MHC class I gene. The gene for β2microglobulin is elsewhere in the genome. (iii) The antigen-binding site is formed by the α1 and α2 domains, the ones farthest from the membrane, which create a peptide-binding groove. The region of the MHC molecule that binds to the T-cell receptor encompasses the α helices of the α1 and α2 domains that make up the outer surfaces of the peptide-binding groove. The α3 domain binds to the T-cell co-receptor CD8. (iv) The most polymorphic parts of the α chain are the regions of the α1 and α2 domains that bind antigen and the T-cell receptor. β2-Microglobulin is invariant; that is, it is the same in all individuals.

B. (i) MHC class II molecules are heterodimers made up of an α chain and a β chain. The α chain consists of α1 and α2 extracellular domains, a transmembrane region, and a cytoplasmic tail. The β chain contains β1 and β2 extracellular domains, a transmembrane region, and a cytoplasmic tail. (ii) In humans there are three polymorphic MHC class II molecules called HLA-DP, HLA-DQ, and HLA-DR. Both chains of an MHC class II molecule are encoded by genes in the MHC region. (iii) Antigen binds in the peptide-binding groove formed by the α1 and β1 domains. The α helices of the α1 and β1 domains interact with the T-cell receptor. The β2 domain binds to the T-cell co-receptor CD4. (iv) With the exception of HLA-DRα, which is 78

dimorphic, both the α and β chains of MHC class II molecules are highly polymorphic.

Polymorphism is concentrated around the regions that bind antigen and the T-cell receptor in the α1 and β1 domains.

5–72 A. Antigen processing is the intracellular breakdown of pathogen-derived proteins into peptide fragments that are of the appropriate size and specificity required to bind to MHC molecules.

B. Antigen presentation is the assembly of peptides with MHC molecules and the display of these complexes on the surface of antigen-presenting cells.

C. Antigen processing and presentation must occur for T cells to be activated because (1) Tcell receptors cannot bind to intact protein, only to peptides, and (2) T-cell receptors do not bind antigen directly, but rather must recognize antigen bound to MHC molecules on the surface of antigen-presenting cells.

5–73 A. Proteins derived from pathogens located in the cytosol are broken down into small peptide fragments in proteasomes. The peptides are transported into the lumen of the endoplasmic reticulum (ER) using the transporter associated with antigen processing (TAP), which is a heterodimer of TAP-1 and TAP-2 proteins anchored in the ER membrane. Meanwhile, MHC class I molecules are assembling and folding in the ER with the assistance of other proteins. Initially, the MHC class I α chain binds calnexin through an asparagine-linked oligosaccharide on the α1 domain. After folding and forming its disulfide bonds, the α chain binds to β2-microglobulin, forming the MHC class I heterodimer. At this stage, calnexin is released and the heterodimer joins the peptide-loading complex composed of tapasin, calreticulin, and ERp57, which position the heterodimer near TAP, stabilize the peptide-loading complex, and render the heterodimer in an open conformation until a high-affinity peptide binds to the heterodimer through a process known as peptide editing. The heterodimer consequently changes its conformation, is released from the peptide-loading complex, and leaves the ER as a vesicle. Arrival at the Golgi apparatus induces final glycosylation, and finally the peptide:MHC class I heterodimer complex is transported in vesicles to the plasma membrane, where it presents peptide to CD8 T cells.

B. (i) If an MHC class I α chain is unable to bind β2-microglobulin, it will be retained in the ER and will not be transported to the cell surface. It will remain bound to calnexin and will not fold into the conformation needed to bind to peptide. Thus, antigens will not be presented using that particular MHC class I molecule. (ii) If TAP-1 or TAP-2 proteins are mutated and not expressed, peptides will not be transported into the lumen of the ER. Without peptide, an MHC class I molecule cannot complete its assembly and will not leave the ER. A rare immunodeficiency disease called bare lymphocyte syndrome (MHC class I immunodeficiency) is characterized by a defective TAP protein, causing less than 1% of MHC class I molecules to be expressed on the cell surface in comparison with normal. Thus, T-cell responses to all pathogen antigens that would normally be recognized on MHC class I molecules will be impaired.

5–74 a

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5–75 A. Extracellular pathogens are taken up by endocytosis or phagocytosis and degraded by enzymes into smaller peptide fragments inside acidified intracellular vesicles called phagolysosomes. MHC class II molecules delivered into the ER and being transported to the cell surface intersect with the phagolysosomes, where these peptides are encountered and loaded into the antigen-binding groove. To prevent MHC class II molecules from binding to peptides prematurely, invariant chain (Ii) binds to the MHC class II antigen-binding site in the ER. Ii is also involved in transporting MHC class II molecules to the phagolysosomes via the Golgi as part of the interconnected vesicle system. Ii is removed from MHC class II molecules once the phagolysosome is reached. Removal is achieved in two steps: (1) proteolysis cleaves Ii into smaller fragments, leaving a small peptide called CLIP (class II-associated invariant chain peptide) in the antigen-binding groove of the MHC class II molecule; and (2) CLIP is then released by HLA-DM catalysis. Once CLIP is removed, HLA-DM remains associated with the MHC class II molecule, enabling the now empty peptide-binding groove to sample other peptides until one binds tightly enough to cause a conformational change that releases HLA-DM. Finally, the peptide:MHC class II complex is transported to the plasma membrane.

B. (i) Defects in the invariant chain would impair normal MHC class II function because invariant chain not only protects the peptide-binding groove from binding prematurely to peptides present in the ER but is also required for transport of MHC class II molecules to the phagolysosome. (ii) If HLA-DM were not expressed, most MHC class II molecules on the cell surface would be occupied by CLIP rather than endocytosed material. This would compromise the presentation of extracellular antigens at the threshold levels required for T-cell activation.

5–76 A. Multigene family refers to the presence of multiple genes for MHC class I and MHC class II molecules in the genome, encoding a set of structurally similar proteins with similar functions. MHC polymorphism is the presence of multiple alleles (in some cases several hundreds) for most of the MHC class I and class II genes in the human population.

B. T cells recognize peptide antigens in the form of peptide:MHC complexes, which they bind using their T-cell receptors. To bind specifically, the T-cell receptor must fit both the peptide and the part of the MHC molecule surrounding it in the peptide-binding groove. (i) Because each individual expresses a number of different MHC molecules from the MHC class I and class II multigene families, the T-cell receptor repertoire is not restricted to recognizing peptides that bind to just one MHC molecule (and thus all must have the same peptide-binding motif). Instead, the T-cell receptor repertoire can recognize peptides with different peptidebinding motifs during an immune response, increasing the likelihood of antigen recognition and, hence, T-cell activation. (ii) The polymorphism in MHC molecules is localized to the regions affecting T-cell receptor and peptide binding. Thus, a T-cell receptor that recognizes a given peptide bound to variant ‗a‘ of a particular MHC molecule is likely not to recognize the same peptide bound to variant ‗b‘ of the same MHC molecule. Polymorphism also means that the MHC molecules of one person will bind a different set of peptides from those in another person.

Taken together, these outcomes mean that because of MHC polymorphism, each individual recognizes a somewhat different range of peptide antigens using a different repertoire of T-cell receptors.

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5–77 MHC polymorphisms are non-randomly localized, predominantly to the region of the molecule that makes contact with peptide and T-cell receptors. Random DNA mutations, in contrast, would be scattered through the gene, giving rise to amino acid changes throughout MHC molecules and not just in those areas important for peptide binding and presentation.

5–78 d 5–79 c 5–80 c 5–81 b 5–82 a 5–83 b 5–84 a—3; b—1, 2; c—5; d—4; e—1 5–85 e 5–86 m and p denote maternal and paternal allotypes, respectively.

A. The answer is 6. The possible combinations are as follows: (1) DRA-m:DRB1-m; (2) DRA-m:DRB1-p; (3) DRA-m:DRB4-p; (4) DRA-p:DRB1-m; (5) DRA-p:DRB1-p; and (6) DRA-p:DRB4-p.

B. The answer is 8. The possible combinations are as follows: (1) DRA-m:DRB1-m; (2) DRA-m:DRB3-m; (3) DRA-m:DRB1-p; (4) DRA-m:DRB4-p; (5) DRA-p:DRB1-m; (6) DRA-p:DRB3-m; (7) DRA-p:DRB1-p; (8) DRA-p:DRB4-p.

5–87 e 5–88 a 5–89 A. There are three MHC class I isotypes in humans (HLA-A, HLA-B, and HLA-C) and they are expressed from both chromosomes. Assuming that each gene is heterozygous, the maximum number of different MHC class I α chains that could be expressed is 6. Because β-microglobulin is invariant, this means that six different MHC class I molecules could be produced. For MHC class II molecules, assuming complete heterozygosity and the presence of two functional DRB genes (DRB1 and DRB3, 4, or 5) on both chromosomes, the maximum number of MHC class II molecules that could be expressed is 16 (Figure A5–89). Therefore, the total number of different MHC class I and MHC class II molecules that can be expressed is 22. <<insert Figure A5-89>>

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Figure A5–89 The number of HLA molecules that can be expressed in a single individual. m, maternal chromosome; p, paternal chromosome.

B. MHC molecules have promiscuous binding specificity, which means that one MHC molecule is able to bind a wide range of peptides with different sequences. For all MHC molecules, only a few of the amino acids in the antigen peptide are critical for binding to amino acids in the peptide-binding groove. The critical amino acids in the peptide are called anchor residues; they are the same or similar in all peptides that bind to a given MHC molecule. The other amino acid residues in the peptides can be different. The pattern of anchor residues that binds to a given MHC molecule is called the peptide-binding motif. Hence, a very large number of discrete peptides can bind to each MHC isoform, the only constraint being the possession of the correct anchor residues at the appropriate positions in the peptide. MHC class I molecules also bind peptides that are typically nine amino acids long, whereas MHC class II molecules bind longer peptides with a range of lengths.

5–90 A. Interallelic conversion is a recombination between homologous alleles of the same gene.

Gene conversion is a recombination between non-homologous alleles of different genes.

B. An example of interallelic conversion would involve recombination between HLA B*5101 and HLA B*3501. An example of gene conversion would involve recombination between HLA B*1501 and HLA Cw*0102.

5–91 Balancing selection maintains a variety of MHC isoforms in a population, whereas directional selection replaces older isoforms with newer variants.

5–92 A. Alloantibodies are antibodies specific for variant antigens encoded at polymorphic genes within a species (for example blood group antigens and MHC class I and class II molecules).

B. They arise naturally during pregnancy when the mother‘s immune system encounters fetal cells expressing variant antigens derived from the father but not expressed by the mother.

C. If present, alloantibodies with specificity for transplanted organs will mediate graft rejection.

CHAPTER 6: THE DEVELOPMENT OF B LYMPHOCYTES 6–1

Describe the six functionally distinct phases of B-cell development.

6–2 Which of the following cell-surface markers differentiates hematopoietic stem cells from other cell constituents in the bone marrow? a. pre-B-cell receptor b.

BAFF receptor c.

CD34 82

d. e.

CD4 membrane-bound stem-cell factor (SCF).

6–3 You are going to use flow cytometry to determine the proportion of developing B cells in the bone marrow that are immature, anergic, or mature. You have three monoclonal antibodies specific for three different B-cell surface proteins. The first has specificity for the cell-surface protein CD19, which is expressed by all developing and mature B cells; the second is specific for the Fc region of IgD; and the third is specific for the Fc region of IgM. The antibodies are conjugated to three different fluorescent tags that can be detected and distinguished by the flow cytometer.

A. Use histograms to show your analysis of CD19-positive cells and indicate which part of your histogram you would gate to analyze IgM and IgD expression. Indicate the gated population with an arrow.

B. Using a two-dimensional dot plot, compare the expression of IgD and IgM of these gated cells, and say which of these populations represents (i) immature B cells, (ii) mature B cells, and (iii) anergic B cells.

6–4 a. b. c. d. e.

Which of the following is characteristic of a large pre-B cell?

VDJ is successfully rearranged and μ heavy chain is made.

V–J is rearranging at the light-chain locus. μ heavy chain and λ or κ light chain is made.

V is rearranging to DJ at the heavy-chain locus.

D–J is rearranging at the heavy-chain locus.

6–5 a. b. c. d. e.

Which of the following statements is correct?

The κ light-chain genes rearrange before the heavy-chain genes.

The κ light-chain genes rearrange before the λ light-chain genes.

The λ light-chain genes rearrange before the heavy-chain genes.

The λ light-chain genes rearrange before the κ light-chain genes.

The μ heavy-chain genes rearrange first and then the λ light-chain genes rearrange.

6–6 a. b. c. d. e.

Immature B cells develop into B cells in the subendosteum bone marrow thymus blood secondary lymphoid organs.

6–7 a. b. c. d. e. f.

Place the following phases of a B cell‘s life history in the correct chronological order. negative selection attacking infection finding infection searching for infection repertoire assembly positive selection.

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6–8 a. b. c. d. e. f.

Place the following stages of B-cell development in the correct chronological order. early pro-B cell large pre-B cell immature B cell stem cell late pre-B cell small pre-B cell.

6–9 A. Discuss the importance of the bone marrow stroma for B-cell development.

B. What would be the effect of anti-IL-7 antibodies on the development of B cells in the bone marrow, and at which stage would development be impaired? Explain your answer.

6–10 A. What are the two main checkpoints of B-cell development in the bone marrow?

B. What is the fate of developing B cells that produce (i) functional or (ii) nonfunctional heavy and light chains?

C. Explain how these two checkpoints correlate with the process of allelic exclusion that ensures that only one heavy-chain locus and one light-chain locus produce functional gene products.

6–11 a. b. c. d. e.

Large pre-B cells are characterized by which of the following?

They do not express CD19 at the cell surface.

Rearrangement of light-chain genes commences.

Nonproductive rearrangement of both heavy-chain loci has already occurred.

Allelic exclusion of the immunoglobulin light-chain loci has already occurred. μ is assembled with VpreBλ5.

6–12 a. b. c. d. e.

All hematopoietic stem cells express CD34 CD127 CD19 VpreBλ5 Pax-5

6–13 a. b. c. d. e. f.

Which of the following do not associate with one another during B-cell development?

IL-7: IL-7 receptor of late pro-B cells Pax-5: CD19 gene surrogate light chain: δ heavy chain VpreB: λ5 SCF: Kit pre-B-cell receptor: Igα and Igβ

6–14 The latest stages of late pro-B-cell development are recognized by the association of a surrogate light chain with a μ chain. The surrogate light chain is composed of a.

E2A and EFB 84

b. c. d. e.

Igα and Igβ VpreB and λ5 RAG-1 and RAG-2 Pax-5 and CD19.

6–15 A genetic defect in the λ5 gene would cause which of the following consequences?

(Select all that apply.) a. inability to produce functional μ chains b. inability to produce a pre-B-cell receptor c. inability to produce functional κ or λ chains d. production of different light chains owing to defects in allelic exclusion e.

B-cell immunodeficiency f. chronic bacterial infections g. requirement for prophylactic injections of antibodies from healthy donors.

6–16 What would be the consequence if terminal deoxynucleotidyl transferase (TdT) were expressed throughout the whole of small pre-B-cell development?

6–17 Which of the following is not paired with its correct complement? a.

N nucleotides: more abundant in rearranged heavy-chain genes than in rearranged lightchain genes b. second checkpoint in B-cell development: assembly of a functional B-cell receptor c. receptor editing: exchange of light chain for one that is not self-reactive d. first checkpoint in B-cell development: selection by the pre-B-cell receptor e. large pre-B-cell stage: constitutive expression of RAG-1 and RAG-2 proteins.

6–18 Which of the following would occur after the production of a functional μ chain as a preB-cell receptor? a.

RAG proteins are degraded. b.

The chromatin structure of the heavy-chain locus is reorganized to prevent gene rearrangement. c.

Transcription of the RAG1 and RAG2 genes ceases. d.

There is allelic exclusion of a second μ chain. e.

All of the above would occur.

6–19 An important advantage of having two gene loci (κ and λ) for the light chain is a. that the likelihood of a successful rearrangement of light-chain genes increases. b. that immunoglobulins are homogeneous and not heterogeneous in mature B cells. c. that different effector functions are conferred by the two different light-chain loci. d. that surrogate light-chain transcription cannot compete with κ and λ transcription and enables B-cell development. e. all of the above.

6–20 Which of the following is correctly matched? (Select all that apply.) a. early pro-B cell: VDJ rearranged b. pre-B-cell receptor: VpreBλ5/μu heavy chain 85

c. d. e.

mature B cell: IgM plus IgD small pre-B cell: VJ rearranged immature B cell: μ heavy chain plus λ or κ light chain on surface.

6–21 Large pre-B cells undergo clonal expansion before the rearrangement of light-chain loci.

Which of the following are beneficial consequences of clonal expansion? (Select all that apply.) a.

Autoreactive B cells are eliminated before the expenditure of energy needed to rearrange a functional light-chain gene. b.

The energy used to make a functional heavy chain is not wasted as a result of the inability to produce a functional light chain. c.

RAG gene expression is decreased, which in turn signals light-chain rearrangement. d.

A diverse population of immature B cells is generated that express the same μ chain but a distinct light chain. e.

Approximately 85% of small pre-B cells will progress to the immature B-cell stage.

6–22 When expression of _______ is turned off in small pre-B cells, the result is the presence of P nucleotides but an absence of N nucleotides in around 50% of light-chain genes. a.

Kit b.

CD19 c.

TdT d.

Pax-5 e.

RAG-1 and RAG-2.

6–23 A defect in which of the following proteins blocks B-cell development at the pre-B-cell stage, resulting in almost no circulating antibodies in individuals with this defect? a.

IL-7 receptor b. terminal deoxynucleotidyltransferase (TdT) c.

Pax-5 d.

Bruton‘s tyrosine kinase (Btk) e.

CD19.

6–24 The consequence of allelic exclusion at the immunoglobulin loci ensures that _____.

(Select all that apply.) a.

B-cell receptors have a low-avidity binding b.

B cells express antigen receptors of a single specificity c. hybrid immunoglobulins are formed d. all functional copies of a gene are expressed e. homogeneous B-cell receptors bind more effectively to antigen.

6–25 A developing B cell unable to generate a productive rearrangement on any of the four light-chain loci will undergo a. self-renewal b. apoptosis c. allelic exclusion d. malignant transformation e. differentiation into a B-1 cell.

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6–26 a. b. c. d. e. f.

All of the following participate in signal transduction in developing B cells except terminal deoxynucleotidyl transferase (TdT) FLT3 CD19 Igα and Igβ Bruton‘s tyrosine kinase (Btk) CD45

6–27 Negative selection of developing B cells ensures that a. there is not an overabundance of circulating B cells that would compete with other important cell types in the circulation b. only antigen-activated B cells leave the bone marrow c. clonal expansion of B cells does not occur in the absence of infection d.

B-cell receptors that bind to normal constituents of the body do not emerge e.

B cells do not leave secondary lymphoid tissues.

6–28 a. b. c. d. e.

Receptor editing occurs _____. (Select all that apply.) in the bone marrow after encounter with foreign antigen in secondary lymphoid organs in mature B cells to establish self-tolerance of the B-cell repertoire to express an excess of IgM over IgD on the surface of mature B cells.

6–29 Which of the following statements about the IgD made by B cells of upper respiratory mucosa is not true? a.

These antibodies bind to airborne bacteria such as Haemophilus influenzae. b. λ light chains are used almost exclusively by these IgD antibodies. c.

Two-thirds of these IgD antibodies possess κ light chains. d.

These IgD antibodies recruit basophils and induce the secretion of antibacterial peptides.

6–30 Individuals who fail to express functional Bruton‘s tyrosine kinase exhibit all of the following characteristics except a.

B-cell development is blocked at the immature B-cell stage. b.

They are usually male because the Btk gene is on the X chromosome. c.

They suffer from an immune deficiency known as X-linked agammaglobulinemia (XLA). d.

Recurrent infections with extracellular bacteria are common. e.

They benefit from treatment with immunoglobulin infusions.

6–31 All of the following are associated with the development of Burkitt‘s lymphoma except a.

The expression of Myc protein is perturbed. b.

A chromosomal translocation involving a proto-oncogene and an immunoglobulin gene occurs. c.

Overproduction of the Bcl-2 protein prolongs the lifetime of B-lineage cells. d.

Cell division restraints on mutated B cells are lifted.

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e.

In addition to a chromosomal translocation event, mutations elsewhere in the genome are usually involved.

6–32 a. b. c. d. e.

Which of the following is a characteristic of B-2 cells?

They are sometimes referred to as CD5 B cells.

They comprise only 5% of the B-cell repertoire.

In adults, they are renewed by cell division in the peripheral circulation.

They are located primarily in secondary lymphoid organs.

They are not dependent on T helper cells for activation.

6–33 a. b. c. d.

Identify the mismatched pair of chemokine and the cells that secrete it.

CCL19: lymph-node dendritic cells CXCL13: follicular dendritic cells CCL21: stromal cells of secondary lymphoid tissues All of the above are correctly matched.

6–34 Plasma cells have all of the properties listed except a. they rapidly proliferate in secondary lymphoid follicles b. they secrete antibody c. they are terminally differentiated B cells d. they no longer express MHC class II molecules e. they cease expressing membrane-bound immunoglobulin f. they differentiate into plasma cells after migration from germinal centers to other sites in lymphoid tissue and bone marrow.

6–35 a. b. c. d. e. f. g.

All of the following events occur within germinal centers except centrocytes mature from centroblasts isotype switching centroblasts arise from activated B ells B cells are activated by CD4 helper T cells affinity maturation somatic hypermutation production of memory B cells.

6–36 a. b. c. d. e. f.

In which location would plasma cells not be present? bone marrow afferent lymphatic vessels medullary cords of lymph nodes lamina propria of gut-associated lymphoid tissues red pulp of spleen efferent lymphatic vessels.

6–37 Match the name of the B-cell tumor in Column A with its correct description in Column B. Column A Column B ___a. multiple myeloma 1. most cases caused by B-1 cells 88

___b. chronic lymphocytic leukemia (CLL)

___c. acute lymphoblastic leukemia (ALL) ___d. Burkitt‘s lymphoma ___e. pre-B-cell leukemia

6–38 a. b. c. d. e.

2. derived from lymphoid progenitor in bone marrow and rearrangement of immunoglobulin loci has not occurred 3. expresses VpreBλ5 4. derived from plasma cells in the bone marrow 5. associated with chromosomal translocations involving the proto-oncogene MYC

Which of the following is true of centrocytes? (Select all that apply.)

Somatic hypermutation has occurred.

They are large proliferating cells.

Isotype switching is complete.

They produce secreted forms of immunoglobulins.

They lack MHC class II molecules on the cell surface.

6–39 Immunological tolerance in the B-cell repertoire is called _______ tolerance when it develops in primary lymphoid organs, and _______ tolerance when it is induced outside the bone marrow. a. primary; secondary b. apoptotic; anergic c. stromal; follicular d. receptor-mediated; systemic e. central; peripheral.

6–40 What is the role of primary lymphoid follicles in eliminating B cells that have antigen receptors specific for soluble self antigen?

6–41 a. b. c. d. e.

A plasma cell is characterized by which of the following features? (Select all that apply.)

It differentiates in the medulla of lymph nodes and the bone marrow.

It dedicates 10–20% of total protein synthesis to antibody production.

Levels of MHC class II molecules are elevated.

It undergoes extensive proliferation in germinal centers.

It produces secreted immunoglobulin instead of the membrane-bound form.

6–42 A. Explain why immunological memory is important in acquired immunity.

B. Describe how immunoglobulin expressed during a primary immune response differs qualitatively and quantitatively from the immunoglobulin expressed during a secondary immune response.

6–43 When producing monoclonal antibodies, why is it important to use as a fusion partner a myeloma cell that is unable to produce its own immunoglobulin?

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a. to ensure that allelic exclusion of μ chain occurs normally b. to ensure that the antibodies are homogeneous and able to make strong bivalent attachments to multivalent antigens c. to ensure that the monoclonal antibodies are not autoreactive d. to provide a greater opportunity for making a successful rearrangement at the light-chain locus e. to ensure that antibodies are secreted and not membrane-bound.

6–44 a. b. c. d. e.

The proto-oncogene _______ is associated with the development of Burkitt‘s lymphoma.

BCL-2 Myc CD5 CD19 BTK.

6–45 Which of the following characterizes the B-1 cells that develop prenatally? a.

They lack N nucleotides. b.

They possess polyspecificity for bacterial polysaccharide antigens. c.

They arise early in embryonic development preceding the development of the majority subset of B cells. d.

They have little or no IgD on the cell surface. e.

All of the above.

6–46 Explain how B cells undergo the process of negative selection and indicate at which stage of development and at which location these events occur.

6–47 What is the fate of an immature B cell that encounters and has specificity for self antigen? a.

If further heavy-chain and light-chain gene rearrangements are possible, it undergoes apoptosis. b.

Somatic hypermutation. c.

Decrease in production of IgD. d.

Continued rearrangement of heavy-chain genes. e.

Continued rearrangement of light-chain genes.

6–48 Which of the following pertains to the fate of immature B cells that have specificity for univalent self antigens? (Select all that apply.) a.

The cells acquire a state of unresponsiveness called anergy. b.

IgD is retained in the cytosol. c.

IgD on the cell surface fails to activate the B cell when bound to self antigen. d.

The cells have a much longer life-span than mature B cells. e.

The cells die by apoptosis.

6–49 The circulatory route through a lymphoid tissue for both immature B cells and mature B cells that do not encounter specific antigen is:

90

a. bloodstream →HEV of lymphoid cortex → primary lymphoid follicle → efferent lymphatic vessel b. afferent lymphatic vessel → primary lymphoid follicle →HEV of lymphoid cortex →efferent lymphatic vessel c. afferent lymphatic vessel →medullary cords → primary lymphoid follicle →efferent lymphatic vessel d. primary lymphoid follicle →HEV of lymphoid cortex →afferent lymphatic vessel →efferent lymphatic vessel e. bloodstream →afferent lymphatic vessel → HEV of lymphoid cortex →efferent lymphatic vessel.

6–50 A. Give three properties that distinguish B-1 cells from B-2 cells.

B. Do you think that B-1 cells should be categorized as participants in innate immune responses or in acquired immune responses? Explain your rationale.

6–51 A. Identify properties that are shared by anergic B cells and plasma cells.

B. What key property is different?

6–52 Indicate which of the following statements concerning memory B cells are true (T) and which are false (F): ___ a. Memory B cells are derived from germinal center B cells as immune responses subside. ___ b. Memory B cells have long life spans. ___ c. Memory B cells possess high-affinity antigen receptors as a consequence of affinity maturation. ___ d. Memory B cells have more stringent requirements for activation than naive B cells do. ___ e. Memory B cells express only IgM and retain the capacity to switch to the most beneficial isotype during secondary responses.

6–53 Hinda Mundy, 26 years old, grew concerned when a lump appeared in her lower neck and she had pain in her chest and a dry cough. She also told her physician that she had experienced fatigue, night sweats, unintentional weight loss, pruritis (dry, itchy skin), and intermittent fevers over the past few months. Immunohistological staining of a biopsy of the enlarged lymph node revealed the presence of large multinucleated Reed–Sternberg cells.

Polymerase chain reaction (PCR) tests confirmed immunoglobulin gene rearrangements; however, B-cell antigen expression was absent. Hinda entered complete remission after treatment with four cycles of chemotherapy combined with radiotherapy. These symptoms and treatment are most consistent with a diagnosis of a.

Hodgkin‘s lymphoma b. multiple myeloma c. acute lymphoblastic leukemia (ALL) d.

Waldenström‘s magroglobulinemia e. chronic lymphocytic leukemia (CLL).

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6–54 Multiple myeloma involves the unregulated proliferation of an antibody-producing plasma cell (myeloma cell) independently of antigen stimulation or T-cell help. Myeloma cells populate multiple sites in the bone marrow, where they produce immense quantities of monoclonal immunoglobulin as well as suppressing normal marrow function. Myeloma cells also synthesize and secrete excessive amounts of free light chains (known as Bence-Jones protein), which, because of their low molecular weight (~25 kDa) are excreted as free light chains in the urine.

In a given patient the free light chains are both monoclonal and all are of either the κ or the λ type.

A. Explain both of these observations.

B. Why do you think patients with multiple myeloma are more susceptible than normal to pyogenic infections, such as pneumonia caused by Streptococcus pneumoniae or Haemophilus influenzae?

ANSWERS 6–1 (1) Repertoire assembly: Bone marrow expression of diverse B-cell receptors. (2) Negative selection: Modification, elimination or inactivation of autoreactive B cells. (3) Positive selection: Selection of a small subset of immature B cells to become mature B cells in secondary lymphoid organs. (4) Searching for infection: Patrolling for infectious material by recirculating continuously between lymph, blood and secondary lymphoid organ compartments. (5) Finding infection: B cells become activated by antigen in secondary lymphoid tissues and then undergo clonal expansion. (6) Attacking infection: B cells differentiate into plasma cells and memory cells in secondary lymphoid tissues.

6–2

c

6–3 A. Histogram. Your histogram should look like the one in the left panel of Figure A6.3, with axes labeled ‗cell number‘ (y) and ‗relative fluorescence intensity‘ (x) depicting total bone marrow cells stained with anti-CD19. Two peaks will be observed. One is the CD19-negative population and the other is the CD19-positive population. Gate the CD19-positive population (developing and mature B cells) for two-dimensional dot-plot analysis.

B. Two-dimensional dot plot. Your dot plot should look like the one in the right panel of Figure A6–46, with relative fluorescence intensity of anti-IgD versus anti-IgM. Three populations of B cells will be distinguished: (1) IgM-high, IgD-low, which represent immature B cells; (2) IgM-low, IgD-high, which represent mature B cells; and (3) IgM-very low (retained in the cell), IgD-high, which represent anergic B cells.

<<insert Figure A6–46>> Figure A6–46 A histogram analysis (left) and two-dimensional dot-plot analysis (right).

6–4

a 92

6–5

b

6–6

e

6–7

e →a →f →d →c →b

6–8

d →a →e →b →f →c

6–9 A. Bone marrow stromal cells provide the necessary environment for B-cell development by expressing secreted products and membrane-bound adhesion molecules. For example, VCAM-1 adhesion molecule binds to the integrin VLA-4 on early B-cell progenitors. Cytokines such as IL-7 have an important role in later stages of B-cell development, serving to stimulate the growth and cell division of late pro-B and pre-B cells.

B. If anti-IL-7 antibody were introduced into this environment, developing B cells would be arrested at the late pro-B-cell or pre-B-cell stage and would not be able to progress normally to the immature B-cell stage. Interestingly, in transgenic mice overexpressing IL-7, significant increases in pre-B cells are observed in the bone marrow and secondary lymphoid organs, whereas in IL-7 knockout mice (in which the gene locus encoding IL-7 is interrupted and no IL-7 is produced) early B-cell expansion is significantly impaired. These experiments in mice clearly demonstrate the importance of IL-7 in B-cell maturation.

6–10 A. Checkpoint 1 is marked by the formation of a complex of a μ heavy chain complexed with the surrogate light chain VpreBλ, Igα, and Igβ. Checkpoint 2 is when a complete B-cell receptor, comprising μ heavy chains, κ or λ light chains, and Igα and Igβ chains, is expressed on the B-cell surface.

B. At checkpoint 1, if the V(D)J rearrangement gives rise to a functional pre-B-cell receptor the late pro-B cell will be permitted to survive and undergo clonal proliferation. If V(D)J rearrangement produces a nonfunctional heavy chain and no pre-B-cell receptor is assembled, the pro-B cell undergoes apoptosis and dies. Similarly, at checkpoint 2, production of a functional light chain results in the assembly of a functional surface immunoglobulin and the survival and maturation of the B cell. Nonproduction of a light chain results eventually in apoptosis.

C. Checkpoint 1 delivers an important signal to the cell, verifying that a functional heavy chain has been made. This triggers the cessation of heavy-chain gene rearrangement followed by the inactivation of surrogate light-chain synthesis. Thus, only one heavy-chain locus ends up producing a product. As surrogate light chain becomes unavailable, μ accumulates and is retained in the endoplasmic reticulum, ready to bind to functional light chain when that is synthesized after successful light-chain gene rearrangement. Checkpoint 2 signals the cessation of light-chain rearrangement. This ensures that only one light-chain locus out of the possible four produces a functional product.

6–11 e

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6–12 a 6–13 c 6–14 c 6–15 b, e, f, g 6–16 N nucleotides would be added at the VJ joints of all rearranged light-chain genes during gene rearrangement (instead of about half), resulting in an increase in immunoglobulin diversity.

It is interesting to note that because TdT is not expressed until after birth, B-1 cells that are generated prenatally lack N nucleotides in the VD and DJ junctions of their rearranged heavychain genes as well as in the VJ junctions of all light-chain genes.

6–17 e 6–18 e 6–19 a 6–20 b, c, e 6–21 b, d, e 6–22 c 6–23 d 6–24 b, e 6–25 b 6–26 a 6–27 d 6–28 a, d 6–29 c 6–30 a 6–31 c 6–32 d

94

6–33 d 6–34 a 6–35 d 6–36 b 6–37 a—4; b—1; c—2; d—5; e—3 6–38 a, c 6–39 e 6–40 To survive, circulating B cells must enter primary follicles where survival signals are delivered by cells in the follicles, including follicular dendritic cells (which are the stromal cells of primary lymphoid follicles). Circulating B cells that fail to enter follicles in secondary lymphoid tissues will die in the peripheral circulation with a half-life of about 3 days. B cells with antigen receptors specific for soluble self antigen are generally rendered anergic in the bone marrow or the circulation. Anergic B cells that enter secondary lymphoid organs are held in the T-cell areas adjacent to primary follicles and are not permitted to penetrate the follicle. As a result, they do not receive the necessary stimulatory signal for survival. Instead, anergic B cells will undergo apoptosis in the T-cell zone. This is an efficient cleansing mechanism and serves to delete potentially autoreactive B cells from the circulation.

6–41 a, b, e 6–42 A. Memory enables faster, more efficient recall responses when antigen is encountered subsequently. This enables the body to get rid of a pathogen before it has time to cause disease.

B. Immunoglobulin produced during a primary immune response is mainly IgM, in low concentration (titer) and of low affinity for the antigen. Immunoglobulin expressed during a secondary immune response has undergone isotype switching and is often of the IgG isotype. It also has a higher titer and, through the process of somatic hypermutation, will have a higher affinity for its corresponding antigen.

6–43 b 6–44 b 6–45 e 6–46 Immature B cells that express receptors specific for common multivalent self antigens undergo apoptosis unless receptor editing can produce a receptor that does not have specificity for self antigen. This process of clonal deletion begins in the bone marrow, and apoptotic cells are phagocytosed by macrophages. Immature B cells bearing receptors for monovalent self 95

antigen are instead rendered anergic. These anergic B cells are produced in the bone marrow and when exported to the periphery survive for only 1–5 days. Immature B cells reactive to self antigen in the periphery cannot carry out receptor editing. They either undergo apoptosis or become anergic.

6–47 e 6–48 a, c 6–49 a 6–50 A. Unlike conventional B-2 cells, B-1 cells express the cell-surface protein CD5, possess few N nucleotides at VDJ junctions, and have a restricted range of antigen specificities. They produce IgM antibodies of low affinity and respond mainly to carbohydrate, rather than protein, epitopes. Individual B-1 cells are polyspecific for antigen; that is, their immunoglobulins bind several different antigens.

B. B-1 cells are probably best associated with innate immune responses because of their rapid response to antigen, their limited diversity, and their polyspecificity.

6–51 A. They both have limited life-spans, express decreased levels of IgM on the cell surface, and are nonresponsive to antigen.

B. Anergic B cells do not secrete antibody. Plasma cells, in contrast, secrete very large amounts of antibody.

6–52 a—T; b—T; c—T; d—F; e—F 6–53 Rationale: The correct answer is a. Two clues are crucial to this diagnosis: the first is the presence of Reed–Sternberg cells, a hallmark of Hodgkin‘s lymphoma; the second is the existence of rearranged immunoglobulin loci in these cells but their inability to express mature B-cell receptors. Multiple myeloma, Waldenström‘s magroglobulinemia, and CLL, in contrast, are B-cell tumors that do make mature B-cell receptors. ALL derives from a lymphoid progenitor, and the immunoglobulin loci are unrearranged.

6–54 A. In a normal response to infection, a diverse array of plasma cells will produce different light chains against many different antigens. In multiple myeloma, the tumor originates from a single plasma cell expressing heavy and light chains with specificity for a single antigen (clonotypic immunoglobulin). Because B cells express only κ or λ light chains, the tumor will also express only κ or λ, but not both. Therefore, Bence-Jones protein for a given patient will be of one type or another, but not both.

B. Although patients will have elevated immunoglobulin levels (usually IgG or IgA), most of the immunoglobulin will be produced by the myeloma cells and will be monospecific. Hence, normal concentrations of polyclonal immunoglobulin will be severely compromised. Pyogenic infections caused by encapsulated bacteria are cleared by humoral immune responses that use 96

antibody-mediated complement activation and antibody-enhanced phagocytosis. An insufficiency of pathogen-specific polyclonal immunoglobulins puts these patients at greater risk of these infections.

CHAPTER 7: THE DEVELOPMENT OF T LYMPHOCYTES 7–1 In which of the following ways does the developmental pathway of α:β T cells differ from that of B cells? (Select all that apply.) a.

Their antigen receptors are derived from gene rearrangement processes. b.

When the first chain of the antigen receptor is produced it combines with a surrogate chain. c.

Cells bearing self-reactive antigen receptors undergo apoptosis. d.

MHC molecules are required to facilitate progression through the developmental pathway. e.

T cells do not rearrange their antigen-receptor genes in the bone marrow.

7–2 Which of the following cell-surface glycoproteins is characteristic of stem cells, but stops being expressed when a cell has committed to the T-cell developmental pathway? a.

CD2 b.

CD3 c.

CD25 d.

CD34 e.

MHC class II. 7–3 Which of the following processes is not dependent on an interaction involving MHC class I or class II molecules? (Select all that apply.) a. positive selection of α:β T cells b. intracellular signaling by pre-T-cell receptors c. negative selection of αβ T cells d. peripheral activation of mature naive T cells e. positive selection of γ:δ T cells.

7–4 If a double-negative thymocyte has just completed a productive β-chain gene rearrangement, which of the following describes the immediate next step in the development of this thymocyte? a.

A pre-T-cell receptor is assembled as a superdimer. b.

Rearrangement of γ- and δ-chain genes commences. c.

Expression levels of RAG-1 and RAG-2 are elevated. d.

The linked δ-chain genes are eliminated. e.

This cell will inevitably differentiate into a committed γ:δ T cell.

7–5 All of the following cell-surface glycoproteins are expressed by double-negative thymocytes undergoing maturation in the thymus except _____. (Select all that apply.) a.

CD2 97

b. c. d. e. f.

CD5 CD127 (IL-7 receptor) CD34 CD1A CD4.

7–6 _____ is a T-cell-specific adhesion molecule expressed before the expression of a functional T-cell receptor while the thymocytes are still in their double-negative stage of development. a.

CD4 b.

CD8 c.

CD25 d.

CD2 e.

CD3.

7–7 a. b. c. d. e.

Which of the following is mismatched: double-negative CD3– thymocytes: cortico-medullary junction double-negative CD3– thymocytes: subcapsular zone double-positive CD3+ thymocytes: cortico-medullary junction cortical epithelial cells: subcapsular regions dendritic cells: cortico-medullary junction.

7–8 After interaction with thymic stromal cells, _____, a glycoprotein not expressed by the uncommitted progenitor cell is activated in developing thymocytes. (Select all that apply.) a.

CD2 b.

CD34 c.

CD5 d.

CD127 (IL-7 receptor) e.

CD44.

7–9 Which of the following statements about Notch 1 is correct? (Select all that apply.) a.

Notch 1 is expressed on thymic epithelial cells. b.

In the absence of Notch 1 expression, T cells can complete their differentiation. c.

Notch 1 is to T-cell development as Pax-5 is to B-cell development. d.

Notch 1 contains two distinct domains, one of which is proteolytically cleaved and becomes a transcription factor in the nucleus. e.

The extracellular domain of Notch 1 must interact with a ligand on thymic epithelium to initiate cleavage and separation of the Notch 1 extracellular and intracellular domains.

7–10 cells? a. b. c. d. e.

Which of the following is the first stage of T-cell receptor gene rearrangement in α:β T Vα→Dα Dα →Jα Vβ→ Dβ Dβ→Jβ Vα→Jα.

98

7–11 Which of the following is the first T-cell receptor complex containing the β chain to reach the cell surface during the development of T lymphocytes? a. γ:β:CD3 b. β:CD3 c. α:β:CD3 d. β:CD44 e. pTα:β:CD3.

7–12 The T-cell receptor β-chain locus can undergo successive gene rearrangements to rescue unproductive V(D)J rearrangements.

A. What aspects of gene segment rearrangement at the TCRβ locus make this possible?

B. Can the immunoglobulin heavy-chain locus, which is also composed of V, D, and J segments, undergo successive rearrangements? If not, give the reasons for the difference.

7–13 Indicate which of the following statements is true (T) or false (F). a. __ Immature T cells failing to successfully recombine a β-chain locus die by apoptosis. b. __ Apoptotic T cells are ingested by medullary epithelial cells. c. __ Allelic exclusion of the T-cell receptor α and β chains is effective; therefore, all T cells express only one T-cell receptor on the cell surface. d. __ T-cell receptor rearrangements have many features in common with immunoglobulin rearrangement, including the use of the RAG-1 and RAG-2 genes. e. __ The expression of the pre-T-cell receptor is required in order to halt β-, γ-, and δ-chain rearrangements.

7–14 Genetic deficiencies in all of the following would impair the development of a fully functional T-cell repertoire except a.

RAG-1 or RAG-2 b.

Notch1 c.

Pax-5 d.

IL-7 receptor (CD127) e.

TAP-1 or TAP-2.

7–15 A. What is Notch1?

B. Which cells express the ligand of Notch1?

C. How does the interaction between Notch1 and its ligand mediate T-cell development?

7–16 There are many parallels between the development of B cells and T cells. Identify the incorrectly matched counterpart in B cells (left) versus T cells (right). a.

VpreBλ5: pTα b.

Igα/Igβ:CD3 c.

Pax-5: FoxP3 d. multiple κ and λ light-chain gene rearrangements: multiple α-chain gene rearrangements.

99

7–17 _______ of thymocytes is necessary to produce a T-cell repertoire capable of interacting with self-MHC molecules. a. positive selection b. negative selection c. apoptosis d. receptor editing e. isotype switching.

7–18 Which of the following statements are true of a T cell that expresses two α chains (and thus two different T-cell receptors) as a result of ineffective allelic exclusion of the α chain during rearrangement? (Select all that apply.) a.

Engaging either of the T-cell receptors on MHC molecules of the thymic epithelium will result in positive selection. b.

One of the T-cell receptors will be functional while the other will most probably be nonfunctional. c.

If either T-cell receptor binds strongly to self-peptides presented by self-MHC molecules, the thymocyte will be negatively selected. d.

One of the T-cell receptors may be autoreactive but escape negative selection because its peptide antigen is present in tissues other than the thymus. e.

Subsequent gene rearrangements may give rise to a γ:δ T-cell receptor.

7–19 Once a thymocyte has productively rearranged a β-chain gene, which of these event(s) can occur subsequently? (Select all that apply.) a. β binds to pTα and is expressed on the cell surface with the CD3 complex and δ chain. b.

Rearrangement of β-, γ-, and δ-chain genes ceases as a result of the suppression of expression of RAG-1 and RAG-2. c.

The pre-T cell proliferates and produces a clone of cells all expressing an identical β chain. d.

Expression of CD34 and CD2 gives rise to double-positive thymocytes. e. α-, γ-, and δ-chain loci rearrange simultaneously.

7–20 Which of the following statements regarding positive selection is correct? a.

All subsets of developing T cells undergo positive selection before export to the peripheral circulation. b.

T-cell receptor editing is linked to the process of positive selection. c.

Positive selection results in the production of T cells bearing T-cell receptors that have the capacity to interact with all allotypes of MHC class I and class II molecules, and not just those of the individual. d.

Positive selection ensures that autoreactive T cells are rendered non-responsive. e.

If there is a genetic defect in AIRE, then T-cell development is arrested as positive selection commences.

7–21 a. b. c.

Thymocytes that are not positively selected undergo genetic reprogramming and differentiate into a different cell type are exported to the periphery, where they are phagocytosed by macrophages make up about 98% of developing thymocytes and die by apoptosis in the thymic cortex 100

d. e.

are eliminated because of their reactivity with self antigens try out different β chains to acquire reactivity with self-MHC molecules.

7–22 If the process of positive selection did not occur, then a. a condition resembling immune dysregulation, polyendocrinopathy, enteropathy, Xlinked syndrome (IPEX) would develop b. a condition resembling autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) would develop c. naive T cells would be unable to undergo differentiation in secondary lymphoid tissues d. malignant transformation would be more likely because of the accumulation of multiple mutations e. only a very small percentage of circulating T lymphocytes would be able to become activated.

7–23 a. b. c. d. e.

Immediately after positive selection the thymocyte reaches maturity and is exported to the periphery RAG proteins are degraded and are no longer synthesized receptor editing commences to eliminate reactivity against self antigens the developing thymocyte acquires a double-negative phenotype expression of pTα is repressed.

7–24 a. b. c. d. e.

Allelic exclusion occurs for all of the following except T-cell receptor α genes T-cell receptor β genes B-cell receptor heavy-chain genes B-cell receptor κ-chain genes B-cell receptor λ-chain genes.

7–25 A. Explain two ways in which the expression and processing of self antigens in thymic epithelium differs from the expression and processing of self antigens outside the thymus.

B. In what way is the thymic situation advantageous for the purposes of negative selection?

7–26 Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is caused by a defect in a. cathepsin L b. a transcription factor that regulates tissue-specific gene expression in the thymus c. the production of regulatory CD4 T cells d.

FoxP3 e.

T-cell receptor gene rearrangement.

7–27 Identify which of the following describes how antigen processing and presentation of self antigens by thymic epithelial cells differs from that of antigen-presenting cells in peripheral tissues. (Select all that apply.) a.

Thymic epithelium expresses MHC class I molecules but not MHC class II molecules. b.

Thymic epithelium uses cathepsin L for proteolytic degradation of self proteins.

101

c.

Thymic epithelium expresses MHC class II molecules but not MHC class I molecules. d.

Thymic epithelium uses the transcription factor AIRE to activate thymic expression of tissue-specific genes. e.

Thymic epithelium expresses transcription repressor protein FoxP3.

7–28 Match the immunodeficiency in Column A with its corresponding cause or consequence in Column B. Column A ___a. IL-7 receptor deficiency ___b. DiGeorge syndrome ___c. IPEX ___d. Bare lymphocyte syndrome ___e. APECED

Column B 1. absence of functional AIRE 2. absence of functional MHC class I or MHC class II molecules 3. absence of T cells because of signaling defects by thymic stromal ells 4. absence of functional FoxP3 5. absence of T cells due to absence of thymus

7–29 All of the following types of protein are processed and presented by macrophages in the thymus except _____ proteins. a. tissue-specific b. soluble proteins from extracellular fluids c. ubiquitous proteins d. proteins made by macrophages e. proteins derived from other cells that macrophages phagocytose.

7–30 a. b. c. d. e.

Healthy individuals have approximately ____ of CD4 T cells compared with CD8 T cells. one quarter the number half the number equal numbers twice the number four times the number

7–31 The surrogate light chain operating during pre-B-cell development is made up of VpreB:λ. Its expression with μ on the pre-B-cell surface is an important checkpoint in B-cell maturation. Name the T-cell analog of VpreB:λ5 and discuss how it is functionally similar.

7–32 Double-negative thymocytes initiate rearrangement at the _____ locus (loci) before all other T-cell receptor genes. a. γ and δ b. β c. α and β d. α, γ, and δ e. β, γ, and δ.

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7–33 a. b. c. d. e.

The function of negative selection of thymocytes in the thymus is to eliminate single-positive thymocytes double-positive thymocytes alloreactive thymocytes autoreactive thymocytes apoptotic thymocytes.

7–34 In T cells, allelic exclusion of the α-chain locus is relatively ineffective, resulting in the production of some T cells with two T-cell receptors of differing antigen specificity on their cell surface.

A. Will both these receptors have to pass positive selection for the cell to survive? Explain your answer.

B. Will both receptors have to pass negative selection for the cell to survive? Explain your answer.

C. Is there a potential problem in having T cells with dual specificity surviving these selection processes and being exported to the periphery?

7–35 Mature B cells undergo somatic hypermutation after activation, which, after affinity maturation, results in the production of antibody with a higher affinity for antigen than in the primary antibody response. Suggest some reasons why T cells have not evolved the same capacity.

7–36 MHC class II deficiency is inherited as an autosomal recessive trait and involves a defect in the coordination of transcription factors involved in regulating the expression of all MHC class II genes (HLA-DP, HLA-DQ, and HLA-DR).

A. What is the effect of MHC class II deficiency?

B. Explain why hypogammaglobulinemia is associated with this deficiency.

7–37 As we age, our thymus shrinks, or atrophies, by a process called involution, yet T-cell immunity is still functional in old age.

A. Explain how T-cell numbers in the periphery remain constant in the absence of continual replenishment from the thymus.

B. How does this differ from the maintenance of the B-cell repertoire?

7–38 A. What is the role of regulatory CD4 T cells (Treg)?

B. How can Treg be distinguished from other non-regulatory CD4 T cells?

7–39 Which of the following statements is correct? a.

In adults the mature T-cell repertoire is self-renewing and long-lived and does not require a thymus for the provision of new T cells. b.

T cells and B cells are both short-lived cells and require continual replenishment from primary lymphoid organs. c.

The human thymus is not fully functional until age 30, at which time it begins to shrink and atrophy.

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d.

In DiGeorge syndrome the bone marrow takes over the function of the thymus and produces mature peripheral T cells. e.

None of the above statements is correct.

7–40 a. b. c. d. e.

Individuals with a defective autoimmune regulator gene (AIRE) exhibit DiGeorge syndrome autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) severe combined immunodeficiency (SCID) MHC class I deficiency MHC class II deficiency.

7–41 Giulia McGettigan was born full term with a malformed jaw, cleft palate, a ventricular septal defect, and hypocalcemia. Within 48 hours of birth she developed muscle tetany, convulsions, tachypnea, and a systolic murmur. A chest X-ray showed an enlarged heart and the absence of a thymic shadow. Blood tests showed severely depleted levels of CD4 and CD8 T cells; B-cell numbers were low but within normal range. Parathyroid hormone was undetectable.

Fluorescence in situ hybridization of the buccal mucosa revealed a small deletion in the long arm of chromosome 22. Giulia failed to thrive and battled chronic diarrhea and opportunistic infections, including oral candidiasis and Pneumocystis jirovecii, the latter infection causing her death. Giulia most probably had which of the following immunodeficiency diseases? a.

AIDS b.

DiGeorge syndrome c. bare lymphocyte syndrome d. chronic granulomatous disease e. hyper IgM syndrome.

7–42 The human thymus begins to degenerate as early as one year after birth. This process is called ______ and is marked by the accumulation of ___ once occupied by thymocytes. a. thymectomy; dendritic cells b. involution; fat c. differentiation; γ:δ T cells d. negative selection; γ:δ T cells e. involution; thymic stroma.

7–43 A. What is immunological tolerance?

B. What is the general name for the antigens against which the immune system is normally tolerant?

ANSWERS 7–1

d, e

7–2

d

7–3

b, e 104

7–4

a

7–5

d, f

7–6

d

7–7

a

7–8

a, c, d

7–9

c, d, e

7–10 d 7–11 e 7–12 A. Successive gene rearrangement is possible at a TCRβ locus because there are two sets of D, J, and C gene segments downstream of the cluster of V gene segments: (Vβ)n…Dβ1…(Jβ1)n…Cβ1…Dβ2…(Jβ2)n…Cβ2. If a first rearrangement involving Dβ1 and a Jβ1 segment is unproductive, an upstream V gene segment can rearrange to the second D gene segment and an associated J segment. If this is unproductive, no more rearrangements can be made.

B. The answer is no. The heavy-chain locus has the following configuration: (V)nheptamer…23 spacer…nonamer…nonamer…12 spacer… heptamer-(D)n-heptamer…12 spacer…nonamer…nonamer… 23 spacer…heptamer (J)n…Cμ. After the first DJ rearrangement, the intervening D segments between the chosen D and J will be deleted. After VDJ rearrangement, the D segments that lie between the chosen V and DJ will be deleted. Therefore, no unrearranged D segments remain after these two rearrangement events. V and J cannot rearrange directly because the recombination signal sequences are not paired appropriately and do not follow the 23/12 rule; rather, they both contain 23-bp spacers in their recombination signal sequences. Successive gene rearrangement is thus not possible at a heavy-chain locus.

7–13 a—F; b—F; c—F; d—T; e—T 7–14 c 7–15 A. Notch1 is a membrane-bound receptor found on thymocytes that participates in the regulation of early T-cell development.

B. Its ligand (Notch ligand) is a membrane-bound protein on the surface of thymic epithelial cells.

C. After binding of the extracellular domain of Notch1 to the extracellular portion of Notch ligand, the intracellular domain of Notch1 is released by proteolysis and subsequently translocates to the nucleus. In the thymocyte nucleus, this domain forms a transcription factor 105

complex that displaces repressor proteins from genes involved in T-cell development and initiates transcription of these genes by recruiting transcription activator proteins.

7–16 c 7–17 a 7–18 a, b, c, d 7–19 a, b, c, e 7–20 b 7–21 c 7–22 e 7–23 b 7–24 a 7–25 A. (i) As well as expressing their own thymus-specific self antigens, medullary epithelial cells in the thymus produce a transcription factor called autoimmune regulator (AIRE), which causes several hundred genes normally expressed in other tissues to be expressed in these cells.

The proteins can then be processed to form self peptides that will be presented by MHC class I molecules. (ii) The thymic epithelium uses different proteases for self-protein degradation; cathepsin L is used for peptide production instead of cathepsin S, which is used by other cell types.

B. Generating a more comprehensive repertoire of self peptides in the thymus increases the types of potentially autoreactive T cell that are removed from the peripheral T-cell repertoire during negative selection.

7–26 b 7–27 b, d 7–28 a—3; b—5; c—4; d—2; e—1 7–29 a 7–30 d 7–31 The analog of VpreB:λ5 in developing T cells is the protein preTα(pTα), which combines with the T-cell receptor β chain, the first of the two T-cell receptor chains to be expressed, to form the pre-T-cell receptor. The β chain, like the immunoglobulin heavy chain, contains V, D, 106

and J segments. pTα also binds CD3 and δ components to this complex, and the assembly of the complete complex induces T-cell proliferation and the cessation of rearrangement at the TCRβ loci (leading to allelic exclusion). Formation of the analogous pre-B-cell receptor complex of VpreB:λ5 and heavy chain with Igα and Igβ in B cells similarly prevents further rearrangement of the heavy-chain loci.

7–32 e 7–33 d 7–34 A. Only one of the receptors will have to be positively selected for the cell to get the survival signals necessary for it to pass on to the next stage. Even if the other receptor does not react with self MHC this will have no effect on the cell.

B. In contrast, both receptors will have to pass the negative selection test for the T cell to survive, because if only one of them fails it, the cell will die.

C. Yes. Imagine this situation. The T cell with dual specificity could be activated appropriately during a genuine infection by a professional antigen-presenting cell plus foreign antigen 1 using T-cell receptor 1. But that same T cell, because it is now an activated effector T cell, would also be able to respond to a second peptide, which might be a self peptide, using Tcell receptor 2, without requiring the co-stimulatory signals that only professional antigenpresenting cells deliver. Thus it could cause a reaction against a self tissue, either directly, if it is a CD8 cytotoxic T cell, or indirectly, if it is a CD4 T cell, by activating potentially autoreactive B cells.

Furthermore, interferon-γ produced in the response against foreign antigen 1 could activate nonprofessional antigen-presenting cells nearby, inducing the expression of MHC class II with presentation of the self peptide above. Effector T cells with T-cell receptor 2 could make an autoimmune response against it.

7–35 Because T cells drive almost all immune responses, once they have been activated their receptors must continue to recognize the exact complex of foreign antigen and MHC molecule (which does not itself change) that activated them. Because of this requirement for dual recognition (MHC restriction), somatic hypermutation would be more likely than not to change the T-cell receptor to make it unable to recognize either the peptide or the MHC molecule, or the combination of both, thus rendering it unable to give help to B cells or to attack infected cells.

This would destroy both the primary immune response and the development of immunity. Even changes that simply increased the affinity of the T cell for its antigen would have no real advantage, because it would not make the immune response any stronger or improve immunological memory in the same way that affinity maturation of B cells does. Also, if somatic hypermutation changed the specificity of the T-cell receptor so that it now recognized a self peptide, this could result in an autoimmune reaction. These considerations do not apply to B cells, because they require T-cell help to produce antibody and will only receive it if their B-cell receptor still recognizes the original antigen.

7–36

107

A. MHC class II deficiency affects the development of CD4 T cells in the thymus. If the thymic epithelium lacks MHC class II, positive selection of CD4 T cells will not take place. CD8 T cells are not affected because MHC class I expression is unaffected by this defect.

B. To produce antibody, B cells require T-cell help in the form of cytokines produced by CD4 TH2 cells. Low immunoglobulin levels (hypogammaglobulinemia) in MHC class II deficiency are attributed to the inability of B cells to proliferate and differentiate into plasma cells in the absence of TH2 cytokines.

7–37 A. After thymic atrophy or thymectomy, T cells in the periphery self-renew by cell division and are long lived.

B. B cells are short lived and replenish from immature precursors derived from the bone marrow.

7–38 A. Treg suppress the proliferation of naive autoreactive CD4 T cells by secreting inhibitory cytokines. This inhibitory action requires that both the Treg and the other CD4 T cell are interacting with the same antigen-presenting cell.

B. Unlike non-regulatory CD4 T cells, Treg express CD25 on the cell surface and the FoxP3 transcriptional repressor protein.

7–39 a 7–40 b 7–41 Rationale: The correct answer is b. Depletion of T cells, but not of B cells, and the absence of a thymic shadow on the X-ray are critical clues. Development of both CD8 and CD4 T cells is affected in this patient because the thymus is the primary lymphoid organ required for T-cell development. Bare lymphocyte syndrome affects either CD8 (type I) or CD4 (type II), but not both. Although patients without a thymus succumb to infections also common in individuals with AIDS, this option can be ruled out because Giulia lacks CD8 T cells, a condition not seen in AIDS patients. Chronic granulomatous disease is a defect of neutrophil, not T-cell, function.

7–42 b 7–43 A. Immunological tolerance is the mechanism that operates to ensure that lymphocytes do not contain antigen receptors specific for host components. This is achieved through a process involving the removal of self-reactive T and B cells called negative selection. Both T and B cells are removed by apoptosis after the engagement of T-cell receptors and immunoglobulins, respectively, if the interaction with their ligands is especially strong. The consequence is the removal of autoreactive lymphocytes that could cause damage to healthy, uninfected cells and tissues.

B. Self antigens.

CHAPTER 8: T CELL-MEDIATED IMMUNITY 108

8–1 a. b. c. d. e.

Which of the following contributes to the activation of naive T cells? neutrophils B cells macrophages dendritic cells basophils

8–2 do.

Why are dendritic cells so important in adaptive immune responses? Explain what they

8–3 Explain what feature of B cells makes them useful as professional antigen-presenting cells in an immune response.

8–4 A. At which anatomical sites do naive T cells encounter antigen?

B. In which sites specifically would a pathogen or its antigens end up, and how would they be transported to these sites, if they (i) entered the body through a small wound in the skin, (ii) entered the body from the gut, or (iii) got into the bloodstream?

C. How do naive T cells arrive at these sites?

D. Do all T cells leave these locations after priming, and if so, how?

8–5 Unlike innate immune responses, which can begin within hours of the onset of an infection, adaptive immune responses involving T cells usually take several days. What accounts for this delay between the initiation of an infection and the engagement of an adaptive immune response?

8–6 a. b. c. e. f.

Macrophages exhibit all of the following characteristics except _____. they trap and degrade pathogens in secondary lymphoid organs they deliver co-stimulatory signals to naive T cells needed for T-cell priming they migrate from sites of infection to nearby secondary lymphoid organs they remove and degrade apoptotic lymphocytes from secondary lymphoid tissues they reside in both the cortex and medulla of lymph nodes.

8–7 A. Which selectins, mucin-like vascular addressins, and integrins have a role in the circulation of T cells between the blood and lymphoid tissues?

B. Describe in chronological order how T cells migrate across lymph node high endothelial venules (HEVs) from the blood by using these molecules.

8–8

Match the molecule in column A with its ligand in column B. Column A Column B ___a. B7 1. sialyl-LewisX carbohydrate of CD34 and GlyCAM-1 ___b. CD2 2. CCL21 and CCL19 ___c. L-selectin 3. LFA-3 ___d. ICAM-1 4. CD28 109

___e. CCR7 ___f. ICAM-3 8–9 A. B. C.

5. LFA-1 6. DC-SIGN

Identify three types of professional antigen-presenting cell.

How are they distributed in secondary lymphoid tissue?

Which kinds of antigen do they present efficiently to T cells?

8–10 A. Explain the functional differences between immature and mature dendritic cells.

B. Discuss why you think these functional changes should occur.

8–11 Why are Toll-like receptors (TLRs) important for adaptive immune responses?

8–12 Which of the following describes an activated dendritic cell upon arriving in a lymph node? a. located in follicles and medulla of the lymph node b. associated mainly with antigen uptake and processing c. bears highly elaborated finger-like processes called dendrites d. expresses low levels of MHC class II molecules e. carries out apoptosis of lymphocytes.

8–13 Dendritic cells take up, process or present antigen by all of the following routes except _____. a. receptor-mediated endocytosis of bacteria b. macropinocytosis of bacteria or viruses c. uptake of viruses using Toll-like receptor TLR9 d. cross-presentation from the MHC class II pathway to the MHC class I pathway e. cross-presentation from incoming infected dendritic cells to healthy resident dendritic cells in secondary lymphoid tissue f. delivery of viral peptides from cytosol to endoplasmic reticulum during viral infection.

8–14 Activated T cells express _____, which binds to B7 with 20 times higher affinity than CD28 and results in _____ of T-cell activity and proliferation. a. high-affinity IL-2 receptor; stimulation b.

CD40L; suppression c.

VLA-4; stimulation d.

CTLA4; suppression.

8–15 A. Which cell-surface glycoprotein distinguishes professional antigen-presenting cells from other cells and is involved in the co-stimulation of T cells?

B. What receptors can it bind on the T cell and what signal does it deliver in each case?

C. Explain the consequence of antigen recognition by T cells in the absence of this glycoprotein on the antigen-presenting cell.

110

8–16 Which of the following is associated with immature dendritic cells in the skin before their activation? a.

Toll-like receptors b.

CTLA4 c.

CCR7 d.

DC-SIGN e.

ICAM-3.

8–17 a. b. c. d. e.

All of the following are correctly matched except _____.

TH1: T-bet Treg: FoxP3 IL-12: dendritic cells TH17: RORγT TH2: Bcl6.

8–18 Match the term in column A with its counterpart in column B. Column A Column B ___a. immunoreceptor tyrosine-based 1. when phosphorylated, it translocates as a activation motifs (ITAMs) dimer to the nucleus and facilitates expression of target genes ___b. signal transducers and activators of 2. facilitates binding of effector T cells to transcription (STATs) activated endothelium ___c. immunological synapse 3. on cytoplasmic tails of CD3 proteins used for transmitting activation signals ___d. VLA-4 4. a receptor on macrophages that facilitates killing of intravesicular bacteria ___e. CD40 5. region of contact containing adhesion molecules and other cell-surface receptor– ligand pairs between a lymphocyte and its target cell 8–19 Naive lymphocytes homing to lymphoid tissue use _____ to bind to CD34 and GlyCAM1 on high endothelial venules. a.

L-selectin b.

CD2 (LFA-2) c.

ICAM-1 d.

CCL21 e.

CD28.

8–20 The co-stimulatory molecule _____ on professional antigen-presenting cells binds _____ on the surface of naive T cells. a.

DC-SIGN; ICAM-3 b.

B7; CD28 c.

ICAM-1; LFA-1 d.

MHC class II; T-cell receptor e.

MHC class II; CD4.

111

8–21 An adhesion molecule called _____ is expressed exclusively on activated dendritic cells and binds to _____ on naive T cells in the T-cell areas of secondary lymphoid tissue. a.

DC-SIGN; ICAM-3 b.

CD2; LFA-3 c.

MHC class II; T-cell receptor d.

L-selectin; GlyCAM-1 e.

ICAM-1; LFA-1.

8–22 The area of contact between membranes of a T cell and an antigen-presenting cell where a clustering of protein–protein interactions occur is called a(n) a. immunoreceptor tyrosine-based activation motif (ITAM) b. polarization c. cross-presentation center d. granuloma e. immunological synapse.

8–23 All of the following are included in the central supramolecular activation complex (cSMAC) except _____. a.

CD4 or CD8 b.

ICAM-1 c.

CD28 d.

T-cell receptor e.

PKC-θ.

8–24 a. b. c. d. e.

Talin is best described as a _____. protein tyrosine kinase transcriptional activator cytoskeletal protein pro-inflammatory cytokine cytokine receptor that associates with Janus kinases (JAKs).

8–25 a. b. c. d. e.

The primary effect of inositol trisphosphate (IP3) during T-cell activation is to _____. cause an increase in cytosolic calcium concentration activate phospholipase C-γ activate a MAP kinase cascade facilitate the differentiation of immature effector T cells align the microtubule-organizing center toward the antigen-presenting cell.

8–26 Which of the following is not a transcription factor, a component of a transcription factor, or an activator of transcription? a.

Fos b.

AP-1 c.

NFκB d.

NFAT e.

JAKs 112

f. g. h. i. j. k. l.

FoxP3 GATA-3 T-bet STATs Jun Bcl6 RORγT

8–27 The enzyme that generates diacylglycerol (DAG) and inositol trisphosphate (IP3) from phosphatidylinositol bisphosphate (PIP2) is _____. a. protein kinase C-θ (PKC-θ) b. calcineurin c. phospholipase C-γ (PLC-γ) d. protein tyrosine kinase ZAP-70 e. protein tyrosine kinase Lck 8–28 All of the following statements regarding interleukin-2 (IL-2) or its receptor are true except _____. a.

The low-affinity IL-2 receptor is a membrane-bound heterodimer composed of α and β chains. b.

IL-2 production increases approximately 100-fold if a co-stimulatory signal is delivered. c.

T-cell proliferation occurs upon binding of IL-2 to the high-affinity IL-2 receptor. d.

The high-affinity IL-2 receptor is assembled after T-cell activation. e.

Rapamycin is an immunosuppressive drug that inhibits signaling of IL-2 through the IL-2 receptor.

8–29 If a non-professional antigen-presenting cell that lacks co-stimulatory molecules presents peptide:MHC complexes to a T cell specific for that peptide, then _____. a. the T cell delivers a signal to the non-professional antigen-presenting cell to activate the expression of co-stimulatory molecules. b. the T cell begins to express the α chain of the IL-2 receptor. c. the T cell differentiates into a TH1 cell. d.

T-cell tolerance occurs as a result of anergy. e. the T cell is more heavily reliant on signals transmitted through CD4 or CD8 in order to become activated.

8–30 Which of the following statements regarding leprosy is false? a.

It is caused by the bacterium Mycobacterium leprae. b.

Disease progression is influenced depending on whether the immune response is polarized toward either a TH1 or TH2 response. c.

The tuberculoid form of leprosy is associated with localized inflammation and granuloma formation. d.

In lepromatous leprosy, the patient makes a TH2 response that clears the mycobacteria from the body. e.

The less severe form of leprosy presents with high levels of IL-2 and IFN-γ produced by responding T cells.

113

8–31 Which of the following statements is false regarding CD8 T cells? a.

CD8 T cells have only one effector function, which is cytotoxicity. b.

Compared with naive CD4 T cells, naive CD8 T cells have more stringent requirements for co-stimulatory activity. c.

Effector CD8 cells require co-stimulation to kill their target cells. d.

The most potent antigen-presenting cell for naive CD8 T cells is the dendritic cell.

8–32 a. b. c. d. cells e.

An important way in which effector T cells differ from naive T cells is that _____. the cell-surface level of LFA-1 is lower on effector T cells L-selectin is upregulated during differentiation of effector T cells cellular proliferation occurs after effector T cells leave the secondary lymphoid tissues the provision of co-stimulatory signals is not required to induce a response by effector T

8–33 a. b. c. d. e.

All of the following indicate correct intermolecular associations except _____.

Janus kinases (JAKs): serglycin L-selectin: GlyCAM-1 VLA-4: VCAM-1 JAKs: signal transducers and activators of transcription (STATs) CD40: CD40 ligand.

effector T cells do not recirculate between lymph, blood, and secondary lymphoid tissues.

8–34 During cytokine signaling, _____ translocate(s) to the nucleus and direct(s) the upregulation of gene expression. a. perforin b.

STATs c.

CD40 ligand d.

TGF-β e.

CXCL2.

8–35 Which of the following cytokines is secreted by both CD8 T cells and TH1 cells? (Select all that apply.) a.

IL-4 b.

IL-5 c.

IFN-γ d.

TNF-α e.

IL-13 f. lymphotoxin (LT).

8–36 a. b. c. d. e.

Which of the following cytokines is not secreted by TH2 cells? (Select all that apply.)

IFN-γ IL-4 IL-5 IL-10 TGF-β 114

f.

lymphotoxin (LT).

8–37 a. b. c. d. e.

In a person with lepromatous leprosy, the lesions would contain mRNA for _____. lymphotoxin (LT) IL-2 IL-5 IFN-γ granulysin.

8–38 The release of lytic granules from cytotoxic T cells is aimed specifically at infected target cells while preserving the integrity of neighboring, uninfected cells. This is best explained by the observation that _____. a. only target cells bearing appropriate peptide:MHC class I complexes are susceptible to necrosis b. redistribution of lytic granules in the T cell delivers them to confined areas on the target cell in contact with the T cell c. regulatory T cells deliver survival signals to uninfected neighboring cells that renders them resistant to cytotoxins d. the amount of cytotoxins in a given cytotoxic T cell is so limited that only the cell closest to the T cell will succumb to the effects of perforin and granzyme e. uninfected cells are highly resistant to the effects of cytotoxins.

8–39 a. b. c. d. e.

All of the following statements refer to regulatory T cells except ____. they produce anti-inflammatory cytokines they express elevated levels of CD25 they express FoxP3 they enhance the production of new effector T cells they suppress the function of existing T cells

8–40 Match the cell type in column A with its description in column B. Column A Column B ___a. mature dendritic cells 1. produce type-1 interferons during viral infections ___b. TH17 cells 2. facilitate antibody production and isotype switching ___c. plasmacytoid dendritic cells 3. express the T-bet transcription factor ___d. TH1 cells 4. possess elaborate finger-like processes that interact with T cells ___e. TFH cells 5. involved in neutrophil recruitment to infected tissues 8–41 a. b. c. d.

Identify the mismatched pair.

TFH cells: Bcl6 TH1: GATA3 TH1 cells: IFN-\gamma TH2: IL-4 115

e.

Treg: TGF-\beta

8–42 Which of the following is incorrect regarding sphingosine 1-phosphate (S1P) and its receptor? a.

It is a lipid that has chemotactic activity. b.

S1P gradients are established in lymph nodes with lowest concentrations in T-cell areas. c.

CD69 upregulates S1P receptor expression on the surface of naive T cells. d.

S1P is synthesized by all cells.

8–43 a. b. c. d. e.

Which of the following is produced by CD8 T cells?

IL-10 TGF-β IFN-γ IL-4 IL-17

8–44 a. b. c. d. e.

Which of the following is not produced by T follicular helper (TFH) cells?

CD4 IL-4 IFN-γ TNF-α IL-21

8–45 a. b. c. d. e.

Which of the following is not produced by TH17 cells?

ICOS (inducible T-cell co-stimulator) IL-17 CD4 IL-21 STAT3

8–46 Virus-infected cells attacked and killed by effector cytotoxic T cells are often surrounded by healthy tissue, which is spared from destruction.

A. Explain the mechanism that ensures that cytotoxic T cells kill only the virus-infected cells (the target cells).

B. What cytotoxins do cytotoxic T cells produce?

8–47 Which of the following is a feature of regulatory T cells (Treg)? (Select all that apply.) a.

Treg express CD8 and control effector cells by inducing apoptosis. b.

Treg express high levels of CD25 (IL-2 receptor α chain) and secrete pro-inflammatory cytokines such as IFN-γ. c.

Physical association between Treg and their target cells is mandatory for Treg function. d.

By interacting with dendritic cells in secondary lymphoid tissue, Treg prevent the interaction and activation of naive T cells. e.

Treg secrete TGF-β and suppress effector T-cell function.

116

8–48 What are the roles of the following molecules in the signal transduction pathway leading from the T-cell receptor: (i) the CD3 complex; (ii) protein tyrosine kinase Lck; (iii) CD45; (iv) ZAP-70; (v) the δ chain; (vi) inositol trisphosphate (IP3); (vii) calcineurin?

8–49 Describe two distinct mechanisms by which naive CD8 T cells can be activated.

8–50 a. b. c. d. e.

T cells failing to encounter specific antigen leave lymph nodes via the _________. germinal center bloodstream high endothelial venules afferent lymph efferent lymph.

8–51 Clonal expansion and differentiation of naive T cells to effector T cells depends on the activation of the transcription factor(s) _____ through a ZAP-70-mediated signal transduction pathway. (Select all that apply.) a.

AP-1 b.

IL-2 c.

NFκB d.

NFAT e.

Ras. 8–52 Fos, a component of the transcription factor AP-1, is activated during T-cell signaling by a process involving a GTP-binding protein called _____. a. inositol trisphosphate b.

Ras c. protein kinase C-θ d.

Lck e.

ZAP-70.

8–53 _____ is a second messenger in the T-cell signaling pathway leading to the activation of NFAT. a. diacylglycerol (DAG) b.

NFκB c. inositol trisphosphate d.

Fos e.

Ras. 8–54 In the absence of a co-receptor (CD4 or CD8 for T helper cells or cytotoxic T cells, respectively), T cells require _____ specific peptide:MHC complexes on the antigen-presenting cell compared with interactions involving a co-receptor. a. more b. fewer c. the same number of.

117

8–55 Which of the following is a protein tyrosine kinase involved in T-cell activation culminating in T-cell proliferation and differentiation? a.

AP-1 b.

ZAP-70 c.

NFκB d.

NFAT e. calcineurin.

8–56 cells. a. b. c. d. e.

Binding of _____ to _____ induces T-cell proliferation and differentiation of activated T CD4; MHC class II CD28; B7 LFA-1; ICAM-1 IL-2; the high-affinity IL-2 receptor IL-2; the low-affinity IL-2 receptor.

8–57 Expression of IFN-γ is induced in a CD4 TH1 cell under the direction of the transcription factor ______. a.

T-bet b.

FoxP3 c.

AP-1 d.

GATA-3 e.

NFAT. 8–58 a. b. c. d. e.

IL-4 is induced in a CD4 TH2 cell under the direction of the transcription factor _____.

T-bet FoxP3 AP-1 GATA-3 NFAT.

8–59 a. b. c. d. e.

Tuberculoid leprosy is characterized by a _____-type response in which patients _____.

TH2; usually survive TH2; eventually die TH1; usually survive TH1; eventually die Treg; eventually die.

8–60 Many cytokine receptors are associated with cytoplasmic protein kinases called _____, which become activated when the cytokine receptors bind to their respective cytokines. a.

ZAP-70 b.

STATs c.

Lck d.

ITAMS e.

JAKs.

118

8–61 Signal transducers and activators of transcription (STATs) are _____ that are phosphorylated by _____. a. transcription factors; JAKs b. protein kinases; other STATs c. cytokine receptors; JAKs d. cytokines; cytokine receptors e. transcription factors; Lck. 8–62 The process by which cytotoxic T cells kill their targets involves _____. (Select all that apply.) a. inducing the target cell to undergo necrosis b. inducing apoptosis (programmed cell death) in the cytotoxic T cell c.

DNA fragmentation in lengths of multiples of 200 base pairs in the target cell d. shedding of membrane-bound vesicles and shrinking of the target cell e. release of granzyme, perforin, and granulysin by the cytotoxic T cell.

8–63 The etiological agent responsible for leprosy is Mycobacterium leprae, which survives and replicates within the vesicular system of macrophages. Explain the difference between tuberculoid leprosy and lepromatous leprosy in the context of T-cell differentiation and effector function.

8–64 Which of the following characteristics permits activated CD8 T cells to destroy any cell type harboring viable and replicating pathogens such as viruses? a.

The pathogen is located in extracellular spaces. b.

CD8 T cells enable macrophages to kill intracellular pathogens. c.

Pathogen-derived peptides bind MHC class I molecules in endocytic vesicles found ubiquitously in most cell types. d.

MHC class II molecules are expressed ubiquitously by most nucleated cells. e.

MHC class I molecules are expressed ubiquitously by most nucleated cells.

8–65 Parents who were distantly related to each other brought their 11-week-old infant Kristen to the emergency room after she had a seizure accompanied by a persistently high fever and running nose. Her liver and spleen were palpable (hepatosplenomegaly). Laboratory tests revealed abnormally high levels of lymphocytes, and of the cytokines IFNγ, TNF-α, and IL-6.

Conversely, levels of hemoglobin and platelets were abnormally low. Bone marrow aspiration showed the presence of macrophages containing phagocytosed red blood cells and numerous large granular lymphocytes. Molecular analysis was carried out to confirm the physician‘s suspicion of a congenital immunodeficiency. A frameshift mutation in the perforin gene PRF1 was found on both chromosomes. Kristen was diagnosed with the rare, potentially lifethreatening disease known as familial hemophagocytic lymphohistiocytosis (FHL). Cytotoxic and aggressive immunosuppressive chemotherapy was administered followed by a matched unrelated hematopoietic stem cell transplant. Two years later Kristen is a healthy toddler. Which of the following would not be consistent with the etiology of FHL? a. impaired cytotoxic activity of CD8 T cells b. inhibition of transcriptional activators required for IL-2 synthesis c. inability to kill virus-infected cells 119

d. persistent activation of CD8 T cells causing secretion of large amounts of IFN-γ e.

IFN-γ activation of macrophages which in turn drives the production of IL-6, TNF-α, and other pro-inflammatory molecules.

ANSWERS 8–1

d

8–2 Dendritic cells engulf, process and then transport antigens to a nearby secondary lymphoid tissue, such as lymph nodes, where they then encounter antigen-specific T cells, which then differentiate into effector T cells. Effector T cells are then able to leave the secondary lymphoid tissue and travel to the site of infection and perform their particular effector response to eradicate the infection.

8–3 B cells are armed with cell-surface immunoglobulin that binds with a very high degree of specificity to intact pathogen moieties. Once bound, the immunoglobulin:native antigen complex is internalized by receptor-mediated endocytosis, and the pathogen is degraded within endocytic vesicles. Pathogen-derived peptides from this degraded material bind to MHC class II molecules within the endocytic vesicles and are subsequently presented on the cell surface to CD4 T cells.

8–4 A. Naive T cells encounter antigen, and start the primary immune response, in a secondary lymphoid tissue (for example lymph nodes, spleen, Peyer‘s patches, tonsils).

B. (i) Lymph nodes. The pathogen, and dendritic cells that have ingested the pathogen, are carried to the nearest lymph node in the afferent lymph. (ii) Gut-associated lymphoid tissues (GALT) such as Peyer‘s patches. Pathogens enter GALT via specialized cells (M cells) in the gut epithelium. (iii) Spleen. Pathogens circulating in the blood enter the spleen directly from the blood vessels that feed it.

C. Naive T cells are delivered to all secondary lymphoid organs from the blood.

They can also pass from one lymph node to another via a lymphatic.

D. After differentiation, CD8 effector cells and CD4 TH1, TH2, TH17, and regulatory T cells exit from the lymphoid tissue (via efferent lymph, which delivers them eventually into the blood) in search of infected tissues. Antigen-activated CD4 TFH cells remain in the lymphoid tissue where they provide help to antigen-specific B cells.

8–5 First, antigen needs to be transported to a nearby secondary lymphoid tissue, processed, and presented by antigen-presenting cells to naive CD8 or CD4 T cells for T-cell priming.

Second, the number of T cells specific for a given pathogen will be only around 1 in 10,000 to 1 in 100,000 (10–4 to 10–6) of the circulating T-cell repertoire; thus it can take some time before the relevant T cells circulating through the secondary lymphoid tissues reach the tissue containing the antigen that will activate them. Finally, it takes several days for an activated T cell to proliferate and differentiate into a large clone of fully functional effector T cells.

8–6

c

120

8–7 A. T cells (and B cells) express L-selectin, which binds to sulfated carbohydrates of mucin-like vascular addressins in HEVs. Three types of mucin-like vascular addressin are involved: GlyCAM-1 and CD34 expressed on lymph-node HEVs, and MAdCAM-1 expressed on mucosal endothelium.

B. Chemokines made by endothelium and bound to its extracellular matrix induce T cells to express LFA-1, an integrin. LFA-1 binds with high affinity to an intercellular adhesion molecule, ICAM-1, expressed on the endothelium. Finally, the T cell squeezes between the endothelium junctions, a process called diapedesis, and hence gains entry into the lymph node.

8–8

a 4, b 3, c 1, d 5, e 2, f 6

8–9 A. The three types of professional antigen-presenting cells are dendritic cells, macrophages, and B cells.

B. Dendritic cells are found in T-cell-rich areas of secondary lymphoid tissue; macrophages are distributed throughout the tissue; B cells are localized in lymphoid follicles.

C. Dendritic cells present all types of antigen but present viral antigens particularly efficiently. Macrophages present bacterial antigens well because they bear generalized receptors that can bind and internalize many different bacteria. B cells present peptides of soluble protein antigens, such as protein toxins, that they have internalized via their antigen receptors.

8–10 A. Immature dendritic cells are very effective in the process of antigen capture, uptake, and processing. They have specialized pathways of antigen processing for extracellular antigens that can present these antigens on both MHC class I and class II molecules. They do not express co-stimulatory molecules. Immature dendritic cells migrate to nearby lymphoid tissue after antigen ingestion. Upon arrival in the lymphoid tissue, they differentiate into mature dendritic cells. These mature dendritic cells are now non-phagocytic and express the costimulatory molecule B7.

B. Immature dendritic cells need to be phagocytic because they are located in sites susceptible to infection. Expression of B7 in non-lymphoid tissue is not required because this is not where T cells circulate and sample peptide:MHC complexes. Once outside the infected tissue, mature dendritic cells no longer need to phagocytose material. They do, however, need to express B7 molecules, because without co-stimulation, T cells do not receive the necessary activation signal for differentiation into effector T cells.

8–11 Stimulation of TLRs on dendritic cells by pathogen components induces the expression of chemokine receptor CCR7 on the dendritic cell. This enables dendritic cells laden with pathogen antigens to migrate from the site of infection to the nearest draining lymph node in response to chemokines produced by the lymph node. Stimulation of TLRs and other receptors on dendritic cells and macrophages also induces the expression of B7 co-stimulatory molecules, which makes these cells into professional antigen-presenting cells that are able to activate naive T cells.

8–12 c 121

8–13 a, b, d, e 8–14 d 8–15 A. Expression of B7, a co-stimulator molecule, distinguishes professional antigenpresenting cells from other cells.

B. When B7 binds to CD28, the B7 receptor expressed earliest on T cells, an activating signal is delivered and T cells undergo clonal expansion and differentiation. This interaction requires, of course, that the T-cell receptor and co-receptor are engaged specifically with a peptide:MHC molecule complex. The second B7 receptor, CTLA4, binds B7 with about 20-fold higher affinity than does CD28. An inhibitory signal is delivered to the T cell when B7 on the professional antigen-presenting cell binds to CTLA4. This mechanism serves to regulate T-cell proliferation and to suppress T-cell activation after an immune response.

C. If they engage antigen in the absence of B7 expression and, hence, co-stimulation, T cells will become irreversibly non-responsive (anergic) instead of activated. This is one mechanism by which T-cell tolerance may be achieved.

8–16 a 8–17 e 8–18 a—3, b—1, c—5, d—2, e—4 8–19 a 8–20 b 8–21 a 8–22 e 8–23 b 8–24 c 8–25 a 8–26 e 8–27 c 8–28 a 8–29 d 122

8–30 d 8–31 c 8–32 d 8–33 a 8–34 b 8–35 c, f 8–36 a, f 8–37 c 8–38 b 8–39 d 8–40 a—4, b—5, c—1, d—3, e—2 8–41 b 8–42 c 8–43 c 8–44 d 8–45 a 8–46 A. Cytotoxic T cells focus their killing machinery on target cells through a process called polarization. The cytoskeleton and the cytoplasmic vesicles containing lytic granules are oriented toward the area on the target cell where peptide:MHC class I complexes are engaging Tcell receptors. In the T cell, the microtubule-organizing center, Golgi apparatus, and lytic granules, which contain cytotoxins, align toward the target cells. The lytic granules then fuse with the cell membrane, releasing their contents into the small gap between the T cell and the target cell, resulting in the deposition of cytotoxins on the surface of the target cell. The cytotoxic T cell is not killed in this process and will continue to make cytotoxins for release onto other target cells, thereby killing numerous target cells in a localized area in succession.

B. The cytotoxins include perforin, granzymes, and granulysin, molecules that induce apoptosis (programmed cell death) of the target cell.

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8–47 c, d, e 8–48 (i) The CD3 subunits γ, δ, and ε associated with the antigen-binding T-cell receptor help transmit the signal from the T-cell receptor–peptide–MHC interaction at the cell surface into the interior of the cell through immunoreceptor tyrosine-based activation motifs (ITAMs) present on their cytoplasmic tails. These are phosphorylated by associated protein tyrosine kinases, such as Fyn, when the antigen receptor is activated, and in turn activate further molecules of the signaling pathway. (ii) Lck associates with the tails of the CD4 and CD8 co-receptors. When these participate in binding to peptide:MHC complexes, Lck is activated and phosphorylates ZAP-70, a cytoplasmic protein tyrosine kinase. (iii) CD45 is a cell-surface protein phosphatase that helps activate Lck and other kinases by removing inhibitory phosphate groups from their tails. (iv) When ZAP-70 is phosphorylated, it binds to the phosphorylated ITAMs of (v) the δ chain, which initiates the signal transduction cascade by activating phospholipase C-γ (PLC-γ) and guanine-exchange factors. (vi) IP3, which is produced by the action of PLC-γ on membrane inositol phospholipids, causes an increase in intracellular Ca2+ levels, which leads to the activation of the protein calcineurin. (vii) Calcineurin activates the transcription factor NFAT by removing an inhibitory phosphate group. Activated NFAT enters the nucleus, and together with the transcription factors NFκB and AP-1 will initiate the transcription of genes that lead to T-cell proliferation and differentiation.

8–49 (i) Virus-infected dendritic cells provide adequate co-stimulation (via B7) and can activate CD8 T cells directly without the involvement of CD4 T cells. CD8 T cells receive signal 1 (MHC:T-cell receptor) and signal 2 (B7:CD28), synthesize IL-2 and the high-affinity IL-2 receptor, and proliferate and differentiate into cytotoxic T cells. (ii) In some cases, virus-infected dendritic cells cannot on their own fully activate naive CD8 T cells but the CD8 T cell begins to express IL-2 receptors. With the provision of help from effector CD4 T cells in the form of IL-2 secretion, these CD8 T cells are fully activated. For this to occur, simultaneous interaction with both the naive CD8 T cell and the effector CD4 T cell must occur.

8–50 e 8–51 a, c, d 8–52 b 8–53 c 8–54 a 8–55 b 8–56 d

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8–57 a 8–58 d 8–59 c 8–60 e 8–61 a 8–62 c, d 8–63 Effective immune responses against intravesicular pathogens living in macrophages are mediated by TH1 cells rather than TH2 cells. In tuberculoid leprosy, the predominant effector T cells produced after infection are TH1 cells. These are effective in containing the infection, although they do not clear it completely. The disease is chronic and progresses slowly, and the damage to skin and peripheral nerves is caused mainly by the inflammatory responses initiated by activated macrophages. In lepromatous leprosy, in contrast, the predominant T cells produced are TH2 cells. Humoral immunity is induced, which results in the production of antibodies that are ineffective against intracellular bacteria. As a result, M. leprae replicates unchecked, causing severe tissue destruction and eventually the death of the patient.

Many factors influence the differentiation of CD4 T cells into TH1 or TH2 cells, including the cytokines produced by the antigen-presenting cells and leukocytes involved in the innate immune responses, the antigen concentration and peptide:MHC density, T-cell receptor affinity for peptide:MHC, and the cytokines produced by TH1 and TH2 cells themselves. If TH1 cells dominate an immune response, a cell-mediated immune response is favored. If TH2 cells dominate, a humoral immune response is favored.

8–64 e 8–65 b

CHAPTER 9: IMMUNITY MEDIATED BY B CELLS AND ANTIBODIES 9–1 a. b. c. d. e.

Which of the following is not a function of antibodies?

They neutralize pathogens by masking their surface.

They act as molecular adaptors that bridge together pathogen and phagocyte surfaces.

They exert toxic effects directly.

They act as opsonins that mediate phagocytosis.

They activate complement fixation.

9–2 To mount the most effective antibody response that results in the synthesis of highaffinity antibodies, which of the following must occur? (Select all that apply.)

125

a. b. c. d. e.

recognition of thymus-independent (TI) antigens isotype switching increased expression of TLR9 by B cells affinity maturation decreased expression of CD40 by B cells.

9–3 a. b. c. d. e.

Immunoreceptor tyrosine-based activation motifs (ITAMs) are located on _____. the cytoplasmic tails of IgM tyrosine kinases Blk, Fyn, and Lyn the cytoplasmic tails of Igα and Igβ breakdown products of C3b deposited on pathogen surfaces thymus-independent antigens.

9–4 a. b. c. d. e. f.

Identify the mismatched association.

Syk: Igβ cytoplasmic tails tyrosine kinase Lyn: CD81 B-cell co-receptor: CD21/CD19/CD81 C3b fragments: C3d and iC3b C3b/CR1: factor I hyper-IgM syndrome: CD40 ligand deficiency.

9–5 A primary focus of clonal expansion is best described as _____. a. the location in the B-cell zone where conjugate pairs of B and T cells undergo cellular proliferation, isotype switching, and somatic hypermutation b. the location in the medullary cords where conjugate pairs of B cells and T cells undergo cellular proliferation and IgM is secreted c. the dark zone of the germinal center where centroblasts divide and pack closely together d. the initial wave of B-cell proliferation induced by T-independent antigens.

9–6 A primary focus forms after a circulating naive B cell forms a conjugate pair with _____ in the _____ of a lymph node. a.

TH1 cell; B-cell zone b. cytotoxic T cell; T-cell zone c. follicular dendritic cell; germinal center d.

TFH; medullary cords e.

CD40 ligand; T-cell zone.

9–7 Which of the following do not bind to components found on the surface of an activated B cell? (Select all that apply.) a.

MHC class II b.

T-cell receptor c. antigen d.

CD40 e.

C3d f.

IL-4 g.

CD4 126

h. i.

LFA-1 CD40 ligand.

9–8 B cells migrating directly from a primary focus to the medullary cords in a lymph node after activation with a T-dependent antigen differentiate into plasma cells that secrete predominantly _____. a.

IgD b.

IgE c. sIgA d.

IgG e.

IgM. 9–9 Lymphoblasts upregulate a transcription factor called _____ when they terminally differentiate into plasma cells. a.

NFκB b.

Bcl-xL c.

B-lymphocyte induced maturation protein 1 (BLIMP-1) d.

CD40 e.

ICAM-1.

9–10 The primary focus of B-cell expansion forms in the _____, whereas a secondary focus of B-cell expansion creates the _____. a.

T-cell area; medullary cords b. medullary cords; T-cell area c.

T-cell area; B-cell area d. medullary cords; germinal center e. light zone; dark zone.

9–11 Proliferating centroblasts use the DNA-modifying enzyme activation-induced cytidine deaminase for ________. (Select all that apply.) a. cell proliferation b. somatic hypermutation c. apoptosis d. upregulation of CD40 e. isotype switching.

9–12 What is the fate of centrocytes in which somatic hypermutation has resulted in high-affinity receptors for antigen? (Select all that apply.) a.

They die by apoptosis. b.

They express Bcl-xL. c.

They process antigen and present it to TFH cells. d.

CD40 on the centrocyte engages with CD40 ligand on TFH cells. e.

They undergo phagocytosis by tingible body macrophages.

9–13 The main function of Bcl-xL is to _____ in the centrocyte. a. provide death signals 127

b. c. d. e.

induce somatic hypermutation upregulate the expression of activation-induced cytidine deaminase prevent apoptosis induce isotype switching.

9–14 a. b. c. d. e.

Engulfment of apoptotic centrocytes is facilitated by _____ in germinal centers. follicular dendritic cells immune-complex coated bodies (iccosomes) tingible body macrophages antigen-specific B cells antigen-specific TFH cells.

9–15 Match the term in column A with its description in column B. Column A Column B ___a. CCP modules 1. expressed in centrocytes and prevents apoptosis ___b. ICAM-1 2. associated with the development of swollen lymph nodes ___c. CR2 3. required to induce production of activationinduced cytidine deaminase ___d. BLIMP-1 4. expressed on B cells, follicular dendritic cells, and subcapsular sinus macrophages and binds C3d ___e. CD40 ligand 5. CR2-associated and needed for binding to C3d-tagged antigens ___f. Bcl-xL 6. controls lymphoblast differentiation by acting as a transcription factor ___g. germinal center reaction 7. binds to LFA-1 on T cells and fortifies cognate B–T interactions ___h. CD69 8. early indicator of B-cell activation and repressor of SIP receptor expression

9–16 Which of the following is an accurate description of how centroblasts differ from centrocytes? a.

Centroblasts cease their expression of cell-surface immunoglobulins. b.

Centroblasts divide more slowly than centrocytes. c.

Centroblasts express CD44 but centrocytes do not. d.

Centrocytes, but not centroblasts, initiate the process of isotype switching. e.

Centroblasts participate in affinity maturation.

9–17 If a centrocyte does not interact with antigen and engage CD40 shortly after its derivation, then _____. a. it recommences somatic hypermutation b. it undergoes apoptosis c. it moves back into the dark zone of the germinal center and switches its isotype 128

d.

its surface immunogloblulin levels decrease and proliferation recommences.

9–18 _____ is a mechanism that drives the preferential selection of immunoglobulins with the highest affinity for antigen. a.

Anergy b.

Isotype-switching c.

Affinity maturation d.

Antibody-dependent cell-mediated cytotoxicity e.

Transcytosis.

9–19 Match the cell type found in the lymph node in column A with its description in column B. Column A Column B ___a. centroblast 1. not bone marrow-derived hematopoietic cells ___b. tingible body macrophage 2. engulf apoptotic centrocytes ___c. naive B cell 3. undergo somatic hypermutation ___d. follicular dendritic cells (FDC) 4. make up the mantle zone ___e. memory B cell 5. differentiate under the influence of an IL-4secreting TFH cell 9–20 _____ in the switch regions positioned 5′ to each heavy-chain C gene is induced by _____. a.

Somatic hypermutation; TI antigens b.

Chromatin remodeling; B-cell co-receptor signaling c.

Recombination; survival signals received from follicular dendritic cells d.

Transcription; helper T-cell cytokines e.

Gene repression; apoptotic signals received from tingible body macrophages.

9–21 a. b. c. d.

Plasma cells and memory B cells differentiate most immediately from _____. centrocytes centroblasts B-1 cells IgG-secreting B cells.

9–22 Which of the following statements is true regarding the complement component C4B? a.

Deficiency of C4B is associated with systemic lupus erythematosus (SLE). b.

C4B has similar properties to those of C4A. c.

The thioester bond of C4B is preferentially acted upon by amino groups of macromolecules. d.

C4B is encoded in the class II region of the MHC. e.

The gene for C4B is duplicated or deleted in some individuals.

9–23 Which of the following is able to bind to C1q? (Select all that apply.) a. bacterial adhesins b. toxoids 129

c. d. e. f. g.

IgM C-reactive protein hemagglutinin lipopolysaccharide classical C3 convertase.

9–24 a. b. c. d. e.

IgM is particularly efficient at fixing complement because it _____. is a much larger antibody than the other isotypes has an extra CH domain is made first in an immune response and therefore has first access to C1q has five binding sites for C1q has easy access to extravascular areas.

9–25 C3 convertase of the classical pathway is _____, whereas C3 convertase of the alternative pathway is _____. a.

C1a; C3bBb b.

C4bC2a; C3bBb c.

C3bCR1; C3bBb d.

C4bC2a; C3bCR1 e.

C1a; C3bCR1.

9–26 Which of the following statements are true regarding C4? (Select all that apply.) a.

There are two forms of C4 encoded by separate genes residing in the class II region of the MHC. b.

Evolution of the different forms of C4 probably occurred as a result of gene duplication and diversification. c.

Because there are two forms of C4, C4 deficiency is the least common human immunodeficiency. d.

More than 30% of the human population lacks either C4A or C4B. e.

C4A and C4B have identical properties. f.

C4B deficiency is associated with increased susceptibility to systemic lupus erythematosus. g.

C4A and C4B are monomorphic.

9–27 Complexes of IgG bound to soluble multivalent antigens can activate the classical pathway of complement, resulting in the deposition of _____ on the complex, targeting it for endocytic uptake by cells bearing _____. a.

C4b; CR2 and Fc receptors b.

C3b; CR2 and Toll-like receptors c.

C5-9; CR1 and Fc receptors d.

C3b; CR1 and Fc receptors e.

C2a; CR2 and Toll-like receptors.

9–28 A distinguishing feature of FcγRIIB1 compared with FcγRIIA is _____. a. its ability to activate cells and induce endocytosis b. the existence of ITIMs in its cytoplasmic tails 130

c. d.

its inability to bind to IgG1 its expression on NK cells.

9–29 a. b. c. d.

For IgG2 to be effective at stimulating uptake of IgG2-coated bacteria, _____. an individual must express allotype H131 of FcγRIIA an individual must express allotype R131 of FcγRIIA the ITIMs of FcγRIIB2 must be non-functional complement must be fixed on the surface of the bacterium.

9–30 Describe the ways in which follicular dendritic cells (FDCs) are similar to subcapsular sinus macrophages.

9–31 Naive B cells search for specific antigen displayed by follicular dendritic cells in primary follicles. Naive T cells, however, search for specific antigen presented by ______. a. dendritic cells b. subcapsular sinus macrophages c. medullary sinus macrophages d. centrocytes e. tingible body macrophages.

9–32 a. b. c. d. e.

Which of the following is consistent with a recently antigen-activated mast cell? high levels of MHC class II molecules on the cell surface the absence of prepackaged granules the absence of IgE on the cell surface high concentrations of C3b on the cell surface the induction of antibody-dependent cell-mediated cytotoxicity.

9–33 Some types of B-cell tumor have been treated with rituximab, an anti-CD20 monoclonal antibody, which exerts its effect through a mechanism known as ______ involving the participation of NK cells. a. degranulation b. neutralization c. opsonization d. antibody-dependent cell-mediated cytoxicity e. receptor-mediated endocytosis.

9–34 Explain why expression of CD40 ligand by TFH cells is important in the boundary area of primary follicles in secondary lymphoid tissue as it relates to the targeted delivery of secreted cytokines to the B-cell surface.

9–35 Which of the following is a characteristic of follicular dendritic cells in the primary follicles of secondary lymphoid tissues? (Select all that apply.) a.

They are bone marrow derived hematopoietic cells. b.

They provide a stable depository of intact antigens able to bind to B-cell receptors. c.

They have a large surface area as a result of forming dendrites. d.

They internalize immune complexes through CR2 receptor cross-linking.

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e.

They produce cytokines that induce B cells to proliferate and become centroblasts.

9–36 A. What is the main effector function of IgM antibody?

B. Why is IgM efficient at (i) preventing blood-borne infections and (ii) fixing complement, but (iii) less efficient than other antibody classes in inducing phagocytosis of immune complexes?

9–37 A. Explain how the poly-Ig receptor transports dimeric IgA antibodies across cellular barriers, and specify the type of cell barrier involved.

B. What are the final locations of the transported material?

9–38 A. What are the similarities between the activation of mast cells and NK cells via FcεRI and FcγRIII, respectively? Be specific.

B. What are the differences? Again, be specific.

9–39 Describe the course of events that results in the swollen lymph nodes characteristic of many infections. Use the following terms in your answer: B lymphoblasts, centroblasts, centrocytes, follicular dendritic cells, germinal center, primary focus, primary follicle, somatic hypermutation, boundary region, and tingible body macrophages.

9–40 A. What is meant by the term ―passive transfer of immunity,‖ and how is it achieved? Give examples.

B. Give the isotype of the antibodies involved in (i) placental transfer and (ii) transfer into breast milk, and explain why these antibodies are important.

C. Do you think it is possible for a pregnant mother who has an autoimmune disease to transfer autoreactive antibodies to the developing fetus? Explain your answer.

9–41 Explain the origin of the secretory component and its significance after the release of dimeric IgA from the apical face of the gut epithelium.

9–42 How does IgE induce the forcible ejection of parasites and toxic substances from the respiratory and gastrointestinal tracts?

9–43 From an immunological viewpoint, why would it be inadvisable for a mother who has recently given birth to move with her newborn to a foreign country where there are endemic diseases not prevalent in her homeland?

9–44 a. b. c. d. e.

The B-cell co-receptor is composed of Igα; Igβ; CD19 Igα; Igβ; Lyn tyrosine kinase CR2 (CD21); CD19; CD81 CD14; CD19; CD81 CD40; MHC class II; CED19.

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9–45 C3d and iC3b are breakdown products of _____, which binds to _____ of the Bcell co-receptor. a.

C3a; CR2 b.

C3b; CR2 c.

C3c; CD81 d.

C3c; CD19 e.

C3b; CD19.

9–46 When bound to CR1, C3b is cleaved by _____, generating pathogen-associated B-cell co-receptor ligands. a. factor I b.

CR2 c.

C3d d.

CD19 e.

Lyn. 9–47 The Igα-associated tyrosine kinase _____ phosphorylates the cytoplasmic tail of CD19, which mediates signal transduction in activated B cells. a.

CD81 b.

Blk c.

Fyn d.

Lyn e.

Syk. 9–48 a. b. c. d. e.

A B cell’s sensitivity to antigen can be increased 1000–10,0000-fold by simultaneously ligating the B-cell receptor and co-receptor simultaneously ligating the B-cell receptor and Toll-like receptor ligating the B-cell co-receptor and phosphorylating Ig-α ITAMs increasing levels of Syk proteins in the vicinity of co-receptor ligation ligating cytokine receptors on the B-cell surface.

9–49 The process that drives an increase in antibody affinity for antigen is known as _____. a. apoptosis b. affinity maturation c. antibody-dependent cell-mediated cytotoxicity d. opsonization e. clonal expansion.

9–50 a. b. c. d.

FcRn has which of the following characteristics? (Select all that apply.)

It binds to monomeric IgA in acidified endocytic vesicles.

It transports IgG out of the blood into tissue across the endothelium.

It is similar in structure to an MHC class II molecule.

It protects IgA from degradation by plasma proteases.

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e.

Two molecules of FcRn are required to bind to each Fc region.

9–51 The process involving receptor-mediated transport of macromolecules from one side of a cell to the other is called a. phagocytosis b. exocytosis c. transcytosis d. signal transduction e. opsonization.

9–52 a. b. c. d. e.

Of the following, which group of children is the most vulnerable to infection? babies born at term babies born prematurely infants of 3–6 months infants receiving first vaccination babies receiving formula and not breast milk.

9–53 _____ occurs as a result of influenza virus binding to oligosaccharide components on erythrocyte surfaces causing them to clump together. a.

Passive immunization b.

Opsonization c.

Hemagglutination d.

Neutralization e.

Complement activation.

9–54 a. b. c. d. e.

Which of the following are correctly matched? (Select all that apply.) protein F; fibronectin neutralization; IgE breast milk; IgG influenza; hemagglutinin mucosal epithelium; IgA.

9–55 a. b. c. d. e.

Bacteria use _____ to attach to the surface of cells during colonization. hemagglutinins toxins breakdown products anti-inflammatory molecules adhesins.

9–56 Denatured toxin molecules called _____ are used to vaccinate individuals to stimulate the production of _____. a. toxoids; neutralizing IgG antibodies b. adhesins; neutralizing antibodies c. toxoids; passive immunity d. adhesins; complement proteins e. toxoids; C-reactive protein.

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9–57 Which of the following are characteristics of systemic lupus erythematosus?

(Select all that apply.) a.

It is an autoimmune disease. b.

It is associated with a deficiency of C4A. c.

Increased levels of immune complexes are detected in the blood. d.

CR1 receptor levels are decreased. e.

Immune complexes are deposited on the kidney glomeruli, which can lead to kidney complications.

9–58 The disadvantage of having a longer hinge region in IgG3 compared with the other IgG subclasses is a reduction in its serum half-life because of its susceptibility to _____. a. increased proteolysis by serum proteases b. clearance by erythrocytes via FcR binding c. immune complex formation and deposition in kidney glomeruli d. complement fixation and uptake by cells bearing receptor CR1 e. opsonization by neutrophils.

9–59 Which of the following antibodies activate the classical pathway of complement?

(Select all that apply.) a.

IgM b.

IgG1 c.

IgD d.

IgG3 e.

IgE. 9–60 The γ chain of the FcγRI receptor is closely related to the _____, which contains _____. a.

FcRn; MHC class I-like structure b. δ chain of the T-cell receptor complex; ITAM motifs c. γ chain of the FcγRIII receptor; ITIM motifs d. γ chain of the FcαRI receptor; ITIM motifs e. γ chain of the FcεRI receptor; ITIM motifs.

9–61 Of the Fc receptors for IgG, which one is similar to FcεRI in its ability to bind antibody in the absence of antigen but does not transduce an activating signal until antigen cross-linking occurs? a.

FcγRI b.

FcγRIIA c.

FcγRIIB2 d.

FcγRIIB1 e.

FcγRIII. 9–62 Which of the following individuals would be most susceptible to fulminant meningococcal disease or septic shock when infected with Neisseria meningitidis?

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a. homozygous for allotype H131 of IgG2 b. heterozygous for allotype H131 of IgG2 c. homozygous for allotype R131 of IgG2 d. heterozygous for allotype R131 of IgG2 e. all of the above would be equally susceptible to infections with Neisseria meningitidis.

9–63 Antibody-dependent cell-mediated cytotoxicity (ADCC) is carried out by _____ after cross-linking of IgG1 or IgG3 antibodies on _____ receptors. a.

NK cells; FcγRI b. neutrophils; FcγRI c.

NK cells; FcγRIII d. macrophages; FcγRIIB2 e. mast cells; FcεRI. 9–64 The symptoms of allergy and asthma are induced after cross-linking of IgE antibody on FcεRI receptors found on the surface of _____. (Select all that apply.) a. basophils b. eosinophils c. macrophages d. mast cells e. neutrophils.

9–65 The FcαRI receptor binds to _____:antigen complexes and facilitates the phagocytosis of opsonized antigens. a. dimeric IgA b.

IgM c.

IgE d.

IgG e. monomeric IgA.

ANSWERS 9–1

c

9–2

b, d

9–3

c

9–4

b

9–5

b

9–6

d

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9–7

a, d

9–8

e

9–9

c

9–10 d 9–11 b, e 9–12 b, c, d 9–13 d 9–14 c 9–15 a—5, b—7, c—4, d—6, e—3, f—1, g—2, h—8 9–16 a 9–17 b 9–18 c 9–19 a—3, b—2, c—4, d—1, e—5 9–20 d 9–21 a 9–22 e 9–23 c, d 9–24 d 9–25 b 9–26 b, d 9–27 d 9–28 b 9–29 a

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9–30 FDCs and subcapsular macrophages use their CR1 and CR2 receptors not for the purpose of receptor-mediated endocytosis, but rather to bind to antigens tagged with C3d or C3b and to hold them at the cell surface for extended periods of time. Tethering the antigen in this manner facilitates screening by naive B cells as they travel through secondary lymphoid tissues.

9–31 a 9–32 b 9–33 d 9–34 CD40 ligand on TFH cells binds to CD40 on B cells, signaling B cells to activate NFκB. NFκB is a transcription factor that upregulates ICAM-1 expression on B cells, which binds to LFA-1 on the TFH cell. As a result, cognate interactions between the B cell and TFH cell are strengthened, and a synapse at the point of contact facilitates the reorientation of the T-cell cytoskeleton and secretory apparatus of the Golgi. This ensures that T-cell cytokines are released onto a localized area of the B-cell surface.

9–35 b, c 9–36 A. The main effector function of IgM is complement activation; it can also neutralize pathogens and toxins.

B. (i) IgM is the first antibody to be produced by plasma cells during a primary antibody response and is secreted as a pentamer that circulates in the blood. Because of the large size of pentameric IgM, it does not penetrate effectively into infected tissues and is most effective against pathogens in the bloodstream. (ii) In the classical pathway of complement activation, at least two Fc regions are needed to bind C1, the first complement component in the pathway. A single pentameric molecule of IgM can thus initiate complement activation. In contrast, two IgG antibodies in close proximity to each other are needed to bind C1. (iii) Phagocytic cells carry both complement receptors and Fc receptors for IgG (FcγR) and IgA (FcαR), but there are no Fc receptors for IgM. Thus, immune complexes of IgM and antigen alone cannot be taken up by macrophages through Fc receptor-mediated endocytosis. An IgM:antigen:C3b complex can be phagocytosed by a macrophage after binding to complement receptors, but this is not as efficient as having both complement receptors and Fc receptors cooperating in inducing phagocytosis.

9–37 A. Dimeric IgA is made in mucosa-associated lymphoid tissue (MALT) and is transported across the barrier of the mucosal epithelium. First, dimeric IgA binds to the poly-Ig receptor on the basolateral surface of an epithelial cell, followed by uptake through receptormediated endocytosis into an endocytic vesicle. On reaching the opposite face of the cell, the apical surface, the vesicle fuses with the membrane. Here the poly-Ig receptor is cleaved proteolytically between the membrane-anchoring and the IgA-binding regions, thus releasing IgA into the mucous layer on the surface of the epithelium. Dimeric IgA remains attached to a small piece of the poly-Ig receptor, called the secretory component, which holds the IgA at the 138

epithelial surface through interactions with molecules in the mucus. The rest of the poly-Ig receptor is degraded and serves no further purpose.

B. Dimeric IgA is released into the lumen of the gastrointestinal, urogenital, and respiratory tracts, onto the surface of the eyes, into the nose and throat, and into breast milk (which is the route by which newborn babies receive protective maternal IgA).

9–38 A. Similarities: (1) Activation of both mast cells and NK cells occurs only when their Fc receptors are bound to antigen:antibody complexes. (2) When cross-linking occurs, both mast cells and NK cells release the contents of granules through exocytosis, which involves the fusion of vesicles containing preformed proteins with the cell membrane.

B. Differences: (1) Mast cells bind IgE, whereas NK cells bind IgG. (2) Exocytosis of granules from mast cells occurs at random around the cell membrane. Exocytosis of granules from NK cells is highly polarized, focusing only on the target cell to minimize damage to neighboring cells. (3) IgE binds to FcεRI with high affinity in the absence of antigen; mast cells become activated when antigen becomes available and binds to the receptor-bound IgE. NK cells bind IgG with low affinity, and bind IgG effectively only when it is already bound to multivalent antigen. (4) Activated mast cells release inflammatory mediators (histamine and serotonin) that affect other cells, for example endothelium, causing increased vascular permeability and vasodilation. Activated NK cells release apoptosis-inducing compounds (perforin and granzyme/fragmentin) that kill target cells directly. (5) Antibody-dependent cell-mediated cytotoxicity (ADCC) carried out by NK cells could be induced in newborn infants by maternal IgG acquired transplacentally. IgE cannot be transferred across the placenta, and so newborn babies cannot activate mast cells via maternal IgE. 9–39 B lymphoblasts that have bound specific antigen and encountered their cognate T cells in the boundary regions between primary follicles and the T-cell area of a lymph node are activated and start to proliferate, forming a primary focus. The B cells move from the primary foci into primary follicles, which are primarily B-cell areas, where they become centroblasts—large, metabolically active, dividing cells. As centroblasts accumulate and proliferate, the primary follicle enlarges and changes morphologically into a germinal center. Centroblasts undergo somatic hypermutation while dividing in the germinal center, producing centrocytes with mutated surface immunoglobulin. Only cells with mutated surface immunoglobulin that can take up antigen efficiently through receptor-mediated endocytosis and present it to helper T cells (TFH) will be selected to differentiate into plasma cells or memory cells. Antigen will be encountered at the surface of follicular dendritic cells as an immune complex. If B cells do not encounter their specific antigen, they will undergo apoptosis and then be ingested and cleared by tingible body macrophages. This process takes around 7 days after an infection begins, and the increase in cell numbers due to lymphocyte proliferation accounts for the swollen lymph nodes.

9–40 A. Passive transfer of immunity refers to the process of transferring preformed immunity from an immune subject to a nonimmune subject. This can be achieved by transferring whole serum (antiserum), purified antibody, monoclonal antibody, or intact effector or memory lymphocytes (adoptive transfer).

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B. (i) IgG antibodies transported transplacentally provide passive protection in the bloodstream and extracellular spaces of tissues until the baby can begin making its own antibodies, after which time maternal IgG levels decrease. (ii) IgA is transferred into the infant‘s gastrointestinal tract in breast milk and protects the gastrointestinal epithelia from colonization and invasion by ingested microorganisms.

C. It is possible for autoreactive antibodies to be transferred passively to a fetus via the placenta if the isotype is IgG. Any reaction will persist only for as long as the antibodies are present.

9–41 During transcytosis the poly-Ig receptor is cleaved by a protease, leaving a small piece of the original receptor, called the secretory component, still bound to the J chain via disulfide bonds. Once dimeric IgA is released at the apical face, the carbohydrate moieties of the secretory component anchor the antibody to mucins of the mucus, enabling the antibodies to bind subsequently to microbes in the mucus and inhibit the ability of microbes to bind to and invade the mucosal epithelium of the gut. Instead, the microbe is expelled from the body via mucosal secretions in the feces.

9–42 When IgE binds to antigen, leading to cross-linking of FcεRI on mast cells in connective and mucosal tissues, the mast cells rapidly release chemicals that activate smooth muscle to contract. Muscle activity leads to vomiting and diarrhea in the gastrointestinal tract, and sneezing and coughing in the respiratory tract, helping to expel the offending pathogen or toxic material.

9–43 Newborn infants are afforded passive immunity to the pathogens in their environment through IgG and dimeric IgA. IgG is transferred transplacentally, and dimeric IgA is acquired through breast milk. If an endemic infection develops in the newborn infant, the IgG antibodies in the infant‘s bloodstream may not have the appropriate specificity for the foreign antigens because the mother would not have encountered these antigens previously in their homeland, and therefore the newborn infant would not have acquired them passively during fetal development.

Furthermore, without maternal IgG, infants are particularly susceptible to infection for the first 6 months of their life, when their immune systems are unable to produce significant levels of IgG. In addition, infections that breach mucosal surfaces may be more likely to develop during this time because dimeric IgA against such a pathogen will not be formed in the breast milk until about a week after the mother has been exposed to the same pathogen.

9–44 c 9–45 b 9–46 a 9–47 d 9–48 a 9–49 b

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9–50 b, e 9–51 c 9–52 b 9–53 c 9–54 a, d, e 9–55 e 9–56 a 9–57 a, b, c, e 9–58 a 9–59 a, b, d 9–60 b 9–61 a 9–62 c 9–63 c 9–64 a, b, d 9–65 e

CHAPTER 10: PREVENTING INFECTION AT MUCOSAL SURFACES 10–1 Explain how secondary lymphoid tissues of the mucosa are (A) similar to and (B) different from secondary lymphoid tissues elsewhere in the body (the systemic immune system).

10–2 a. b. c. d. e.

Because the mucosae _____, this tissue is predisposed to infection. constitute thin, permeable barriers secrete a continuous layer of mucus generate enzymes and proteoglycans are associated with secretory IgA production are not connected to the lymphatics.

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10–3 a. b. c. d. e. f.

Identify which of the following is not a property of secreted mucins. contain glycosylated cysteine residues contain many repetitive sequence motifs constitute a viscous matrix stabilized by disulfide bonds bind to positively charged effector molecules encoded by seven genes in humans expressed in different mucosal tissues.

10–4 a. b. c. d. e.

Unlike secreted mucins, membrane mucins _____. do not trap and kill nearby microorganisms are not cross-linked by disulfide bonds do not possess repetitive domains are not glycosylated are encoded by only one gene in humans.

10–5 Commensal microorganisms in the gastrointestinal tract facilitate all of the following except _____. a. compete with pathogenic variants for nutrients and space b. convert toxic substances to benign derivatives c. degrade plant fibers to make their nutrients available d. secrete enzymes required for protein degradation e. synthesize essential metabolites f. induce the development of gut-associated lymphoid tissue.

10–6 The large population of microbes that contribute to the gut microbiota and have an important role in food processing are called _____. a. lamina propria b.

Peyer‘s patches c. microfold cells d. commensal microorganisms e. opportunists.

10–7 a. b. c. d.

All of the following are part of Waldeyer‘s ring except _____. appendix palatine tonsils lingual tonsils adenoids.

10–8 a. b. c. d. e. f.

Which of the following pairs is mismatched? (Select all that apply.) appendix: large intestine mesenteric lymph nodes: urogenital tract effector compartment: induction of adaptive immune responses adenoids: base of nose villi: small intestine Peyer‘s patches: afferent lymphatics.

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10–9 a. b. c. d. e.

At which anatomical location are Peyer‘s patches? stomach small intestine cecum large intestine Waldeyer‘s ring.

10–10 Laboratory animals reared in gnotobiotic conditions _____. a. are fed probiotics to disrupt the composition of their microflora b. lack normal gut microbiota c. develop appendicitis d. have larger secondary lymphoid tissues than do control animals e. have elevated levels of SIgA in the gut lumen.

10–11 _____ microorganisms are microbes that colonize mucosal surfaces but under normal circumstances do not cause disease. a.

Opportunistic b.

Commensal c.

Parasitic d.

Mesenteric e.

Pathogenic.

10–12 _____ makes up the membranes of connective tissue that help to anchor the gastrointestinal tract and hold it in place. a.

The mesentery b.

Peyer‘s patches c.

The lamina propria d.

The subepithelial dome e.

Waldeyer‘s ring.

10–13 Waldeyer‘s ring includes which of the following? (Select all that apply.) a.

Peyer‘s patches b. lingual tonsils c. adenoids d. mesenteric lymph nodes e. palatine tonsils.

10–14 Which of the following describe M cells in the gut? (Select all that apply.) a.

They derive their name from mucus cells. b.

They are located in the dome of a Peyer‘s patch. c.

They deliver antigens and pathogens from the lymphoid tissue to the luminal side of the gut mucosa by transcytosis. d.

They are protected from digestive enzymes by a thick glycocalyx and a layer of mucus. e.

They do not directly participate in antigen processing or presentation.

10–15 Mucosae of a healthy intestinal tract _____. (Select all that apply.)

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a. b. c. d. e.

have a large number of activated T and B cells harbor T cells bearing a very wide diversity of antigen specificities contain intraepithelial lymphocytes have large numbers of resident neutrophils are populated with both α:β and γ:δ effector T cells.

10–16 Which of the following migrates from non-mucosal tissue to draining lymph nodes to facilitate the induction of adaptive immune responses? a. dendritic cells b. macrophages c.

NK cells d. neutrophils e. commensal microorganisms.

10–17 Describe two ways in which dendritic cells capture antigen from the intestine for presentation to T lymphocytes.

10–18 Describe the route that a Peyer‘s patch-activated T lymphocyte follows, beginning with a naive T lymphocyte in a high endothelial venule and ending with an effector T lymphocyte in the lamina propria.

10–19 Identify three locations where secretory IgA can bind to antigens in mucosal tissue, and for each give the fate of the antigen upon binding to secretory IgA. 10–20 Identify ways in which intestinal macrophages are (A) similar to and (B) different from macrophages in non-mucosal tissues.

10–21 _____ assists in the differentiation of blood-derived monocytes into intestinal macrophages. a.

TGF-β b.

B7 c.

IL-12 d.

CXCL8 e.

CD14.

10–22 All of the following are expressed by intestinal epithelial cells except _____. a.

NOD receptors b.

FcαR c.

TLRs d.

MHC class II e.

NFκB. 10–23 Match the term in column A with its function in column B. Column A Column B ___a. M cells

1. mucus secretion 144

___b. brush border ___c. FoxP3-positive T cells ___d. Paneth cells ___e. goblet cells

2. antimicrobial products in crypts 3. portals for antigen transport 4. suppress immune responses to food antigen 5. microvilli on enterocytes for nutrient absorption

10–24 M cells, unlike dendritic cells, _____. a. do not secrete digestive enzymes into the lumen of the gut b. are not associated with Peyer‘s patches c. do not facilitate the transport of microbes from the gut lumen to the GALT d. do not process and present their antigen to naive T cells.

10–25 The significance of MAdCAM-1 on the endothelium of blood vessels is that it binds to _____. a. the integrin α4β7 on effector lymphocytes homing to mucosal tissues b.

B cells destined to become intraepithelial lymphocytes c. dendritic cells, and causes the upregulation of antigen processing and presentation d. the chemokine CCL25, which is secreted by gut epithelia e. intestinal helminths, and mediates killing of these parasites.

10–26 In addition to M cells, _____ can capture pathogens directly from the lumen of the gut. a. intraepithelial lymphocytes b. plasma cells c.

Paneth cells d. dendritic cells e. macrophages.

10–27 Which of the following is not associated with the process by which B cells produce secretory IgA in breast milk? a.

J chain b.

MAdCAM-1 c. αE:β7 d. poly-Ig receptor e.

CCR9 f. transcytosis.

10–28 Intracytoplasmic bacteria in enterocytes of the gastrointestinal tract are detected by _____. a. poly-Ig receptor b. major basic protein c.

MIC-A and MIC-B d.

NOD proteins e. receptors for phosphoantigens.

10–29 Secretory IgA binds to pathogens in all of the following locations except the _____. a. endosomes of an M cell 145

b. c. d. e.

lamina propria lumen of the gut blood Peyer‘s patches.

10–30 What is the function of the TNF-family cytokine APRIL made by epithelial cells of the colon? a. elevates rate of M-cell proliferation b. degrades IgA1 c. mediates isotype switching from IgM to IgA2 d. binds to J chain of dimeric IgA e. upregulates MAdCAM-1 production.

10–31 All of the following soluble factors enhance isotype switching from IgM to IgA in B cells except _____. a. retinoic acid b.

IL-9 c.

TGF-β d.

IL-4 e.

IL-10 f.

B-cell activating factor (BAFF) g.

APRIL. 10–32 Match the term in column A with the receptor involved in its transport across mucosal epithelia in column B. Responses may be used more than once or not at all.

Column A Column B ___a. IgA 1. FcRn ___b. IgE 2. poly-Ig receptor ___c. IgG 3. CD23 ___d. IgM 4. none of the above receptors are used by this immunoglobulin for transport

10–33 Which of the following is not an activity associated with secretory IgA and secretory IgM in mucosal secretions? a. toxin neutralization b. complement fixation c. binds to mucin through disulfide bonds d. restricts commensal microorganisms to gut lumen e. limits population size of commensal microorganisms.

10–34 IgA proteases produced by Streptococcus pneumoniae mediate all of the following effects except _____. a. separation of Fab and Fc regions b. interference with FcαR-mediated endocytosis c. enhanced adherence of Fab-coated bacteria to mucosal epithelium 146

d.

preferential cleavage of IgA2 over IgA1.

10–35 _____ compensates for the absence of secretory IgA in selective IgA deficiency because it can be secreted by mucosal tissues using the same receptor needed for transcytosis. a.

Monomeric IgA b.

IgD c.

IgE d.

IgG e.

IgM. 10–36 Match the term in column A with its correct match in column B. Column A Column B ___a. IL-13 1. stimulation of protective TH2-mediated immune responses ___b. αE:β7 integrin 2. stem-cell hyperplasia in intestinal crypts ___c. major basic protein 3. IgA protease activity ___d. helminthic infections 4. adhesion of CD8 T cells to gut epithelium ___e. Haemophilus influenzae 5. cytotoxic eosinophil product

10–37 The cytokine influencing eosinophil development and function during helminth infections is _____. a.

IL-3 b.

IL-9 c.

IL-19 d.

IL-10 e.

IL-5.

10–38 Why do children who have had their tonsils or adenoids removed respond less effectively to the oral polio vaccine than children who still have these tissues?

10–39 What property of the mucosal immune system enables breast milk to contain antibodies against microorganisms encountered in the gut or other mucosal tissues? Explain your answer.

10–40 Explain why individuals who have the condition selective IgA deficiency do not succumb to repeated infection through mucosal surfaces.

10–41 Describe four actions of effector CD4 TH2 cells that provide protection from infections by intestinal helminths and lead to expulsion of the parasites from the gastrointestinal tract.

10–42 _____ is the vascular addressin found on endothelial cells of intestinal mucosa that binds to integrins of gut-homing effector lymphocytes. a.

CCL25 b.

C-cadherin c.

NOD1 d.

MAdCAM-1 147

e.

CCR9.

10–43 The dominant immunoglobulin synthesized at mucosal surfaces is _____. a.

IgA b.

IgD c.

IgE d.

IgG e.

IgM. 10–44 If a B cell has been activated by antigen in the mucosa of the respiratory tract, then _____. (Select all that apply.) a. lactating mothers will provide antigen-specific natural IgA in breast milk b. secretory IgA will be synthesized in the lamina propria of all mucosae c. it does not enter the bloodstream but instead remains in the mucosa and differentiates into an effector B cell d. it will recirculate through all mucosal tissues, including respiratory and gastrointestinal mucosae e. monomeric IgA is secreted into the lamina propria.

10–45 In which of the following tissues is IgA2 produced at approximately twice the level of IgA1? a. spleen b. mammary glands c. large intestine d. gastric mucosa e. upper small intestine.

10–46 Secretory IgA is best described as _____. a. a non-inflammatory immunoglobulin that restricts the passage of antigens across mucosal surfaces b. a complement-activating immunoglobulin that causes destruction of invasive microflora through the membrane-attack complex c. an opsonizing antibody that facilitates uptake by M cells through Fc receptors d. an inflammatory immunoglobulin that stimulates the chemotaxis of neutrophils into mucosal surfaces e. a monomeric IgA that neutralizes antigen effectively at mucosal surfaces.

10–47 Secretory IgA and _____ can bind to the poly-Ig receptor and be transported into the lumen of the gut or across other mucosal surfaces. a.

IgG b.

IgE c.

IgD d. monomeric IgM e. pentameric IgM.

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10–48 Which of the following types of immune response are most beneficial in clearing helminth infections in the intestinal tract? (Select all that apply.) a. production of IgG2 antibodies b. production of IgE antibodies c. complement fixation d. eosinophil activation e. antibody-dependent cell-mediated cytotoxicity f.

IFN-γ-induced production of mucus g.

TH1-derived cytokines.

ANSWERS 10–1 A. Mucosal secondary lymphoid tissues have the same general microanatomy and organization as those of secondary lymphoid tissues found at other anatomical locations, with distinct compartmentalization of B-cell and T-cell zones. Both mucosal and systemic secondary lymphoid tissues function as sites where naive lymphocytes are activated by antigen and adaptive immune responses are initiated.

B. In the systemic immune system, adaptive immune responses are activated in secondary lymphoid tissues that are quite distinct from and often distant from the site of infection. In contrast, in the mucosal immune system, the adaptive immune response is initiated at secondary lymphoid tissues at the site of infection.

10–2 a 10–3 a 10–4 b 10–5 d 10–6 d 10–7 a 10–8 b, c, f 10–9 b 10–10 b 10–11 b 10–12 a 10–13 b, c, e 149

10–14 b, e 10–15 a, c, e 10–16 a 10–17 (i) M-cell-dependent capture relies on the transcytosis of microorganisms across the gut epithelium into pockets containing dendritic cells. The dendritic cells then process and present antigens to T lymphocytes in either the T-cell areas of the Peyer‘s patch or the mesenteric lymph node. (ii) M-cell independent capture occurs in the lamina propria as a result of dendritic cells extending cytoplasmic processes between intracellular enterocyte junctions. Antigen is taken up by these processes and processed, and the dendritic cell then presents antigens to T cells in gut-associated lymphoid tissue or mesenteric lymph nodes.

10–18 The chemokines CCL21 and CCL19 synthesized in Peyer‘s patches bind to CCR7 on naive T cells and recruit them into the lymphoid tissue across a high endothelial venule. The T cells bearing appropriate antigen-specific receptors are stimulated by dendritic cells and undergo proliferation and differentiation within the Peyer‘s patches. Activated T cells then leave the Peyer‘s patch and enter the lymph, and travel through mesenteric lymph nodes before arriving via the lymph at the thoracic duct and then enter the bloodstream. From the bloodstream, activated T cells home only to mucosa-associated lymphoid tissue because during their differentiation they cease to express CCR7 and L-selectin, which are otherwise required to enter systemic lymphoid tissues. Instead, they now express α4:β7, which binds to MAdCAM-1 on gutassociated endothelia and CCR9, the chemokine receptor for CCL25, which is synthesized in the lamina propria. They cross the vascular endothelium into the lamina propria (some subsequently entering the epithelium), where they secrete cytokines and mediate killing.

10–19 (i) (ii) (iii)

lamina propria; transcytosis to mucosal layer endosomal compartment; neutralization of endocytosed antigen mucosal layer; neutralization of antigen at mucosal surfaces.

10–20 A. Intestinal macrophages recognize, phagocytose, and kill microorganisms that have breached the epithelial surface, and eliminate cells dying by apoptosis.

B. Intestinal macrophages, unlike non-mucosal macrophages, do not create or sustain a state of inflammation. They do not produce inflammatory cytokines, induce a respiratory burst, express B7 co-stimulators, or secrete cytokines needed for T-cell activation. Intestinal macrophages also have a shorter life-span than systemic macrophages.

10–21 a 10–22 b 150

10–23 a—3; b—5; c—4; d—2; e—1 10–24 d 10–25 a 10–26 d 10–27 c 10–28 d 10–29 d 10–30 c 10–31 b 10–32 a—2; b—3; c—1; d—2 10–33 b 10–34 d 10–35 e 10–36 a—2; b—4; c—5; d—1; e—3 10–37 e 10–38 Tonsils and adenoids are located in the oral cavity and are composed of extensive secondary lymphoid tissue making up Waldeyer‘s ring. They are responsible for the production of secretory IgA specific for infectious material entering the gut and airways. The oral polio vaccine elicits the most effect protective immunity through the production of secretory IgA, including the secondary lymphoid tissues of Waldeyer‘s ring.

10–39 In nursing mothers, B cells activated in the gut or other mucosal tissue can home to the lactating mammary gland and secrete their dimeric IgA antibodies into the breast milk. This is due to a general property of the mucosal immune system in that lymphocytes activated in a mucosal tissue carry the integrin α4:β7 that binds to the vascular addressin MAdCAM-1, which is expressed on the walls of blood vessels serving different types of mucosal tissue. Thus lymphocytes activated in one mucosal tissue can recirculate to another one as well as to the tissue in which they were activated.

151

10–40 Individuals with selective IgA deficiency possess compensatory mechanisms for combating infections at mucosal surfaces, most notably by making increased levels of IgM, which can be secreted as a pentamer across mucosal epithelium.

10–41 (i) IL-13 secreted by TH2 cells enhances epithelial cell turnover and the sloughing of parasitized epithelial cells. IL-13 also stimulates goblet cells to produce mucus, which then interferes with adherence of helminths to mucosal surfaces (see Figure 10.27). (ii) IL-5 secreted by TH2 cells attracts eosinophils and activates them to secrete major basic protein, which is cytotoxic to helminths. Eosinophils can also attack parasites directly when their Fc receptors are cross-linked by parasites that have become coated with antibody, especially IgE. In this situation the eosinophil pours out its toxic granule contents directly onto the parasite surface. (iii) CD4 TFH cells engage antigen-specific B cells and influence the switch to the IgE isotype. The anti-parasite IgE antibodies produced then bind to high-affinity Fcε receptors on mast cells. Cross-linking of the bound IgE by parasite antigens activates the mast cells to release inflammatory mediators such as histamine. These mediators induce muscles spasms and watery feces in the gut that help to eliminate the parasite from the body. (iv) IL-3 and IL-9 secreted by TH2 cells attract mast cells to the site of parasite infection.

10–42 d 10–43 a 10–44 a, b, d 10–45 c 10–46 a 10–47 e 10–48 b, d, e

CHAPTER 11: IMMUNOLOGICAL MEMORY AND VACCINATION 11–1 Give four reasons why secondary immune responses are faster and more effective than primary immune responses.

11–2 Explain (A) why only memory B cells, and not naive B cells, participate in secondary immune responses to particular pathogens, and (B) why this is advantageous to the host.

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11–3 Explain briefly how immunological memory operates in (A) the short term and (B) the long term.

11–4 Which of the following statements is incorrect regarding memory B cells? a.

Memory B cells are maintained for life. b.

In secondary responses, the number of pathogen-specific B cells is about 10–100-fold that seen in primary responses. c.

The sensitivity of memory B cells is improved compared with naive B bells because affinity maturation has occurred. d.

Memory B cells express lower levels of MHC class II and B7 than do naive B cells. e.

Memory B cells differentiate into plasma cells more rapidly than do naive B cells.

11–5 a. b. c. d. e. f.

Which of the following characterizes immunological memory? (Select all that apply.)

The host retains the capacity to mount a secondary immune response.

The host retains the ability to respond to pathogen many years after primary exposure.

Naive T cells are activated more quickly when exposed to pathogen.

Memory B cells produce higher-affinity antibody than naive B cells.

Memory T cells undergo somatic hypermutation.

Memory T cells express CD45RA.

11–6 What would be the outcome if a naive B cell were to bind to pathogen coated with specific antibody made by an effector B cell in a primary immune response using FcγRIIB1, and simultaneously bind to the same pathogen using its B-cell receptor? a. a positive signal leading to the production of low-affinity IgM antibodies b. a positive signal leading to isotype switching and the production of IgG, IgA, or IgE antibodies c. a positive signal leading to somatic hypermutation and the production of high-affinity IgM antibodies d. a negative signal leading to inhibition of the production of low-affinity IgM antibodies e. a negative signal leading to apoptosis.

11–7 Which of the following explains why the first baby born to a RhD– mother and a RhD+ father does not develop hemolytic disease of the newborn? a.

Fetal erythrocytes do not cross the placenta and therefore do not stimulate an antibody response. b.

The antibodies made by the RhD– mother during the first pregnancy are predominantly IgM and have low affinity for the Rhesus antigen. c.

Maternal macrophages in the placenta bind to anti-Rhesus antibodies and prevent their transfer to the fetus. d.

Hemolytic disease of the newborn is a T-cell-mediated disease and maternal T cells do not cross the placenta during pregnancy. e.

The Rhesus antigen is not immunogenic and does not stimulate an antibody response.

11–8 By which process are fetal erythrocytes destroyed in hemolytic anemia of the newborn? a. lysis of erythrocytes by cytotoxic T cells b. lysis of erythrocytes by complement activation 153

c. d. e.

clearance of antibody-coated erythrocytes by macrophages in the fetal spleen lysis of erythrocytes by NK cells via antibody-dependent cell-mediated cytotoxicity cytotoxicity caused by major basic protein released from eosinophils.

11–9 When a naive B cell binds to an IgG:antigen complex on its cell surface using FcγRIIB1, while simultaneously binding to the same antigen using membrane-bound IgM, _____. a. the IgG:antigen complex is endocytosed b. the B cell becomes anergic c. the B cell will switch isotype to IgG d. the B cell undergoes affinity maturation e. the B cell secretes large amounts of IgM before becoming a memory B cell.

11–10 ―Original antigenic sin‖ is best described as a phenomenon in which _____. a. a highly mutable virus gradually escapes from immunological memory and interferes with compensatory immune responses. b. latent viruses periodically activate effector T cells specific for the original antigen recognized in the primary immune response. c. the persistence of antigen is necessary to sustain maintenance of immunological memory. d. memory T cells no longer express the same profile of adhesion molecules and cytokine receptors compared with the original profile of the naive precursor T cell.

11–11 Imagine a situation in which an individual who has a latent cytomegalovirus (CMV) infection receives a hematopoietic stem-cell transplant. Which of the following is likely to occur? a.

The memory T cells present at the time of transplantation would inhibit activation of newly generated naive T cells. b.

The CMV viral load would increase exponentially, overcoming the host and causing death. c.

The transplant-derived naive T cells would be activated and give rise to memory T cells that would persist and control viral load. d.

There would be a rapid increase in CMV viral load and expansion of T cells bearing CD45RA. 11–12 Which of the following are not a component of immunological memory? a. effector B cells b. memory T cells c. memory B cells d. long-lived plasma cells.

11–13 Identify three reasons why memory B cells respond more forcefully and effectively during secondary immune responses than naive B cells during primary immune responses.

11–14 The efficiency and specificity of adaptive immune defenses and immunological memory improve each time a particular pathogen is encountered because _____. a. of protective immunity b. effector memory T cells outnumber central memory T cells 154

c. the half-life of antibodies made in secondary and tertiary immune responses exceeds that of antibodies made in primary immune responses. d. of affinity maturation.

11–15 Unlike naive lymphocytes, memory lymphocytes _____. a. do not recirculate between the blood and secondary lymphoid organs b. do not require the receipt of survival signals through their antigen receptors in order to persist c. are immortal and continue to divide throughout the lifetime of an individual d. secrete antibody continuously, although at a much lower rate than plasma cells e. do not express CD27.

11–16 All of the following are ways in which plasma cells differ from memory cells except _____. a. plasma cells lack surface immunoglobulin b. cellular morphology c. plasma cells are CD27-negative d. plasma cells have undergone isotype switching e. plasma cells are short-lived.

11–17 During a secondary immune response, high-affinity IgG antibodies are produced. Which of the following best explains why low-affinity IgM antibodies are not made? a.

Naive pathogen-specific B cells are suppressed by negative signaling through FcγRIIB1. b.

Naive pathogen-specific B cells isotype switch and hypermutate much more quickly during secondary immune responses. c.

Memory B cells outnumber naive B cells. d.

Low-affinity IgM antibodies are made only when antigen concentration is exceedingly high.

11–18 Which of the following molecules is not elevated on the surface of memory B cells compared with naive B cells? a.

MHC class II molecules b.

CD45RA c. antigen receptor d.

CD27 e. co-stimulatory molecules.

11–19 Explain why memory B cells are more efficient at responding to pathogens than are naive B cells.

11–20 _____ accounts for the production of different isoforms of the CD45 protein observed in naive, effector, and memory T cells. a.

Isotype switching b.

Affinity maturation c.

Alternative splicing d.

Somatic hypermutation 155

e.

Recirculation to peripheral tissues.

11–21 Memory B cells differ from memory T cells in the following ways. (Select all that apply.) a.

They suppress naive antigen-specific lymphocytes during secondary immune responses. b.

They recirculate only through secondary lymphoid organs. c.

They secrete their antigen receptors throughout their life-span. d.

They generate long-lived clones of memory cells during the primary immune response.

11–22 RhoGAM is administered to pregnant RhD– women so as to _____. (Select all that apply.) a. stimulate only anti-RhD IgM antibody b. cause selective removal of anti-RhD memory B cells from the maternal circulation c. inhibit a primary immune response to RhD antigen d. block transcytosis of IgG to fetal circulation by interfering with FcRn function e. prevent hemolytic anemia of the newborn 11–23 Identify three characteristics of smallpox that aided in the global eradication of this disease through a rigorous vaccination program.

11–24 Identify the mismatched pair. (Select all that apply.) a. variolation: smallpox b.

Salk vaccine: killed poliovirus c. vaccinia virus: cowpox d. rotavirus: segmented DNA virus e.

Sabin vaccine: TVOP f. rabies vaccine: live attenuated vaccine.

11–25 Recombinant DNA technology has been especially useful for the production of _____ that are used in subunit vaccines. a. viral proteins b. viral nucleic acids c. mutated viruses d. viral polysaccharides e. infectious particles.

11–26 With reference to RotaTaq, identify the incorrect statement. (Select all that apply.) a.

It is an attenuated vaccine derived from a human rotavirus. b.

It has been genetically engineered to express a variety of human VP4 and VP7 glycoproteins. c.

It is a mixture of five cattle rotaviruses. d.

It is nonpathogenic in humans unless a genetic reversion occurs. e.

Standard tissue culture methods are used for its production. f.

It took decades of research to develop this vaccine to an adequate standard.

11–27 Which of the following is an example of a subunit vaccine? (Select all that apply.) a. hepatitis B vaccine 156

b. c. d. e.

Bacille Calmette–Guérin (BCG) vaccine trivalent oral polio vaccine influenza vaccine Bexsero®.

11–28 A. Explain the challenges associated with generating effective vaccines against encapsulated bacteria.

B. How have these challenges been overcome?

C. Explain the cellular events required for the production of protective IgG antibodies against bacterial polysaccharide components and the development of memory.

11–29 All of the following are examples of adjuvants except _____. a. alum b.

MF59 c. inactivated Bordetella pertussis d. virosomes e.

RhoGAM. 11–30 Explain why the DTP vaccine stimulates a much stronger protective immunity than does the DT vaccine.

11–31 A newly identified antigen protein of Neisseria meningitidis called fHbp increases virulence by _____. a. interfering with the alternative pathway of complement activation b. binding to host-derived heparin c. increasing the adhesiveness of the bacterium d. inhibiting phagocytosis e. inducing inflammation.

11–32 _____ is the approach that mines a pathogen‘s genome to reveal potential antigens and derives clues about cellular location, function, and ability to stimulate protective antibodies based on nucleotide sequence. a.

Conjugation b.

Attenuation c.

Reverse vaccinology d.

Herd immunity e.

Neutralization.

11–33 The reason that vaccines against influenza must be administered annually, unlike vaccines against measles, is _____. a. the antigens that stimulate protection against influenza virus are inside the virion and not on the surface b. influenza is an RNA virus with a higher mutation rate c. influenza stimulates T-independent responses that fail to generate memory cells d. the polysaccharide antigens of influenza stimulate poor immune responses.

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11–34 When a subpopulation of unvaccinated individuals are protected against a pathogen because the vast majority of individuals in the overall population are vaccinated, this is called _____. a. reverse vaccinology b. subunit vaccination c. partial immunization d. combined immunity e. herd immunity.

11–35 After a campus outbreak of Neisseria meningitidis (meningococcal serogroup B), a devastating bacterial disease, which affected at least eight students at Princeton University, the US Food and Drug Administration approved the use of Bexsero to prevent the development of additional cases on that campus. Bexsero is considered to provide broader protective coverage than the US-licenced vaccines conventionally used against this disease. Which of the following methodologies was used to develop Bexsero? a. conjugation of neisserial capsular polysaccharide to tetanus toxoid b. reverse vaccinology c. formalin treatment of secreted toxins d. production of a combination vaccine that includes DTP plus a meningococcal polysaccharide diphtheria toxoid conjugate e. engineering a nonpathogenic cattle strain of N. meningitidis to express antigens associated with pathogenic human strains.

11–36 Explain why the suppression of naive B cells in secondary immune responses is advantageous for fighting the measles virus but disadvantageous for fighting the influenza virus.

11–37 Differentiate between the following types of vaccine and give an example of each: (A) inactivated virus vaccines; (B) live-attenuated virus vaccines; (C) subunit vaccines; (D) toxoid vaccines; (E) conjugate vaccines; and (F) combination vaccines.

11–38 What risks are associated with live-attenuated virus vaccines?

11–39 Bacterial vaccines differ from viral vaccines in that only in bacterial vaccines are _____ used. (Select all that apply.) a. subunit components b. toxoids c. whole infectious components d. capsular polysaccharides e. capsule:carrier protein conjugates.

11–40 Reasons complicating the development of vaccines to combat chronic diseases include _____. (Select all that apply.) a. evasion of the host‘s immune system by the pathogen b. the polymorphic diversity of MHC class I and class II molecules c. the generation of inappropriate immune responses that do not eradicate the pathogen 158

d. e.

survival of the infectious agent for long periods inside the host high mutation rates in the pathogen.

11–41 A. What is the risk to a population that reduces its use of particular vaccines over a period?

B. Identify two cases in which this has happened and the underlying reason for distrust in the benefit of the vaccine.

11–42 A. Explain the difference between the Rotarix and the RotaTeq vaccines used to protect against rotavirus infections.

B. Which vaccine provides broader protection?

C. Why is this important?

11–43 Why is determining the genome sequences of human pathogens important in the development of new and more effective vaccines?

11–44 On an otherwise uneventful sunny Sunday afternoon, an extremist group enters your city in a large van and drives to the front entrance of the Convention Center where the annual flower show is taking place. The occupants unload large crates resembling flats of assorted flowers, and then drive off. Within minutes the crates explode, showering the visitors with an opaque powder.

Medical teams are called to the scene to care for the injured, and CDC officials wearing level 4 containment suits arrive in a few hours to test the contents of the powder for human pathogens using multiplex PCR methodology (a rapid method for identifying pathogens by their DNA).

Which of the following potential bioterrorism agents would pose the most serious threat to those exposed? a.

Bacillus anthracis (anthrax) b.

Corynebacterium diphtheriae toxin (diphtheria) c.

Yersinia pestis (plague) d. variola major (smallpox) e.

Clostridium botulinum toxin (botulism).

11–45 In which ways do memory B cells active in a secondary immune response differ from the naive B-cell population activated in a primary immune response? (Select all that apply.) a.

The antibody produced is of higher affinity in a secondary immune response. b.

The frequency of antigen-specific B cells is lower in a secondary immune response. c.

The level of somatic hypermutation is higher in a secondary immune response. d.

Higher levels of IgM are produced in secondary immune responses. e.

B cells do not require T-cell help in secondary immune responses. f.

Memory B cells express higher levels of MHC class II molecules. g.

Naive B cells express higher levels of co-stimulatory molecules.

11–46 Which of the following explain why infections with influenza virus erode immunological memory over time? (Select all that apply.) a.

Influenza is a highly mutable virus that changes its epitope composition. b.

A compensatory immune response to new epitope variants is suppressed in naive B cells.

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c.

The antibody response is directed only toward new epitope variants, resulting in a decreased memory response. d.

Cross-linking of B-cell receptor and FcγRIIB1 on memory B cells induces anergy. e.

Naive B cells are suppressed by cytokines made by memory B cells.

11–47 Naive T cells do not express _____. (Select all that apply.) a.

CD25 b.

CD45RA c.

CCR7 d.

IFN-γ e.

FasL. 11–48 The production of CD45RO results from the removal of _____ during _____ processing. a. domain A; post-translational b. domain A; post-transcriptional c. exons A, B, and C; post-translational d. exons A, B, and C; post-transcriptional e. exon A; post-transcriptional.

11–49 Effector memory cells enter _____, whereas central memory cells enter _____. a.

B-cell follicles; T-cell zones of secondary lymphoid tissues b.

T-cell zones of secondary lymphoid tissues; B-cell follicles c. secondary lymphoid tissues; primary lymphoid tissues d.

T-cell zones of secondary lymphoid tissues; inflamed tissues e. inflamed tissues; T-cell zones of secondary lymphoid tissues.

11–50 Indicate whether each of the following statements is true (T) or false (F). ___ a. Memory T cells can persist in the absence of antigen. ___ b. The CD45RA isoform is associated with stronger signals in response to antigen. ___ c. T-cell survival is dependent on the cytokines IL-7 and IL-15. ___ d. Naive B cells are more sensitive to specific antigen than are memory B cells because they express higher levels of co-stimulatory molecules.

11–51 Fill in the blanks.

A. Cross-linking ________ and ________ on a ______ B cell by a specific antigen:IgG complex renders the B cell anergic.

B. Treatment based on the above phenomenon is used to prevent hemolytic disease of the newborn, which can occur in families in which the mother is ______ and the father _______.

11–52 _____ involves deliberate stimulation of the immune system and induction of protective immunity to a particular disease-causing pathogen by mimicking infection in the absence of disease. a.

Variolation b.

Attenuation c.

Vaccination d.

Conjugation 160

e.

Herd immunity.

11–53 Inactivation of viruses for vaccine use can be achieved by _____. (Select all that apply.) a. irradiation b. heat treatment c. mutation d. neutralization e. formalin treatment.

11–54 An example of a live-attenuated virus vaccine is _____. (Select all that apply.) a. vaccinia b.

Salk polio vaccine c. measles vaccine d. yellow fever vaccine e. rabies vaccine.

11–55 A. What is the difference between the Salk and Sabin polio vaccines?

B. Which one should be used for an individual who has an immunodeficiency disease, and why?

11–56 In the context of providing protection against smallpox, describe (A) the similarities and (B) the differences between variolation and vaccination. (C) Now explain the mechanisms by which immunization with vaccinia virus provides protection against smallpox.

11–57 An example of an inactivated virus vaccine is _____. (Select all that apply.) a.

Sabin polio vaccine b. influenza vaccine c. mumps vaccine d. hepatitis B vaccine e. rabies vaccine.

11–58 For a viral subunit vaccine to be effective, _____. (Select all that apply.) a.

B cells must be activated b. cytotoxic T cells must be activated c. neutralizing antibodies must be induced d.

CD4 TFH cells must be activated e.

NK cells must be activated f. it must be derived from viral surface components.

11–59 Indicate whether each of the following statements is true (T) or false (F). ___ a. The Bacille Calmette–Guérin (BCG) vaccine is commonly used in the United States to provide protection against tuberculosis. ___ b. BCG is a heat-killed strain of bovine Mycobacterium tuberculosis. ___ c. Lipopolysaccharide-deficient Salmonella typhi is used to vaccinate against typhoid fever.

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___ d. Capsular polysaccharide vaccines are equally effective in infants and adults, and stimulate strong T-independent antibody responses. ___ e. A state of inflammation impairs effective immune responses to microbial products.

11–60 A conjugate vaccine is one that couples _____ to _____ so as to stimulate T-dependent antibody responses. a. polysaccharide; a protein carrier b. a protein carrier; irradiated DNA c. protein carrier; toxoids d. adjuvant; toxoids e. polysaccharide; filamentous hemagglutinin.

11–61 _____ vaccines are the most effective at evoking memory responses against a virus in an immunized host. a.

Conjugate b.

Subunit c.

Killed d.

Live-attenuated e.

Toxoid.

11–62 Which of the following vaccines is least likely to pose a risk in an individual with an immunodeficiency? a.

Sabin polio vaccine b. measles vaccine c. hepatitis B vaccine d. vaccinia vaccine e. yellow fever vaccine.

11–63 Approximately one-quarter of individuals infected with hepatitis C _____. a. develop a chronic infection of hepatocytes b. are at risk of developing liver cancer c. experience episodes of liver destruction and regeneration d. require a liver transplant e. mount an effective immune response and eradicate the virus.

11–64 Which of the following explain why the safety standards for vaccines are set higher than those for drugs? (Select all that apply.) a.

Some vaccines can induce a disease state. b.

Vaccines provoke side-effects in otherwise healthy children. c.

Vaccines are much more costly to develop and test than most drugs. d.

Vaccination programs are targeted at large populations. e.

Subunit vaccines can potentially integrate into the host genome and activate host oncogenes, leading to the development of cancer.

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11–65 An adjuvant enhances the effectiveness of vaccines by inducing the expression of _____ on ________. a. co-stimulatory molecules; dendritic cells b.

CD28; macrophages c.

MHC class II molecules; T cells d.

T-cell receptor; T cells e. immunoreceptor tyrosine-based activation motifs; dendritic cells.

11–66 B cells are activated by CD4 TH2 cells only if both cell types recognize the same antigen.

The same epitope, however, does not need to be shared for recognition.

A. Discuss why this characteristic is important in vaccine design.

B. Provide an example of a conjugate vaccine used to stimulate the synthesis of IgG antibody against Haemophilus influenzae B polysaccharide.

11–67 Tim Smith, aged 16 years, was hit by a car while riding his motorcycle. At the hospital he showed only minor abrasions and no bone fractures. He was discharged later that day. In the morning he experienced severe abdominal pain and returned to the hospital. Examination revealed tachycardia, low blood pressure, and a weak pulse. He received a blood transfusion without improvement. Laparoscopic surgery confirmed peritoneal hemorrhage due to a ruptured spleen. In addition to a splenectomy, which of the following treatments would be administered? a. plasmapheresis to remove autoantibodies (antibodies generated against self constituents) b. regular intravenous injections of gamma globulin c. vaccination and regular boosters with capsular polysaccharides from pathogenic pneumococcal strains d. booster immunization with DTP (diphtheria toxoid, killed Bordetella pertussis, and tetanus toxoid) e. regular blood transfusions 11–68 Jenny O‘Mara was five months pregnant when she stepped on a rusty piece of scrap metal while hauling rotted wood from a dilapidated shed in her garden. The sliver of metal cut through her sneaker and pierced her heel deeply. Her physician gave her a tetanus booster. When Jenny‘s baby was born she decided to breastfeed. If the baby‘s antibodies were tested for specificity to tetanus 2 months after birth, what would be the expected finding? a. the presence of anti-tetanus toxoid IgA antibodies b. the presence of anti-tetanus toxoid IgM antibodies c. the presence of anti-tetanus toxoid IgG antibodies d. the presence of IgM antibody specific for Clostridium tetani cell-wall components e. the presence of IgG antibody specific for Clostridium tetani cell-wall components.

ANSWERS

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11–1 (i) Memory cells outnumber naive pathogen-specific lymphocytes because they have already gone through clonal selection and proliferation when antigen was encountered previously. (ii) Memory cells can be activated more quickly than naive lymphocytes. (iii) Memory cells are not restricted to circulation between the bloodstream and secondary lymphoid organs, but can also enter non-lymphoid tissues and can therefore respond to infections sooner. (iv) Owing to the molecular processes of somatic hypermutation and isotype switching, immunoglobulins made by memory B cells are of a higher quality and possess constant regions that will direct secreted antibody to the appropriate anatomical locations to combat infection.They will therefore compete more efficiently for antigen than naive lymphocytes and in so doing will inhibit the activation of naive lymphocytes.

11–2 A. Naive B cells carry the inhibitory Fc receptor FcγRIIB1. Complexes composed of antigen and IgG produced in the primary response, or by reactivated memory cells, cross-link FcγRIIB1 and the B-cell receptor, which suppresses naive B-cell activation. In contrast, memory B cells do not carry this receptor, and so are not inhibited in this way.

B. The suppression of naive B cells means that only reactivated memory B cells (which have already undergone isotype switching and somatic hypermutation) make antibodies.

Thus all the antibodies made are of high affinity and are primarily of the IgG, IgA, or IgE isotype. Suppression of naive B cells eliminates repetition of the events that took place in the primary immune response, which would, if not inhibited, lead to the production of low-affinity IgM antibodies rather than high-affinity, isotype-switched antibodies that are more effective at removing the pathogen.

11–3 A. Short-term immunological memory operates shortly after an adaptive immune response has cleared the infection in an individual and while the pathogen is still present in the community. If the individual is re-exposed and reinfected, antibodies generated in the first round of infection can bind immediately to the pathogen, blocking its action by neutralization and mediating its removal and destruction by complement fixation and phagocytosis. In addition, any remaining effector T cells or activated B cells can respond straight away to the presence of 164

antigen. These activities ensure that the infection does not re-establish itself and also generate a fresh supply of antibodies and effector cells.

B. Long-term immunological memory is mediated through long-lived memory lymphocytes that are generated in the primary immune response. These are cells that can be rapidly stimulated by re-exposure to the same antigen to produce a strong and effective immune response that rapidly clears the pathogen.

11–4 d

11–5 a, b, d

11–6 d

11–7 b

11–8 c

11–9 b

11–10 a

11–11 c

11–12 a

11–13

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(i) Memory B cells bearing pathogen-specific immunoglobulin are more numerous than naive B cells. (ii) Memory B cells are activated more easily than naive B cells. (iii) Memory B cells have already undergone isotype switching, somatic hypermutation, and affinity maturation.

11–14 d

11–15 b

11–16 d

11–17 a

11–18 b

11–19 During germinal-center reactions, isotype switching, somatic hypermutation, and affinity maturation generate memory B cells with higher-affinity receptors than those of naive B cells.

This feature enables memory B cells to bind to pathogen antigens at very early stages of infection when the pathogen population is very small. Memory B cells also differentiate into plasma cells more rapidly than do naive B cells. These two characteristics allow antibody production to occur much sooner than would be the case with naive B cells. Cognate interactions with CD4 TFH cells are also more efficient owing to elevated MHC class II and co-stimulatory molecules on the surface of memory B cells compared with naive B cells.

11–20 c

11–21 a, b

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11–22 c, e

11–23 (i) The smallpox virus evolves slowly, so the antigenic epitopes encountered in a vaccine are likely to be the same as or very similar to the actual virus if exposed to the virus later in life. (ii) The vaccine is a live virus administered through the skin, so the immune responses that are induced will closely resemble those provoked by a natural infection and establish longlived memory B cells and memory T cells. (iii) Smallpox, unlike other poxviruses, infects only humans. This eliminates the possibility of alternative reservoirs in other animal populations and therefore requires the interruption of only one chain of transmission (namely human-to-human) to impede dissemination.

11–24 d, f

11–25 a

11–26 a, d

11–27 a, e

11–28 A. Encapsulated bacteria possess a polysaccharide capsule that not only resists phagocytosis but also inhibits the activation of the alternative pathway of complement activation.

Vaccines containing purified polysaccharide components induce weak T-cell-independent B-cell responses limited to low-affinity IgM antibodies and no memory B cell production.

B. These challenges have been overcome by recognizing the need to activate CD4 TFH cells so that high-affinity, neutralizing IgG antibodies are made after exposure to 167

encapsulated pathogens. Because CD4 TFH cells require peptide epitopes presented by MHC class II molecules, a new class of vaccine, a conjugate vaccine, was designed that enabled this goal to be achieved. By linking the bacterial polysaccharide covalently to a potent IgGstimulating protein such as the tetanus or diphtheria toxoid, peptide epitopes become available for the activation of CD4 TFH cells.

C. First, dendritic cells process the toxoid epitope and activate CD4 T cells, which differentiate into TFH cells. Then naive B cells bearing IgM antibodies specific for the polysaccharide take up the conjugate by receptor-mediated endocytosis. The toxoid epitopes are subsequently presented with MHC class II molecules on the B-cell surface to activated toxoidspecific CD4 TFH. The resulting T cell–B cell cognate interaction provides everything needed for an efficient immune response generating high-affinity, polysaccharide-specific protective IgG antibodies and the establishment of both T-cell memory and B-cell memory.

11–29 e

11–30 The diphtheria (D) and tetanus (T) toxoids are purified proteins that on their own do not stimulate Toll-like receptors or other receptors of the innate immune response. Hence, an inflammatory response is not initiated by the DT vaccine, which consequently results in the failure to initiate an adaptive immune response. When inactivated Bordetella pertussis is added to make the tripartite vaccine (DTP), it efficiently activates the innate immune response by acting as an adjuvant and inducing inflammation. It also provides additional pathogenic antigens to which the host responds.

11–31 a

11–32 c

11–33 b

11–34 e

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11–35 Rationale: The correct answer is b. Reverse vaccinology was the novel technique used to develop Bexsero®. The genome of Neisseria meningitidis strain MC58 was used to identify candidate proteins that not only were exposed on the bacterial surface or secreted but were also conserved across many different pathogenic strains. Four such candidate proteins were identified, including factor H binding protein (fHbp); Neisseria heparin-binding antigen (NHBA); neisserial adhesin A (NadA); and porin A (PorA). The vaccine consists of all four components. There are conjugate vaccines available (for example Menactra®), but Bexsero is not a conjugate vaccine. There are no toxoid-only vaccines for meningococcal disease. Finally, there are no known cattle strains of N. meningitidis, which is a strictly human pathogen.

11–36 The measles virus is a relatively invariant pathogen that has little, if any, antigenic change. Antibodies made by memory B cells will be just as effective in a recall response as those made in a primary challenge. In fact, antibodies made in secondary immune responses by memory B cells will be more effective because of isotype switching and somatic hypermutation.

In contrast, the influenza virus is highly mutable; as a result, new strains emerge each year bearing new epitopes that have not previously stimulated a primary response. Memory response and the suppression of naive B cells restrict antibody production to only those epitopes shared by the infecting strain and the original strain. Over time, the influenza virus will express only a limited number of epitopes that are able to activate memory B cells, and the new epitopes will lack the capacity to stimulate naive B cells.

11–37 A. Inactivated virus vaccines are made of virus particles that are not able to replicate because they have been chemically or physically treated (for example by heat) in a way that inactivates the nucleic acid. Examples are Salk polio vaccine, rabies vaccine, and influenza vaccine.

B. Live-attenuated virus vaccines are made of viruses that have lost their pathogenicity and ability to reproduce efficiently in human cells through mutations accumulated as a result of growing the virus in non-human cells. Examples are Sabin polio vaccine (oral), measles vaccine, mumps vaccine, yellow fever vaccine, BCG and Salmonella typhi vaccine, and varicella vaccine.

C. Subunit vaccines are composed only of particular antigenic pathogen components known to induce protective immune responses. Recombinant DNA technology enables the production of antigenic proteins in the absence of other pathogen gene products. Examples are hepatitis B vaccine and Bexsero vaccine.

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D. Toxoid vaccines are made from chemically inactivated toxins purified from pathogenic bacteria. Toxin activity is eliminated but antigenic activity is not, so an immune response is generated in the absence of pathological damage. Examples are diphtheria vaccine and tetanus vaccine.

E. Conjugate vaccines are made by covalently coupling antigenic polysaccharide found in bacterial capsules to a carrier protein (often a toxoid). This converts the otherwise Tindependent bacterial polysaccharide antigen into a T-dependent antigen. T cells respond to an epitope on the protein carrier, whereas B cells respond to epitopes on the polysaccharide portion of the conjugate. This ensures that T-cell help is provided to B cells making anti-capsule antibodies. Examples include vaccines against Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae.

F. Combination vaccines consist of components that stimulate protective immunity against more than one pathogen. DTP (diphtheria, tetanus, pertussis) vaccine is an example.

11–38 Live-attenuated virus vaccines are mutant viruses that can replicate, albeit inefficiently, in human cells, thus simulating conditions of a normal viral infection. The attenuated vaccine strains of virus have been obtained by growing the virus over many generations in non-human cells (for example monkey cells) so that it acquires multiple mutations that allow it to replicate but prevent it from spreading in the human body and causing disease. When introduced into humans as a vaccine, there is a small chance that some or all of the mutations may revert to the original nucleotide sequence, restoring the properties of the virulent strain of the virus. This occurs very rarely with the poliovirus used in the trivalent oral polio vaccine (TVOP) and, now that polio is very rare in the United States, this vaccine is no longer recommended and an inactivated poliovirus vaccine is used instead. The more rounds of replication the vaccine virus undergoes in the human host before being contained by the immune response, the greater is the potential for genetic reversion. This is why individuals who suffer from inherited or acquired immunodeficiencies should never receive live-attenuated virus vaccines.

11–39 b, d, e

11–40 a, b, c, d, e

11–41

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A. As the number of susceptible individuals increases to a particular threshold, herd immunity is no longer effective in protecting individuals who have never been vaccinated. The outcome is the resurgence of the disease and an epidemic.

B. (i) A resurgence of whooping cough was documented in Japan between 1975 and 1980. Distrust in the vaccine followed the death of two children who had recently been vaccinated with DTP. (ii) A resurgence of measles was documented in the UK at the turn of the 21st century. Distrust was linked to unsubstantiated claims that the MMR vaccine induced autism in children.

11–42 A. The Rotarix vaccine is a live–attenuated single human rotavirus strain that expresses the G1 variant of V7 (VP7G1) and the P8 variant of VP4 (VP4P8). Both variable proteins are common in disease-causing strains. The RotaTeq vaccine is a mixture of five different non-pathogenic cattle rotaviruses engineered to express VP4P8 and VP7G1, VP7G2, VP7G3, and VP7G4 variants from common human pathogenic strains, in addition to cattlespecific variable proteins.

B. The RotaTeq vaccine protects against a broader range of variable proteins than Rotarix does. Both vaccines stimulate neutralizing antibodies against VP4P8 and VP7G1, but RotaTeq also stimulates antibodies against VP7G2, VP7G3, and VP7G4, providing broader protection against the different naturally occurring rotavirus variants.

C. Broader protection is important because there are five naturally occurring variants of rotavirus that cause disease. In addition, rotavirus has the potential of RNA reassortment, as seen in influenza, because the genome is made up of 11 separate double-stranded RNA molecules, providing opportunities for the generation of additional diversity.

11–43 Determination of genome composition enables researchers to understand the life cycle and pathophysiology of the pathogen. This type of information assists with the identification of the types of immune responses that are evoked in the host, including NK-cell, T-cell, and B-cell responses. In addition, armed with specific sequence knowledge, recombinant DNA methodology can be used to engineer attenuated strains, either through site-directed mutagenesis or the deletion of virulence genes.

11–44 Rationale: The correct answer is d. The most serious threat would be posed by the biological agent to which there is no immediate defense or antidote. Antibiotics would be 171

effective against bacterial agents such as Bacillus anthracis and Yersinia pestis, and antitoxin against diphtheria and botulism toxins could be administered to those affected. If the powder contained the smallpox virus, however, the population would be particularly susceptible, because there are no antibiotics available to protect the non-immune population, and vaccination would take time to take effect. Those infected in the initial attack could spread this highly infectious virus, which has severe morbidity and a mortality rate of about 30%.

11–45 a, c, f

11–46 a, b

11–47 a, d, e

11–48 d

11–49 e

11–50 a—T; b—F; c—T; d—F

11–51 A.

B-cell receptor; FcγRIIB1; naive

B.

RhD–; RhD+

11–52 c

11–53 a, b, e

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11–54 c, d

11–55 A. The Salk polio vaccine is an inactivated virus vaccine, whereas the Sabin polio vaccine is a live-attenuated virus vaccine.

B. The Salk vaccine should be used for immunocompromised individuals. Live attenuated vaccines carry a risk of mutational reversion in an immunocompromised host to a more virulent, disease-causing strain. This occurs because the virus is able to replicate at higher levels and acquire a significant number of mutations, some of which may lead to reversion to a pathogenic strain.

11–56 A. Variolation and vaccination are both procedures used to confer immunological protection against the smallpox virus, variola. They both use live virus and stimulate humoral and cell-mediated immune responses against the smallpox virus.

B. Variolation, a method used for only a short period in the 18th and 19th centuries because of the risk of developing smallpox, used dried pustules derived from humans exhibiting relatively mild symptoms of smallpox infection. Vaccination, a safer alternative causing only mild infection, used dried pustules from cows infected with cowpox.

C. Vaccinia and variola have some viral surface antigens in common. Some of the antibodies made against cowpox surface antigens during immunization are able to bind to shared surface antigens also expressed on the surface of the smallpox virus. Through neutralization, these anti-cowpox antibodies are able to bind to and prevent the entry of smallpox into host cells if the host is infected naturally with the smallpox virus.

11–57 b, e

11–58 a, c, d, f

11–59 a—F; b—F; c—T; d—F; e—F

173

11–60 a

11–61 d

11–62 c

11–63 e

11–64 a, b, d

11–65 a

11–66 A. Many bacteria are surrounded by a polysaccharide capsule. In some cases, antibodies against the capsular polysaccharides give protective immunity against the pathogen.

Antibodies produced against polysaccharide antigens are generally restricted to the IgM isotype, because the help needed to switch isotypes to IgG is provided by T cells, which recognize only peptide antigens. Adult humans make effective immune responses to polysaccharides alone and thus can be protected by subunit vaccines made from the capsular polysaccharides of encapsulated bacteria. Their antibody responses are polysaccharide-specific, T-cell independent, and involve antibodies of the IgM isotype. In contrast, children do not make effective immune responses to polysaccharides alone and thus cannot be immunized with such vaccines.

However, if the polysaccharide is conjugated to a protein, peptides from the protein part of the molecule can activate specific TH2 cells. B cells specific for polysaccharide will bind and internalize the whole antigen via their antigen receptors, process it, and then present peptides from the protein part on their surface. T cells specific for these peptides will interact with the B cell, delivering the necessary cytokines (such as IL-4) and the CD40–CD40-ligand signal required for isotype switching. The B cell will then produce IgG anti-polysaccharide antibodies.

This type of vaccine can be used to immunize children so as to induce protective antipolysaccharide antigens.

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B. A vaccine of this type has been produced against Haemophilus influenzae B (HiBC), which can cause pneumonia and meningitis. The conjugate vaccine is composed of a capsular polysaccharide of H. influenzae conjugated to tetanus or diphtheria toxoid (a protein).

The antibody response is polysaccharide-specific, T-cell dependent, and comprises IgG that protects children from the meningitis caused by this microorganism.

11–67 c

11–68 Rationale: The correct answer is c. This is a case of passive immunity provided to the fetus during pregnancy through transplacental transfer of IgG. Only IgG antibodies cross the placenta, with the aid of FcRn, and enter the fetal circulation during pregnancy, providing passive immunity for the newborn for the first 3–6 months, after which antibody levels diminish as a result of catabolism, and IgG must then be made by the infant. The antibody specificity will be against the tetanus toxoid, not cell-wall entities, because the booster vaccine is a subunit vaccine made of toxoid from Clostridium tetani, not whole bacterial cells. Sophie will make IgG anti-toxoid antibodies, not IgA, because of the route of immunization; intramuscular injection would stimulate the production of IgG antibodies. IgA antibody production would require mucosal delivery. Therefore, even though the newborn is breastfeeding and passively receiving IgA antibodies from Sophie, the IgA antibodies will not have specificity for tetanus toxoid.

CHAPTER 12: COEVOLUTION OF INNATE AND ADAPTIVE IMMUNITY 12–1 a. b. c. d. e.

All of the following are characteristic of NK cells except _____. they express Toll-like receptors they are tolerant of healthy cells they circulate in a partly activated state they all express the same selection of activating and inhibitory NK-cell receptors they can be activated by FcγRIIIA (CD16a).

12–2 Which of the following statements regarding NK cells is false? a.

They express either inhibitory receptors or activating receptors, but not both. b.

Their inhibitory receptors are necessary to prevent killing of healthy cells. c.

They all express CD56. d.

Because NK cells express diverse combinations of receptors, no single NK cell expresses them all. e.

Some of their activating and inhibitory receptors use MHC class I ligands.

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12–3 The only single receptor that can activate NK cells without the need for a second activating receptor is _____. a.

NKG2D b.

CD56 c.

2B4 d.

CD94:NKG2A e.

CD16a.

12–4 a. b. c. d.

Identify which of the following would be sufficient to activate NK cells.

NKG2A and CD94 NKG2D and 2B4 KIR2DL1 and KIR3DL1 CD56 and LFA-1.

12–5 a. b. c. d. e.

Identify which of the following is not a characteristic of CD94:NKG2A. contains a C-type lectin domain is an inhibitory NK-cell receptor binds to carbohydrate ligands is a disulfide-linked heterodimer contains an immunoreceptor tyrosine-based inhibitory motif (ITIM).

12–6 Explain (A) how the ligand for CD94:NKG2A serves as an indicator of non-infectious or non-malignant states of potential target cells, and (B) the consequence if ligand expression is compromised on target cells.

12–7 a. b. c. d. e.

Identify the mismatched pair: CD94:NKG2A; ITIM NKG2D; MIC proteins SHP-1; Vav1 2B4; IgG HLA-E; leader-sequence peptide.

12–8 _____ has/have tyrosine phosphatase activity that interrupts the signaling pathways required for the activation of NK cells. a.

SHP-1 b.

MIC proteins c.

KIR ligands d. phosphoantigens e. lipid-transfer proteins.

12–9 a. b. c. d.

All of the following describe Vav1 except _____. guanine-nucleotide exchange factor regulated by SHP-1 active when phosphorylated found on the surface of NK cells 176

e.

mediates signaling that promotes NK cells‘ release of cytotoxic granules.

12–10 All of the following contribute to the generation of functional NK cells in the bone marrow with diverse KIR phenotypes except _____. a. competing bi-directional promoters of KIR genes b. delay of KIR expression until NK cells enter the circulation c. closely packed KIR genes on chromosome 19 d. establishment of a level balance between activating and inhibitory signals e. gene silencing by DNA methylation f. the number of KIR ligands brought by the HLA-A, -B, and -C tissue type.

12–11 Which of the following is false regarding HLA-G? a.

It is expressed as transmembrane or secreted forms. b.

It binds to LILRB1 inside endosomes of NK cells. c.

It stimulates the production of angiogenic factors by activating NK cells. d.

It is expressed exclusively by extravillous trophoblast cells. e.

It engages inhibitory receptors on uterine NK cells.

12–12 Extravillous trophoblast cells do not express _____. (Select all that apply.) a.

HLA-A b.

HLA-B c.

HLA-C d.

HLA-E e.

HLA-F f.

HLA-G g.

HLA class II. 12–13 Which of the following maternal profiles is most strongly correlated with pre-eclampsia where the fetus has a C2 epitope inherited from the father? a. homozygous for KIR A haplotype and C1 epitope b. homozygous for KIR B haplotype and C1 epitope c. homozygous for KIR A haplotype and C2 epitope d. homozygous for KIR B haplotype and C2 epitope e. heterozygous for KIR A/B haplotypes and C1/C2 epitopes f. homozygous for KIR A haplotype and heterozygous for C1/C2 epitopes g. homozygous for KIR B haplotype and heterozygous for C1/C2 epitopes h. heterozygous for KIR A/B haplotypes and homozygous for C1 epitopes i. heterozygous for KIR A/B haplotypes and homozygous for C2 epitopes.

12–14 Which of the following maternal profiles is most strongly correlated with obstructed labor where the fetus has a C2 epitope inherited from the father? a. homozygous for KIR A haplotype and C1 epitope b. homozygous for KIR B haplotype and C1 epitope c. homozygous for KIR A haplotype and C2 epitope d. homozygous for KIR B haplotype and C2 epitope e. heterozygous for KIR A/B haplotypes and C1/C2 epitopes 177

f. g. h. i.

homozygous for KIR A haplotype and heterozygous for C1/C2 epitopes homozygous for KIR B haplotype and heterozygous for C1/C2 epitopes heterozygous for KIR A/B haplotypes and homozygous for C1 epitopes heterozygous for KIR A/B haplotypes and homozygous for C2 epitopes.

12–15 In the context of NK-cell inhibitory and activating receptors and maternal arterial invasion, explain the cause of (A) pre-eclampsia and (B) obstructed labor. Base your response on a pregnancy involving a fetus who has inherited a C2 epitope from the father but whose mother is homozygous for C1.

12–16 Identify which of the following is not a characteristic of γ:δ T cells. (Select all that apply.) a.

Some express a homodimer of the CD8 α chain. b.

They do not express CD28. c.

They are subject to MHC restriction. d.

Most do not express either CD4 or CD8. e.

Most circulating cells do not enter secondary lymphoid tissue. f.

They undergo gene rearrangement. g.

They originate from the same precursor cells as do α:β T cells. h.

Their response is solely dependent on the T-cell receptor. i.

They make up the minority of resident T cells in tissues. j.

Circulating cells express Vγ9:Vγ2.

12–17 At birth, the size of the repertoire of γ:δ T-cell receptors is _____ its size at adolescence. a. smaller than b. larger than c. about the same as.

12–18 Match the term in column A with its description in column B. Column A Column B ___a. CCR7 1. permits entry of γ:δ T cells into infected tissues ___b. CCR5 2. expressed on central memory γ:δ T cells but not effector memory γ:δ T cells ___c. CD27 3. expressed on ~20% of circulating γ:δ T cells ___d. CD45RA 4. presents lipid antigens to γ:δ T cells ___e. CD1d 5. expressed on terminally differentiated γ:δ T cells 12–19 Match the receptor in column A with its ligand in column B. Responses in column B may be used more than once.

Column A Column B ___a. Vα24–Jα18:Vβ11 1. phosphoantigens presented by BTN3A1 ___b. Vγ9:Vδ2

2. lipid antigens presented by CD1d

178

___c. Vγ:Vδ1

3. ringed metabolites of riboflavin presented by MR1

___d. Vγ4:Vδ5

4. phospholipid antigens presented by endothelial protein C receptor (EPCR)

___e. Vα7.2–Jα33:Vβ2, -13, or -22.

12–20 Which of the following is not a ligand for α:β T cells? a. peptide antigens b. lipid antigen c. sulfatides d. heterocyclic organic molecules.

12–21 In contrast to CD1d, CD1a, b, and c are not expressed by _____. a. professional antigen-presenting cells b. epithelial cells c. developing thymocytes.

12–22 Match the term in column A with its complement in column B. Column A Column B ___a. saposin 1. NKT-cell development ___b. sulfatide 2. fills up bottom of antigen-binding site to allow antigenic lipid to be accessible on the top ___c. scaffold lipid 3. MR1 ___d. BTN3A 4. phosphoantigen ___e. lipid-transfer protein 5. CD1d ___f. promyelocytic leukemia zinc finger 6. CD1e protein (PLZF) ___g. second signal for NKT-cell activation 7. IL-12 ___h. riboflavin 8. an example of a lipid-transfer molecule found in endosomes

12–23 All of the following develop in the thymus except _____. a. α:β T cells b. γ:δT cells c.

NK cells d.

NKT cells e.

MAIT cells.

12–24 All of the following are correct regarding MAIT cells except _____. (Select all that apply.) a.

CD8+ b. respond to viral infection c. α:β T-cell receptors 179

d. populate lungs, mucosal tissues, liver, and blood e. activated by microbiota that make riboflavin f. respond to antigen presented by BTN3A g. comprise 20–40% of lymphocytes in liver as oligoclonal populations of effector cells with memory phenotype h. positively selected by thymic epithelium expressing high levels of MR1.

12–25 Which of the following is not a characteristic of MR1? a.

MHC class-I-like molecule b. binding site is populated with large basic and aromatic amino acid residues c. associated with β2-microglobulin d. highly polymorphic in mammals e. encoded on chromosome 1 f. binds to metabolites of riboflavin.

12–26 Natural killer cells (NK cells) carry activating and inhibitory receptors on their surface.

A. What property of NK cells do these receptors activate or inhibit, respectively? Explain your answer.

B. How are NK cells thought to use these receptors to recognize and eliminate virus-infected cells?

C. Why are the actions of NK cells categorized as innate immunity, and what do we know of their specificity for MHC class I molecules?

D. Why do the NK cells of the recipient of an organ transplant sometimes attack the transplanted tissue?

12–27 Which of the following characterize MIC-A and MIC-B proteins? (Select all that apply.) a. recognized by NKG2D receptors of NK cells and some CD8 T cells b. activate the NFB signaling pathway c. activate mast cells in the intestinal wall d. closely related to MHC class I heavy chains e. bind to MHC class I molecules and activate CD8 T cells.

12–28 Vγ9:Vδ2 T cells differ from α:β T cells in that they _____. (Select all that apply.) a. respond to phosphorylated metabolic intermediates (phosphoantigens) of isoprenoid biosynthesis pathways b. bind to lipid antigens presented by CD1 c. do not carry out gene rearrangement d. are not subject to positive and negative selection in the thymus e. have limited diversity of V gene rearrangement.

12–29 Which of the following are expressed by Vγ9:Vδ2 T cells? (Select all that apply.) a.

IFN-γ b.

MHC class I c. granulysin d.

CD56 e.

CCR5 180

f. g. h.

IL-4 CD40L CD28.

12–30 _____ binds to MIC-A and MIC-B, which are synthesized in response to infection in gut epithelium. (Select all that apply.) a.

MHC class I b.

NKG2D c.

Vγ:Vδ1 d. fibroblast growth factor e.

CD1.

12–31 _____ express a limited range of diversity in their antigen receptors yet can still bind to large groups of pathogens expressing common chemical entities. (Select all that apply.) a. α:βT cells b. γ:δT cells c.

NK cells d.

NKT cells e.

B-1 cells.

12–32 Explain the path taken by CD1 molecules that eventually bind to pathogen-derived lipids inside endosomes of the MHC class II compartment.

12–33 All NK cells express _____. (Select all that apply.) a.

CD3 b.

MIC c.

NKG2D d.

KIR2DL1 e.

CD56.

12–34 Which of the following describe the characteristics of CD94:NKG2A? (Select all that apply.) a.

It is an activating receptor of NK cells. b.

It is an inhibitory receptor of NK cells. c.

It binds to specific allotypes of HLA-A, -B, and -C heavy chains. d.

It binds to complexes of leader sequences of HLA-A, -B, and -C heavy chains bound to HLA-E. e.

It is a member of the killer-cell immunoglobulin-like receptor (KIR) family.

12–35 In regard to killer-cell immunoglobulin-like receptors (KIRs) indicate which of the following statements is true (T) or false (F). ___ a. KIRs have a broader range of specificity for HLA class I compared with CD94:NKG2A. ___ b. KIRs are activating receptors of NK cells and stimulate the release of perforin and granzyme. ___ c. KIRs bind to monomorphic determinants on HLA-A, -B, and -C molecules. ___ d. All HLA-C allotypes are suitable ligands for KIRs. 181

___ e. KIRs are encoded in the leukocyte receptor complex (LRC) on chromosome 19. ___ f. MIC-A and MIC-B are suitable ligands for KIRs. 12–36 Match the molecule in column A with its appropriate ligand in column B. (Answers may be used more than once.)

Column A Column B ___ a. Vγ:Vδ T-cell receptor 1. HLA-A ___ b. CD94:NKG2A 2. FasL ___ c. NKG2D 3. phosphoantigen ___ d. LILRBI 4. HLA-E ___ e. FAS 5. MIC-A and MIC-B ___ f. Vγ:Vδ2 T-cell receptor 6. HLA-C ___ g. KIR2DL1 7. glycolipid antigen ___ h. CD1 12–37 _____ is a molecule expressed on NK cells and Vγ:Vδ1 T cells. a.

CD3 b.

MIC-A c.

NKG2D d.

CD94:NKG2A e. killer-cell immunoglobulin-like receptor (KIR).

12–38 If, during development, none of the KIRs expressed by a NK cell are able to interact with self-MHC class I molecules, then the NK cell retains expression of _____. a.

LILRBI b.

KIR2DL1 c.

KIR2DL2/3 d.

KIR3DL1 e.

CD94:NKG2A. 12–39 CD1a, CD1b, and CD1c _____. (Select all that apply.) a. are highly polymorphic and bind to a variety of pathogen-specific lipids b. are encoded within the MHC on chromosome 6 c. express antigen-binding sites distinct from classical MHC class I molecules d. are associated with β2-microglobulin at the surface of antigen-presenting cells e. can bind to lipids in the endoplasmic reticulum or in endocytic vesicles.

12–40 CD1d differs from CD1a, CD1b, and CD1c in that _____. (Select all that apply.) a.

CD1d does not present lipid antigens b.

CD1d is expressed in a variety of epithelial tissues c.

CD1d presents antigen to NK T cells d. strong memory responses are generated by CD1d e.

CD1d has a restricted receptor repertoire.

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12–41 Charlene Cook, a 38-year-old primigravida, is 35 weeks pregnant. Until recently she has had an uneventful pregnancy. Two weeks ago, her obstetrician noted lower-extremity edema, trace protein in her urine (10–20 mg/dl), and normal blood pressure (120/80 mmHg). At today‘s appointment her blood pressure is elevated at 160/100 mmHg, she has marked proteinuria (3+; 300 mg/dl), worsening of ankle swelling, facial and hand swelling, and she mentions sudden onset of headache and visual disturbance. Charlene is admitted immediately to hospital and is diagnosed with pre-eclampsia. Within hours she is induced and gives birth to a healthy baby girl.

In the context of uterine NK-cell function, which of the following is inconsistent with the cause of Charlene‘s pre-eclampsia? a.

There is inadequate extravillous trophoblast invasion of the spiral arteries or the uterus. b.

She has maternal homozygosity for the KIR A haplotype. c.

Uterine NK cells fail to secrete adequate amount of cytokines and growth factors needed to promote angiogenesis and remodeling of the maternal arteries. d.

The baby‘s father and mother are homozygous for the C1 epitope. e.

Insufficient activating signals were delivered to uterine NK cells.

ANSWERS 12–1 d 12–2 a 12–3 e 12–4 b 12–5 c 12–6 A. The ligand for the inhibitory receptor CD94:NKG2A on NK cells is HLA-E, a conserved HLA class I molecule. In common with HLA-A, -B, and -C, HLA-E must acquire a peptide in the lumen of the endoplasmic reticulum (ER) if it is to exit from the ER and progress to the surface of the target cell. Unlike HLA-A, -B, and -C, however, HLA-E is only able to bind to peptides generated from the leader sequence of HLA-A, -B, or -C after its removal from these MHC molecules. Uninfected and non-cancerous cells express adequate levels of MHC molecules and a steady supply of leader-sequence peptides ensures that normal levels of HLA-E arrive at the cell surface. This serves as an indicator of good health.

B. If a cell is infected or malignant, the levels of HLA class I molecules are decreased. This interrupts the supply of leader-sequence peptides, and thereby also causes a decrease in HLA-E on the cell surface. In the absence of ligand, NK cells bearing CD94:NKG2A are then unable to engage their inhibitory receptors; the signals from the activating receptors mobilize the killing mechanism, leading to the elimination of the unhealthy cell.

12–7 d

183

12–8 a 12–9 d 12–10 b 12–11 b 12–12 a, b, g 12–13 a 12–14 b 12–15 A. If a mother is homozygous for the KIR A haplotype, she expresses KIR2DL1 (an inhibitory NK-cell receptor) that binds to the C2 epitope of HLA-C on extravillous trophoblast cells. She does not, however, express KIR2DS1 (an activating NK-cell receptor) that uses the same C2 epitope ligand as KIR2DL1. In this combination, uterine NK cells do not receive sufficient activation to secrete the cytokines and growth factors that are required to adequately promote new blood vessel formation (angiogenesis). The result is shallow trophoblast invasion of the spiral arteries during implantation, which can result in an increased risk of pre-eclampsia in which the baby does not receive sufficient nutrients and the mother‘s blood pressure rises to dangerously high levels that could lead to hemorrhage.

B. If a mother is homozygous for the KIR B haplotype, she expresses KIR2DS1, which counterbalances the effect of inhibitory C2-specific receptors. In this combination, uterine NK cells are activated in a manner that favors deep placental invasion and over-nourishment during pregnancy. Elevated birth weight can lead to an obstructed labor.

12–16 c, h, i 12–17 b 12–18 a—3; b—1; c—2; d—5; e—4 12–19 a—2; b—1; c—2; d—4; e—3 12–20 c 12–21 b 12–22 a—8; b—5; c—2; d—4; e—6; f—1; g—7; h—3 12–23 c 12–24 b, f, h 184

12–25 d 12–26 A. The killing activity of the NK cell. Like cytotoxic T cells, NK cells can kill other cells by releasing molecules that induce apoptosis. When an activating receptor on an NK cell recognizes its ligand on the surface of a target cell, this tends to activate the killing function of the NK cell. But when an inhibitory receptor also recognizes its ligand on the target cell, this tends to inhibit the killing activity of the NK cell, even if activating receptors are also engaged.

Whether the NK cell kills the target cell depends on the balance between the activating and inhibiting signals. The known ligands for the inhibitory receptors are MHC class I molecules, and if there are normal levels of these molecules on the target-cell surface, the cell is not killed.

B. Virus-infected cells often have lower levels of MHC class I molecules on their surface. This feature is thought to be exploited by NK cells, which are continually monitoring levels of MHC class I molecules on host cells. When an NK cell finds a cell that lacks or has decreased MHC class I on its surface, the signals from the activating receptors predominate over those from the inhibitory receptors and the target cell is killed. Some viruses encode proteins that mimic MHC class I molecules and interfere with NK-cell attack by ligation of the NK cells‘ inhibitory receptors.

C. The actions of NK cells are considered part of innate immunity because NK cells can, in principle, act against any virus-infected cell: their killing activity is not dependent on the recognition of viral protein epitopes. In addition, NK cells are already present and ready to act immediately after they encounter an infected cell. Although there are large numbers of different inhibitory and activating receptors in the NK-cell repertoire, none of these receptors is encoded by a rearranging gene, and in most cases the receptors specifically recognize HLA allotypes and are relatively insensitive to the peptides bound.

D. Individual inhibitory NK-cell receptors are specific for particular allotypes of a given MHC class I molecule. The NK-cell repertoire of a person seems to be tailored to their own MHC tissue type, so that all NK cells in that person will carry at least one inhibitory receptor recognizing one of the person‘s own HLA class I molecules. This ensures that NK cells do not attack the healthy tissues of their own body. However, because MHC class I molecules are highly polymorphic, one person may have HLA class I allotypes that are not recognized by all the NK cells from another individual. If a tissue transplant is not matched exactly for HLA class I, therefore, some of the recipient‘s NK cells may not recognize the HLA class I molecules on the transplanted tissue and will attack it.

12–27 a, d 12–28 a, d, e 12–29 a, b, c, e, g 12–30 b, c 12–31 b, d, e

185

12–32 CD1 begins assembly with β2-microglobulin and self lipid in the endoplasmic reticulum of restricted cell types. It progresses through the Golgi, then to Golgi-derived vesicles, and is eventually presented on the cell surface. The complex is subsequently endocytosed via clathrincoated pits and intersects the endosomal pathway and the MHC class II compartment. Then self lipids are exchanged for pathogen-derived lipids before the complex is transported back to the cell surface for presentation to α:β T cells.

12–33 c, e 12–34 b, d 12–35 a—F; b—F; c—F; d—T; e—T; f—F 12–36 a—1, 6; b—4; c—5; d—1, 4, 6; e—2; f—3; g—6; h—7 12–37 c 12–38 e 12–39 c, d, e 12–40 b, c, e 12–41 Rationale: The correct answer is d. The conditions for adequate nourishment of the fetus are established early in pregnancy and involve converting the narrow spiral arteries of the uterus into wider conduits after extravillous trophoblast invasion. These high-conductance vessels direct sufficient blood flow to placenta during pregnancy and serve to regulate the blood pressure of the mother. Uterine NK cells interact with invading extravillous trophoblast cells using both inhibitory and activating receptors; which receptors are used is dependent on maternal haplotype.

The KIR A haplotype lacks the activating KIR2DS1 receptor, which engages the C2 epitope, but the KIR B haplotype expresses this receptor. Additionally, the KIR A haplotype expresses the strong inhibitory KIR2DL1 receptor which also engages the C2 epitope. In mothers who are homozygous for KIR A, the uterine NK cells encounter C2 epitopes on extravillous trophoblast cells using these strong inhibitory receptors. This causes an imbalance between inhibitory and activating signals delivered to the NK cells; KIR2DL1 will deliver strong inhibitory signals through the C2 epitope, but in the absence of KIR2DS1 there will be no activating signals delivered through the C2 epitope. If the uterine NK cells are not activated sufficiently, they will not secrete the cytokines and growth factors needed for complete invasion of the extravillous trophoblast cells, remodeling of the maternal spiral arteries, and promotion of new blood vessels.

If the baby is homozygous for the C1 epitope (which would happen 100% of the time if both mother and father were homozygous for the C1 epitope), then failure to activate through KIR2DS1 or induce inhibition through KIR2DL1 is no longer an issue. In the context of uterine NK cells, the increased risk for pre-eclampsia arises only when there is a combination of maternal homozygosity of the KIR A haplotype, and the fetus inherits the C2 epitope from the father.

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CHAPTER 13: FAILURES OF THE BODY’S DEFENSES 13–1 Match the term in column A with its description in column B. Column A ___ a. latency

___ b. seroconversion ___ c. serotype ___ d. superantigen ___ e. gene conversion

Column B 1. rearrangement of homologous genes to expression sites by an excision and replacement mechanism 2. differences between genetic strains of bacteria based on antibody assays 3. development of a quiescent state that does not cause disease 4. the cause of nonspecific activation of T cells and excessive cytokine production 5. the initial onset of antiviral antibody production

13–2 _____ results when a gene affecting the immune system mutates, thereby compromising the body‘s defense against infection. a. gene conversion b. epidemics c. primary immunodeficiency disease d. secondary immunodeficiency disease e. seroconversion.

13–3 A primary immune response against influenza virus produces antibodies that bind to _____. a. hemagglutinin and neuraminidase b. variable surface glycoproteins c.

EBNA-1 d. protein toxins e. gp41 and gp120.

13–4 a. b. c. d. e. f.

The serotypes of Streptococcus pneumoniae differ in their _____. superantigen products ability to fix complement rates of gene conversion capsular polysaccharides variable surface glycoproteins neuraminidase epitopes.

13–5 All of the following are associated with the ability of influenza virus to escape from immunity except _____. a. age b. error-prone replication of its DNA genome c. co-infection with avian and human influenza viruses 187

d. e.

recombinant strains the phenomenon of ‗original antigenic sin.‘

13–6 a. b. c. d.

All of the following use gene conversion to avoid immune detection except _____.

Salmonella typhimurium Trypanosoma brucei Treponema pallidum Neisseria gonorrhoeae.

13–7 Genes encoding _____ rearrange in trypanosomes permitting replication and survival of the pathogen until the host produces an antibody response against the altered gene product. a. pilin b. flagellin c. variable surface glycoproteins (VSGs) d. hemagglutinin.

13–8 _____ is a strategy used by herpesviruses where replication and the generation of virusderived peptides are avoided in order to hide from the immune response. a. latency b. antigenic shift c. antigenic drift d. seroconversion e. gene conversion.

13–9 Which of the following statements regarding herpes simplex virus is false? a.

Because sensory neurons express low levels of MHC class I molecules, they provide appropriate sites for viral dormancy. b.

Reactivation of herpesviruses follows stressful incidents. c.

Cold sores develop as a consequence of CD8 T-cell killing. d.

In one‘s lifetime, periodic episodes of reactivation are common. e.

Herpes simplex virus infects B lymphocytes.

13–10 Which of the following is not associated with the reactivation of herpesviruses? a. hormonal fluctuations b. antibody deficiency c. bacterial infection d. immunosuppression e. ultraviolet radiation.

13–11 Herpesviruses include all of the following except _____. a. varicella-zoster b.

Epstein–Barr virus c. herpes simplex virus d. cytomegalovirus e.

All of the above are herpesviruses.

188

13–12 Shingles is associated with infection by _____. a.

Epstein–Barr virus b.

Staphylococcus aureus c. herpes zoster d.

Candida albicans e.

Listeria monocytogenes.

13–13 Match the pathogen in column A with the condition or disease it causes in column B. There may be more than one correct answer, and answers may be used more than once.

Column A Column B ___ a. Staphylococcus aureus 1. glandular fever ___ b. Trypanosoma brucei 2. chickenpox ___ c. Epstein–Barr virus 3. sleeping sickness ___ d. Treponema pallidum 4. toxic shock ___ e. Varicella-zoster virus 5. B-cell lymphoproliferative disease ___ f. Salmonella typhimurium 6. shingles ___ g. Human immunodeficiency virus 7. food poisoning ___ h. Neisseria gonorrhoeae 8. sexually transmitted disease 9. acquired immune deficiency syndrome 13–14 Epstein–Barr virus-infected cells are poor targets for CD8 T-cell killing because _____. a. the virus inhibits MHC class I expression b. the virus escapes from the phagosome into the cytosol c. infected cells do not express any viral proteins during latency d. the proteasome cannot generate viral peptides for presentation by MHC class I molecules.

13–15 Superantigens bind to all of the following molecules except _____. a.

CD4 b.

MHC class II α chain c.

CD28 d.

T-cell receptor Vβ chain.

13–16 All of the following are associated with superantigens except _____. a. effective at minuscule concentrations b. nonspecific activation of 2–20% of body‘s CD8 T cells c. processing to peptides is not required for T-cell activation d. massive production of IL-2, IFN-γ, and TNF-α e. activate α:β T cells f. provoke vomiting and diarrhea when ingested.

13–17 Staphylococcal superantigen-like protein 7 (SSLP7) produced by Staphylococcus aureus, binds to _____ and thereby prevents the killing of the bacterium by the host‘s immune system during infection. (Select all that apply.) a.

NK-cell activating receptors b.

C5 complement protein c.

CD8 co-receptor 189

d. e.

T-cell receptor Vβ chain Fc region of IgA.

13–18 Which of the following is not associated with bacterial infection due to a genetic defect in or pathogen-induced subversion of normal phagocytic processes? a. leukocyte adhesion deficiency b. chronic granulomatous disease c. hereditary angioedema d.

Chédiak–Higashi syndrome e.

Listeria monocytogenes f.

Mycobacterium tuberculosis.

13–19 Which of these characteristics is not true of IFN-γ? a.

When it acts on target cells, it enhances the engulfment and killing of bacteria. b.

It is the major activating cytokine of macrophages. c.

It activates the JAK–STAT signal transduction pathway after binding to its cognate receptor. d.

It is secreted by CD8 cytotoxic T cells, CD4 TH1 cells, and NK cells. e.

It is secreted and functions as a monomer but facilitates the dimerization of its receptor. f.

It is able to render target cells responsive even if they express only one functional allele of IFNγR1.

13–20 Dominant mutant forms of IFNγR1 exhibit all of the following in heterozygotes except _____. a. they are recycled by endocytosis more quickly than the normal receptor b. the cytoplasmic tail is truncated c. they are able to form stable dimers with the normal form d. they cause less severe immunodeficiency than do the homozygous recessive forms e. they are unable to transduce signals when bound to the normal form.

13–21 Individuals with an antibody deficiency are more susceptible to infections by all of the following except _____. a.

Streptococcus pneumoniae b.

Haemophilus influenzae c.

Streptococcus pyogenes d.

Mycobacterium tuberculosis e.

Staphylococcus aureus.

13–22 When deficient, which of the following proteins does not render the individual more susceptible to encapsulated bacteria? a.

C1INH b.

C3 c.

Bruton‘s tyrosine kinase d. factor D e. factor I f.

CD40 ligand.

190

13–23 Which of the following pairs is mismatched? a.

X-linked agammaglobulinemia: gamma globulin injections b.

X-linked hyper IgM syndrome: GM-CSF injections c.

X-linked hyper IgM syndrome: gamma globulin injections d. hereditary angioedema: C1INH infusions e.

None of the above is mismatched.

13–24 All of the following are X-linked immunodeficiencies except _____. a.

Wiskott–Aldrich syndrome caused by deficiency of WASP b. hyper IgM syndrome caused by deficiency of CD40 ligand c. lymphoproliferative syndrome caused by deficiency of SH2D1A d.

Chédiak–Higashi syndrome caused by deficiency of CHS1 e. agammaglobulinemia caused by deficiency of Bruton‘s tyrosine kinase f.

SCID caused by deficiency of common γ chain.

13–25 Deficiencies in complement components C5–C9 and properdin (factor P) are associated with _____. a. immune-complex disease b. susceptibility to Neisseria c. secondary immunodeficiency diseases d. hereditary angioedema e. leukocyte adhesion deficiency.

13–26 Paroxysmal nocturnal hemoglobinuria is caused by _____. a. a profound deficiency of neutrophils b. leukocytosis c. immune-complex deposition in tissues d. defects in recruitment of phagocytes to infected tissues e. complement-mediated lysis of erythrocytes.

13–27 All of the following are associated with hereditary angioedema except _____. a. possible death by suffocation b. overproduction of vasoactive C2a fragment and peptide bradykinin c. hyporesponsiveness of classical complement pathway d. subepithelial edema e.

C1 inhibitor deficiency.

13–28 Which of the following statements regarding C1 inhibitor (C1INH) is false? (Select all that apply.) a.

C1INH belongs to a family of serine and cysteine protease inhibitors called the serpins. b.

C1INH inhibits C1r but not C1s, so partial serine protease activation is achieved in the classical complement pathway. c.

C1INH is cleaved by C1. d.

When bound to C1 as a pseudosubstrate, it activates the protease activity of C1.

191

e.

Heterozygous individuals who have a single-gene defect in C1INH cannot make sufficient quantities of the gene product and must receive recombinant C1INH by infusion.

13–29 Severe combined immune deficiency (SCID) describes a condition in which neither _____ nor _____ are functional. a. classical; alternative pathways of complement b.

T-cell-dependent antibody responses; cell-mediated immune responses c. innate; acquired immune responses d.

MHC class I; MHC class II molecules.

13–30 Wiskott–Aldrich syndrome involves an impairment of _____. a. lymphocytes and platelets b. classical complement and blood-clotting pathways c. the expression of MHC class I and class II molecules d.

T-cell and B-cell development e. cytokine and cytokine receptor production.

13–31 Mutations affecting all of the following except _____ interfere directly with the rearrangement of immunoglobulin and T-cell receptor genes. a.

Artemis b. purine nucleoside phosphorylase (PNP) c.

DNA-dependent protein kinase (DNA-PK) d.

RAG-1 e.

RAG-2.

13–32 A deficiency in _____ causes a condition that closely resembles X-linked severe combined immunodeficiency and is characterized by inefficient cytokine signaling. a. adenosine deaminase (ADA) b. class II transactivator (CIITA) c.

TAP1 or TAP2 d.

RAG1 or RAG2 e.

Janus 3 kinase (Jak3) f.

SH2D1A. 13–33 Patients who lack _____ are very susceptible to infections with intracellular bacteria, including the ubiquitous nontuberculous strains of mycobacteria. (Select all that apply.) a.

CD40 ligand b. the IL-12 receptor c. the IFN-γ receptor d. properdin (factor P) e.

CD18.

13–34 Which of the following explains why Streptococcus pneumoniae can infect an individual recurrently? a.

Previous infection with S. pneumoniae wears down the immune system over time.

192

b.

S. pneumoniae is never completely eradicated during an infection and can reactivate if the host is immunocompromised. c.

Immune responses against S. pneumoniae are serotype-specific and protect only against strains that possess the same capsular polysaccharide antigens. d.

Anti-capsular antibodies are cleared from the host quickly after an active infection. e.

The capsular polysaccharide antigens of S. pneumoniae do not induce immunological memory.

13–35 Protective antibodies generated in response to influenza virus bind to _____ of the viral envelope. a. hemagglutinin and neuraminidase b. polysaccharides c. variable surface glycoproteins d. superantigens e. gp41 and gp120.

13–36 Which of the following contribute to new epidemics and the long-term survival of the influenza virus in the human population? (Select all that apply.) a.

New viral strains possess epitopes not recognized by antibodies made in the previous epidemic. b.

The first influenza strain provoking a primary immune response constrains the types of antibodies made during a subsequent encounter with a different strain. c.

The virus loses the capacity to express hemagglutinin, thereby rendering neutralizing antibodies useless. d.

The virus uses gene rearrangement to achieve antigenic variation, which creates new epitopes. e.

The RNA genome of the influenza virus is subject to point mutations during viral replication.

13–37 An epidemic affects _____, whereas a pandemic affects _____. a. susceptible individuals; immune individuals b. immune individuals; susceptible individuals c. global populations; local populations d. local populations; global populations.

13–38 The mode of evolution responsible for the production of recombinant influenza viruses composed of a genome derived from two different influenza variants is called _____. a. gene conversion b. antigenic shift c. latency d. immune evasion e. antigenic drift.

13–39 _____ cause(s) mild and limited disease, whereas _____ cause(s) more severe disease and higher mortality. a.

Antigenic drift; antigenic shift 193

b. c. d.

Antigenic shift; antigenic drift Epidemics; pandemics Pandemics; epidemics.

13–40 Which of the following is not a virus that can cause a persistent infection in the host by establishing latency? a. influenza virus b. herpes simplex virus c. varicella-zoster d.

Epstein–Barr virus e. human immunodeficiency virus.

13–41 Trypanosomes escape from adaptive immunity by altering the type of _____ expressed on the parasite surface. a. neuraminidase b. hemagglutinin c. variable surface glycoprotein (VSG) d. superantigen e. capsular polysaccharide.

13–42 Epstein–Barr virus infects and establishes latency in _____, gaining entry by binding to _____. a.

B cells; CR2 b.

T cells; CD4 c.

T cells; CD8 d. neurons; MHC class I e.

B cells; EBNA-1.

13–43 Which of the following is not used by the herpes simplex virus to subvert host immune responses? a. a virus-encoded Fc receptor b. a virus-encoded complement receptor c. inhibition of MHC class I expression d. inhibition of peptide transport by transporter associated with antigen processing (TAP) e. inhibition of ICAM-1 expression.

13–44 Listeria monocytogenes replicates in _____ of macrophages after _____. a. the phagosome; inhibition of fusion of the phagosome with the lysosome b. the cytosol; escaping from the phagosome c. a specialized membrane-bound vesicle; infection of the cell d. extracellular spaces; coating itself with human proteins e. nucleus; fusion with the nuclear membrane.

13–45 Which of the following is not a characteristic of staphylococcal enterotoxins? a.

They bind to MHC class I molecules and T-cell receptors. b.

They cause T cells to divide and differentiate into effector T cells.

194

c.

They stimulate between 2% and 20% of the total T-cell population. d.

They cause excessive synthesis and release of cytokines. e.

They induce suppression of the immune response by causing T cells to undergo apoptosis.

13–46 Using the table below, match the deficiency disease in column A with its specific abnormality in column B. Column A Column B ___a. Hereditary angioneurotic edema 1. Thymic aplasia ___b. DiGeorge‘s syndrome 2. Defective transporter associated with antigen processing (TAP) ___c. X-linked hyper IgM syndrome 3. Defective RAG1 or RAG2 ___d. Severe combined immunodeficiency 4. Defective C1 inhibitor ___e. Bare lymphocyte syndrome (MHC 5. Defective CD40 ligand class I) ___f. X-linked agammaglobulinemia 6. Defective Btk tyrosine kinase ___g. Leukocyte adhesion deficiency 7. Defective CD18 ___h. Chronic granulomatous disease 8. Defective NADPH oxidase 13–47 Which of the following statements regarding inherited immunodeficiency diseases is correct? a.

Affected individuals are less susceptible to infection. b.

Mortality rates are reduced by the administration of antibiotics to affected individuals. c.

Most deficiency syndromes are caused by dominant gene defects. d.

Women are more likely than men to inherit X-linked immunodeficiencies. e.

Extracellular bacterial infections are common in deficiency syndromes with T-cell defects.

13–48 Individuals with an immunodeficiency affecting B-cell function are more susceptible to infections caused by which of the following pathogens? a.

Toxoplasma gondii b. respiratory syncytial virus c.

Haemophilus influenzae d.

Listeria monocytogenes e.

Mycobacterium tuberculosis.

13–49 Women who are heterozygous for a defective Bruton‘s tyrosine kinase (Btk) gene _____. a. are more susceptible to infections caused by extracellular pyogenic bacteria b. have a 50% chance of having a son with X-linked hyper IgM syndrome c. mount normal B-cell immune responses despite having lowered levels of serum IgG d. exhibit X-linked agammaglobulinemia e. have non-random X inactivation in their B cells.

13–50 Which of the following deficiency syndromes affects T-cell but not B-cell function? a.

X-linked agammaglobulinemia b.

X-linked hyper IgM syndrome 195

c. d. e.

X-linked lymphoproliferative syndrome X-linked SCID X-linked Wiskott–Aldrich syndrome.

13–51 _____ results in defective phagocytic processes causing chronic bacterial infections.

(Select all that apply.) a.

Chédiak–Higashi syndrome b.

Wiskott–Aldrich syndrome c. myeloperoxidase deficiency d.

X-linked agammaglobulinemia (XLA) e. chronic granulomatous disease (CGD).

13–52 _____ participates in the T-cell cytoskeletal reorganization required for T-cell cytokine production and cell-mediated interactions. a. adenosine deaminase (ADA) b. purine nucleotide phosphorylase (PNP) c.

Wiskott–Aldrich syndrome protein (WASP) d. myeloperoxidase e.

Bruton‘s tyrosine kinase (Btk).

13–53 Chronic granulomatous disease (CGD), a condition resulting in chronic bacterial and fungal infections, is caused by one or more defects in _____, compromising the ability of macrophages to _____. a.

CD18; produce cell adhesion molecules b.

NADPH oxidase; produce superoxide radical (O2–) c.

CD40 ligand; produce GM-CSF d.

C5–C9; defend against Neisseria e.

C3; opsonize capsulated bacteria.

13–54 A genetic defect in _____ results in the accumulation of toxic levels of nucleotide metabolites and loss of T-cell function. a.

NADPH oxidase b. glucose-6-phosphate dehydrogenase c. myeloperoxidase d.

SH2D1A e. adenosine deaminase (ADA).

13–55 Explain why a staphylococcal infection might produce a medical emergency.

13–56 Bare lymphocyte syndrome leading to a lack of HLA class II molecule expression is due to a defect in _____. a. transcriptional regulators of HLA class II loci b. the sequence of the conserved X box of the HLA class II promoter c. a TAP peptide transporter d.

RAG-1 or RAG-2 e. thymic development.

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13–57 A. Which antigens are most important in the immune response to the influenza virus?

B. Explain the difference between antigenic drift and antigenic shift in the influenza virus.

C. Which is most likely to lead to a major worldwide pandemic?

D. What is the role of the phenomenon of ‗original antigenic sin‘ in immunity to this virus?

13–58 Why does it benefit the African trypanosome (T. brucei) to maintain more than 1000 genes encoding surface glycoproteins, when only one of these glycoproteins is expressed on the surface of the parasite at any given time?

13–59 Using Table Q13-59, match the mechanism of evasion and subversion of the immune system in column A with the pathogen in column B. Table Q13-59 Column A

Column B

a. Variant pilin protein expression

1. Staphylococcus aureus

b. Induction of quiescent (latent) state in neurons

2. Toxoplasma gondii

c. Reactivation of infected ganglia after stress or immunosuppression

3. Salmonella typhimurium

d. Alternative expression of two antigenic forms of flagellin

4. Influenza virus

e. Recombination of RNA genomes of avian and human origins

5. Mycobacterium tuberculosis

f. Escape from phagosome and growth and replication in cytosol

6. Varicella-zoster

g. Survival in a membrane-bounded vesicle resistant to fusion with other cellular vesicles

7. Neisseria gonorrhoeae

h. Coating its surface with human proteins

8. Treponema pallidum

i. Inhibiting fusion of phagosome with lysosome and survival in the host cell‘s vesicular system

9. Listeria monocytogenes

j. Immunosuppression caused by nonspecific proliferation and apoptosis of T cells

10. Herpes simplex virus

13–60 Herpes simplex virus favors neurons for latency because of the low level of _____, which reduces the likelihood of killing by CD8 T cells. a.

LFA-3 b.

Toll-like receptors (TLRs) c. transporter associated with antigen processing (TAP) d.

MHC class I e.

MHC class II. 13–61 197

A. Deficiencies in antibody production can be due to a variety of underlying genetic defects.

Name two immunodeficiency diseases, other than the severe combined immunodeficiencies, in which a defect in antibody production is the cause of the disease, and for which the underlying genetic defect is known. For each disease, say (i) how antibody production is affected, and (ii) what the underlying defect is and why it has this effect.

B. What is the main clinical manifestation of immunodeficiency diseases in which antibody production is defective but cell-mediated immune responses are intact?

13–62 Explain why women who show no disease symptoms themselves can pass on some heritable diseases to their sons, whereas their daughters seem to be unaffected. Would a disease with this pattern of inheritance be caused by a recessive or a dominant allele?

13–63 A. Name three immunodeficiency diseases caused by defects in phagocytes.

B. Which immunodeficiency disease is caused by a defect in the phagocyte NADPH oxidase system, and what is the cellular effect of this defect?

C. What are the main clinical effects of defects in phagocyte function?

13–64 A. What type of immune deficiency would you see in a child lacking the common γ chain of the receptor for cytokines IL-2, IL-4, and IL-7, among others? Explain your answer.

B. Why would you see the same type of immunodeficiency in a child lacking Jak3 kinase function?

C. What treatment might be possible to remedy this immunodeficiency?

13–65 Christiana Carter had no obvious problems until she was 18 months old, when she stopped gaining weight, her appetite became poor, and she had recurrent episodes of diarrhea. At 24 months, Christiana developed a cough with pulmonary infiltrates unresponsive to treatment with the antibiotics clarithromycin and trimethoprim/sulfamethoxazole. Within 3 months, she developed lymphadenopathy, hepatosplenomegaly, and fevers. A computed tomography scan revealed enlarged mesenteric and para-aortic lymph nodes. A biopsy of an enlarged axillary lymph node revealed acid-fast bacilli, and cultures from the lymph node and blood grew Mycobacterium fortuitum. HIV was ruled out after negative tests by ELISA and PCR. Serologic testing for tetanus antitoxoid antibody showed a normal post-vaccination level. Christiana‘s peripheral blood mononuclear cells (PBMCs) were cultured with interferon-γ plus lipopolysaccharide with no significant increase in TNF-α production. A variety of broadspectrum and anti-mycobacterial antibiotics were administered, lowering the fever, and over the course of the next 2 months Christiana began to gain weight but continued to show signs of persistent infection. Which of the following is the most likely explanation for these clinical findings? a. leukocyte adhesion deficiency b. chronic granulomatous disease c. interferon-γ receptor deficiency d.

X-linked agammaglobulinemia e. severe combined immune deficiency.

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13–66 Which statement regarding retrovirus proviruses is false? a.

Proviruses form immediately after the RNA genome assembles with viral proteins and infectious virions are produced. b.

Proviruses consist of double-stranded DNA. c.

Proviruses are flanked by repetitive sequences called long terminal repeats (LTRs). d.

The host cell must provide the transcriptional and translational machinery in order for RNA and protein products to be made from proviruses. e.

A cDNA intermediate is required in order to produce a provirus.

13–67 In reference to human immunodeficiency virus (HIV), match the term in column A with its description in column B. Column A Column B ___ a. highly active anti-retroviral therapy 1. healthy individuals with low viremia (2000 copies or fewer of viral RNA per milliliter of blood) ___ b. endogenous retrovirus 2. asymptomatic period that follows the initial phase of infection ___ c. clinical latency 3. anti-HIV antibodies first appear in circulatory system ___ d. seroconversion 4. naturally occurring retrovirus-like sequences making up 8% of the human genome ___ e. provirus 5. prevents progression to AIDS ___ f. opportunistic pathogens 6. commensal microorganisms actively controlled by healthy people ___ g. viremic controllers 7. produced after cDNA integrates into the genome of the host cell 13–68 The pol gene of HIV produces all of the following except _____. a. integrase b. protease c. matrix protein d. reverse transcriptase.

13–69 For infectious HIV virions to be made, the infected cell must _____. (Select all that apply.) a. be CD4-positive b. express low levels of CCR5 c. express functional NFκB d. be latent e. be polyreactive.

13–70 Match the nine HIV genes in column A with its product(s) in column B. Column A Column B ___ a. pol 1. core and matrix protein ___ b. rev 2. affects particle infectivity ___ c. env 3. transcriptional regulator 199

___ d. nef ___ e. vif

___ f. gag ___ g. vpu ___ h. vpr ___ i. tat

4. gp120 and gp41 5. assists viral replication, and decreases expression of MHC class I and class II molecules and CD4 6. transcript export from nucleus 7. reverse transcriptase, protease, and integrase 8. initiates CD4 degradation and release of infectious virions from the cell 9. cell-cycle arrest, DNA transport to nucleus, and influences virion production

13–71 In reference to column B in Question 13-70, which of the protein products are present in the virion? (Select all that apply.)

13–72 Explain the difference between (A) elite controllers and (B) elite neutralizers.

13–73 A. Explain the mechanism by which human immunodeficiency virus (HIV) enters a host cell.

B. Explain the cellular tropism of HIV, discussing the difference between macrophagetropic and lymphocyte-tropic HIV. C. Some people seem to be resistant to HIV infection because a primary infection cannot be established in macrophages. What is the reason for this?

13–74 A. What does the term seroconversion mean in relation to an HIV infection?

B. What relationship does seroconversion have to the time course of an HIV infection?

13–75 Which property of HIV renders the virus difficult to eradicate by the body‘s immune defenses and also limits the efficacy of drug therapies?

13–76 Which of the following is required for fusion of the human immunodeficiency viral envelope with the host cell membrane and subsequent internalization? a. reverse transcriptase b. gp120 c. gp41 d. integrase e. protease.

13–77 Which of the following statements about human immunodeficiency virus (HIV) are correct? (Select all that apply.) a.

HIV has a DNA genome. b.

HIV must synthesize reverse transcriptase immediately after infecting a cell. c.

HIV infects cells expressing CD4. d.

HIV requires the CXCR4 co-receptor for internalization by T cells. e.

NFB is a transcription factor that facilitates the transcription of proviral RNA. 200

13–78 During infection with HIV, a person is said to undergo seroconversion when _____. a.

HIV variants convert from macrophage-tropic to lymphocyte-tropic late in infection b. anti-HIV antibodies are detectable in their blood serum c. cellular transcription favors the production of HIV-encoded RNA d.

HIV is transferred from an infected person to an uninfected recipient e. the initial phase of infection is followed by clinical latency.

13–79 A patient is diagnosed with AIDS when CD4 T-cell counts _____. a. rise markedly after T-cell activation b. fall below the CD8 T-cell count c. fall below 1000 cells/l d. fall below 500 cells/l e. fall below 200 cells/l.

13–80 Reverse transcriptase is a _____ encoded by _____. a.

DNA-dependent DNA polymerase; HIV b.

DNA-dependent DNA polymerase; influenza virus c.

RNA-dependent DNA polymerase; HIV d.

RNA-dependent DNA polymerase; influenza virus e.

RNA-dependent RNA polymerase; HIV. 13–81 Preferred viral targets for HIV therapy include (select all that apply): a. reverse transcriptase b. matrix protein c. gp120 d.

CD4 e. protease.

13–82 Explain why HIV-infected individuals develop resistance more quickly to protease inhibitors than to inhibitors of reverse transcriptase.

13–83 What would you predict might happen to the course of the HIV infection in a person who developed toxic shock syndrome while in the latent phase of HIV? Explain your answer.

ANSWERS 13–1 a—3; b—5; c—2; d—4; e—1 13–2 c 13–3 a 13–4 d 201

13–5 b 13–6 c 13–7 c 13–8 a 13–9 e 13–10 b 13–11 e 13–12 c 13–13 a—4, 7; b—3; c—1, 5; d—8; e—2, 6; f—7; g—8, 9; h—8 13–14 d 13–15 a 13–16 b 13–17 b, e 13–18 c 13–19 e 13–20 a 13–21 d 13–22 a 13–23 e 13–24 d 13–25 b 13–26 e 13–27 c

202

13–28 b, d 13–29 b 13–30 a 13–31 b 13–32 e 13–33 b, c 13–34 c 13–35 a 13–36 a, b, e 13–37 d 13–38 b 13–39 a 13–40 a 13–41 c 13–42 a 13–43 e 13–44 b 13–45 a 13–46 a—4; b—1; c—5; d—3; e—2; f—6; g—7; h—8 13–47 b 13–48 c 13–49 e 13–50 e

203

13–51 a, c, e 13–52 c 13–53 b 13–54 e 13–55 Some staphylococci produce toxins that act as superantigens, for example the staphylococcal enterotoxins and toxic shock syndrome toxin-1 (TSST-1). Superantigens can bind simultaneously to MHC class II molecules and to T-cell receptors that possess certain types of Vβ region, resulting in the activation of all T cells carrying such a receptor. Superantigens thus nonspecifically activate a large proportion of the CD4 T-cell repertoire, resulting in the production of large quantities of cytokines from the activated T cells and from macrophages activated by these cells. The systemic production of cytokines (for example TNF-α) causes increased vascular permeability and vasodilation throughout the body, leading to loss of fluid into the tissues, rapid collapse of the circulatory system (systemic shock), and organ failure.

Toxic shock therefore requires immediate medical attention, primarily to replace the intravascular fluid.

11–56 a 11–57 A. Influenza hemagglutinin (HA) and neuraminidase (NA) bear the main epitopes against which protective antibodies are made.

B. Antigenic drift is due to the frequent point mutations in the RNA genome of influenza virus. Mutants that acquire changes in the HA and NA epitopes are selected because they are not subject to the serotype-specific immunity generated against the original strain. Because point mutation causes only relatively small changes at a time, this process is known as antigenic drift.

Antigenic shift is due to recombination between a human influenza virus and an avian influenza virus, leading to replacement of the human NA and/or HA with the avian type. The genome of the influenza virus is composed of eight separate pieces of RNA. When a human influenza virus and an avian influenza virus infect the same cell (usually in domestic livestock such as pigs, ducks, or chickens), reassortment of the RNAs can lead to the generation of a new human virus encoding the avian HA and/or NA that has never before been encountered by the human population.

C. Worldwide pandemics are caused by influenza viruses that have undergone antigenic shift, because no human population has any immunity to them. In antigenic drift, where the changes are more gradual, a population will contain some people who are immune to some epitopes and some to others. Epidemics due to antigenic drift are usually relatively mild and limited.

D. The phenomenon of ‗original antigenic sin‘ means that when a person is reinfected with a new strain of influenza virus that shares some epitopes with the virus they were first infected by, they will make an immune response (which will be a secondary immune response) only to the shared epitopes and not to the new epitopes. This is because when the virus binds via a new epitope (say HA*) to the B-cell receptor of a HA*-specific naive B cell, preexisting IgG 204

antibodies against other epitopes on the virus can bind via their Fc regions to FcγRIIB1 receptors on the surface of the same cell. Cross-linking of the B-cell receptor and Fc receptor delivers an inhibitory signal to the B cell, thus blocking the production of a HA*-specific antibody response.

As an influenza virus undergoes antigenic drift, some HA and NA epitopes change while others remain the same, so the person retains some immunity. However, when a completely new HA or NA is produced as a result of antigenic shift, and it shares no epitopes with the original antigens, the body sees the virus as a completely new infection, and disease results while the body is making a new primary response against the virus.

13–58 This strategy has been selected by evolution to maintain the long-term survival of the parasite in its host. The surface glycoproteins, known as variable surface glycoproteins (VSGs) are involved in enabling the parasite to evade the immune response of its host. The trypanosome can change the VSG that is expressed, thus rendering antibodies made against the previously expressed VSG ineffective at controlling the parasite. Switching occurs at random during the life cycle of the trypanosome by a process called gene conversion, in which a different VSG gene is rearranged to the single ‗expression site,‘ replacing the original gene, and is expressed instead.

This process is called antigenic variation and leads to the periodic rise and fall in the number of parasites that is characteristic of trypanosome infections. Antibodies made by the host against the VSG expressed on the infecting trypanosomes will start to suppress the infection and parasite numbers will fall. But if some parasites switch VSG, these antibodies will be ineffective, and parasites bearing the new VSG will multiply. Parasite numbers will rise for a time until the new immune response begins to suppress them in turn. By then a third VSG gene is likely to have been expressed, and parasites bearing that one will begin to predominate in the host, and so the cycle continues.

13–59 a—7; b—10; c—6; d—3; e—4; f—9; g—2; h—8; i—5; j—1 11–60 d 11–61 A. 1. X-linked agammaglobulinemia. (i) No antibody at all. (ii) It is caused by a defect in the tyrosine kinase Btk, which is necessary for B-cell development and is encoded on the X chromosome. No mature B cells develop. 2. X-linked hyper IgM syndrome. (i) Large amounts of IgM antibody, but no antibodies of isotypes other than IgM, are produced. Virtually no antibodies are made against T-cell dependent antigens. (ii) It is caused by a defect in the protein CD40 ligand, which is encoded on the X chromosome and is expressed on T cells. T cells lacking CD40 ligand cannot give help to B cells, which thus cannot respond to most protein antigens and cannot switch isotype.

Other diseases in which defects in antibodies seem to be the main deficiency are common variable immunodeficiency (defective antibody production; cause unknown) and selective IgA and/or IgG deficiency (no IgA or IgG synthesis; cause unknown).

B. Defective antibody responses lead to increased susceptibility to extracellular bacteria and to some viruses.

13–62 Diseases with this pattern of inheritance are caused by defective alleles carried on the X chromosome and are called X-linked diseases. Women have two X chromosomes, one inherited 205

from each parent. A man only has one X chromosome, which he always inherits from his mother. A woman with one X chromosome carrying a recessive disease allele and one X chromosome with a normal allele will show no symptoms of the disease because the normal allele will compensate. However, if she passes on the defective X chromosome to a son, he will show the disease because he has no compensating normal allele. Unless her husband also has the defective allele, which is extremely unlikely because most of these immune defects are very rare, her daughter will also not show the disease even if she inherits a defective X chromosome from her mother. Diseases that show this pattern of inheritance are always recessive. A dominant disease allele carried on an X chromosome will show up as disease equally in women (even if they are heterozygous for the gene) and in men.

13–63 A. Chronic granulomatous disease, Chédiak–Higashi syndrome, and leukocyte adhesion deficiency. Others are: glucose-6-phosphate dehydrogenase deficiency and myeloperoxidase deficiency.

B. Chronic granulomatous disease is caused by defects in phagocyte NADPH oxidase.

Phagocytes with this defect cannot produce superoxide radicals and are less effective at intracellular killing of ingested bacteria. Macrophages infected with bacteria that they cannot kill form the granulomas characteristic of this condition.

C. Persistent infections with bacteria, especially encapsulated bacteria, and fungi.

13–64 A. Severe combined immune deficiency (SCID), characterized by an almost complete absence of T-cell and B-cell function and the inability to make any effective immune responses.

Because the child cannot make functional receptors for these important cytokines, their lymphocytes cannot respond to them. The inability of naive T cells to respond to IL-2 in particular blocks the proliferation and differentiation of T cells and thus all cell-mediated immune responses and T-cell dependent antibody responses. Without treatment, children with SCID die early in infancy from common bacterial or viral infections.

B. Jak3 kinase is part of the intracellular signaling pathway that leads from activated cytokine receptors. Thus, a lack of Jak3 kinase also leads to SCID. C. Reconstitution of a functioning immune system by bone marrow transplantation from a healthy donor can treat those types of SCID in which the genetic defect is intrinsic to lymphocytes or other bone marrow derived cells.

13–65 Rationale: The correct answer is c. The key finding here is the unresponsiveness of Christiana‘s PBMCs to interferon-γ (IFN-γ) plus LPS. When IFNγ binds the IFNγ receptors of macrophages, these cells become stimulated and very effective at killing intravesicular bacteria such as mycobacteria. Defects in the IFN-γ a receptor are associated with persistent mycobacterial infections. Because of Christiana‘s age, she is likely to be homozygous for a recessive mutation in IFNγR1 that leads to the lack of receptor. Chronic granulomatous disease and leukocyte adhesion disease result from defects in NADPH oxidase and CD18, respectively, but these defects would not hinder the ability of PBMCs from affected individuals to produce TNF-α in response to IFN-γ. Because Christiana has normal levels of tetanus antitoxoid antibody, she does not have X-linked agammaglobulinemia or severe combined immune deficiency.

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13–66 a 13–67 a—5; b—4; c—2; d—3; e—7; f—6; g—1 13–68 c 13–69 a, c 13–70 a—7; b—6; c—4; d—5; e—2; f—1; g—8; h—9; i—3 13–71 1, 4, 7 13–72 A. Elite controllers, who make up about 1 in 300 of HIV-infected people, suppress their infection so effectively that HIV RNA cannot be detected in blood samples using the standard clinical assay. They live healthy lives for decades. Genome analysis indicates that certain HLAB types are associated with elite and viremic (low viremia) controllers, where 67% of controllers have HLA-B*13, -B*27, -B*57 or -B*58, compared to only 37% of progressors who had these HLA-B types.

B. Elite neutralizers, who make up about 1 in 500 of HIV-infected people, make broadly neutralizing antibodies after exposure to several HIV strains. These antibodies possess many more somatic mutations than other antibodies, indicating that B cells making the broadly neutralizing antibodies have undergone many different episodes of antigen-mediated somatic mutation. These antibodies are capable of neutralizing many strains of HIV. 13–73 A. Human immunodeficiency virus (HIV) infects cells bearing CD4 molecules on their surface. These include TH1 and TH2 cells, macrophages, and dendritic cells. CD4 acts as a receptor involved in binding the gp120 envelope glycoprotein of HIV. A co-receptor is also required for virus entry. Two are used by HIV: the chemokine receptors CCR5 and CXCR4.

CCR5 is expressed on all CD4+ cells, whereas CXCR4 is restricted to T cells. After binding to the co-receptor, another viral envelope glycoprotein, gp41, facilitates fusion between the host cell‘s plasma membrane and viral envelope with the release of viral components into the cytoplasm.

B. The cell tropism of HIV depends on which co-receptor is used for entry. Macrophagetropic HIV, associated with early infection, uses the CCR5 co-receptor. Lymphocyte-tropic HIV, associated with a phenotypic change in late infection in about 50% of cases, uses CXCR4.

C. About 1% of the caucasoid population is homozygous for a mutant form of CCR5 that cannot be used by HIV as a co-receptor. The mutation involves a 32-nucleotide deletion called CCR5-δ32, which alters the reading frame and results in a nonfunctional CCR5 protein. This renders such individuals resistant to primary infection by macrophage-tropic variants of HIV but still susceptible to lymphocyte-tropic strains that use the CXCR4 co-receptor.

13–74 A. Seroconversion is the point during an infection at which antibodies specific for the 207

pathogen can first be detected in the blood serum. In an HIV infection, antibody is produced when virions are being released from infected cells and are thus accessible to B-cell antigen receptors, a period referred to as acute viremia. During clinical latency, the level of infectious virus in plasma decreases markedly but does not disappear.

B. Immediately after seroconversion, the levels of free virus decline, T-cell numbers rise, and for a time the infection is held in check. Eventually, however, virus levels start to rise again and T-cell numbers decrease, leading eventually to AIDS. The level of virus in the blood after seroconversion is positively correlated with the severity and progression of the disease: the more virus that remains at this time, the more rapid is the progress to AIDS. 13–75 HIV is a retrovirus that uses the enzyme reverse transcriptase to complete its life cycle.

This enzyme uses the single-stranded RNA genome of HIV as a template to make a doublestranded DNA (complementary DNA or cDNA) that integrates into the host genome as a provirus. Reverse transcriptase is an error-prone DNA polymerase that lacks proofreading capabilities. Mutations are therefore introduced into the HIV genome each time it is replicated.

Such rapid mutation leads to variant viruses with modified antigens, which thus escape detection by antibodies or cytotoxic T cells specific for the original epitopes.

The high rate of mutation in HIV also causes the emergence of resistance to the antiviral drugs used to treat HIV infection, which are mainly drugs that inhibit viral reverse transcriptase and protease. Mutation produces viruses with mutant enzymes that are not blocked by the drugs.

Multidrug regimes are used to try to eliminate the virus before the multiple mutations needed to resist all of the drugs have accumulated.

13–76 c 13–77 c, d, e 13–78 b 13–79 e 13–80 c 13–81 a, e 13–82 Resistance to protease inhibitors can result from as little as one mutation in the HIV protease gene. Resistance to reverse transcriptase inhibitors, however, requires the accumulated effects of three or four mutations in the reverse transcriptase gene, which takes longer to acquire.

13–83 Toxic shock syndrome is caused when superantigens, such as toxic shock syndrome toxin-1 (TSST-1) produced by some strains of Staphylococcus, nonspecifically activate large numbers of CD4 T cells. When a T cell is activated, the transcription factor NFκB is activated and switches on genes involved in the normal T-cell response. However, NFκB can also bind to the promoter of the HIV provirus to initiate its transcription and subsequent viral replication.

Thus, if a T cell activated during toxic shock coincidentally contains an HIV provirus, NFκB will initiate the replication of HIV and the cell will die. If a significant proportion of the person‘s T 208

cells harbor the provirus, one would predict widespread reactivation of the virus and a sharp rise in the amount of HIV in the blood (viremia) after the onset of toxic shock.

CHAPTER 14: IgE-MEDIATED IMMUNITY AND ALLERGY 14–1 a. b. c. d. e.

Which of the following are matched correctly? (Select all that apply.) type I hypersensitivity: IgE type II hypersensitivity: IgG type III hypersensitivity: immune complexes type IV hypersensitivity: IgG type IV hypersensitivity: delayed-type hypersensitivity.

14–2 a. b. c. d. e.

Which of the following are associated with soluble antigen? (Select all that apply.) type I hypersensitivity type II hypersensitivity type III hypersensitivity type IV hypersensitivity mast-cell activation.

14–3 Match the term in column A with its description in column B. Column A ___ a. delayed-type hypersensitivity

Column B 1. innocuous environmental antigen

___ b. hygiene hypothesis

2. type IV hypersensitivity

___ c. allergy

3. a state of hypersensitivity

___ d. immediate hypersensitivity

4. type I hypersensitivity

___ e. allergen

5. epidemic of allergy

14–4 a. b. c. d.

Which of the following is not mediated by antibodies? type I hypersensitivity type II hypersensitivity type III hypersensitivity type IV hypersensitivity.

14–5 Which of the following is associated with type III hypersensitivity? a. nickel b. recombinant human insulin 209

c. d. e.

plant oil mouse-derived monoclonal antibody helminth infection.

14–6 _____ hypersensitivity reactions interact with soluble epitopes and not cell-surface associated epitopes. a. type I and II b. type I and III c. type I and IV d. type II and III e. type II and IV f. type III and IV. 14–7 Identify four different ways in which an individual may come into contact with an allergen and provide two examples of allergens for each type of contact.

14–8 A. Describe in detail the mechanism responsible for mast-cell activation during a type I hypersensitivity reaction.

B. What are the products of mast-cell activation?

14–9 Adaptive immune responses targeted at infections by helminth worms and other parasitic multicellular animals employ all of the following except _____. (Select all that apply.) a.

CD8 T cells b.

IgE c. eosinophils d. mast cells e.

CD4 TH2 cells f. basophils g. neutrophils h.

IL-4.

14–10 During a primary immune response IgM sometimes switches to IgE. Which of the following best describes the consequence of this early switch? a.

The B cell would switch again to IgG3. b.

The B cell would remain in the germinal center but would not differentiate into a plasma cell. c.

The B cell would die by apoptosis. d.

The IgE produced would have low affinity for antigen.

14–11 Which of the following regarding FcεRI is false? a.

It is expressed on the surface of mast cells and basophils. b.

It is a low-affinity receptor involved in type I hypersensitivity reactions. c.

It binds to IgE in the absence of antigen. d.

It is a membrane-bound tetramer. e.

It contains signaling components that re activated following antigen cross-linking.

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14–12 A. Explain why it is essential that FcεRI and Fcε RII are not able to bind simultaneously to the same IgE molecule.

B. Why does simultaneous binding not occur?

14–13 The sheddase _____ cleaves FcεRII on the cell surface, resulting in the production of monomeric and trimeric forms of FcεRII. a. cathepsin G b.

CR2 c. eotaxin d. major basic protein e.

ADAM10.

14–14 All of the following are released immediately by mast cells after FcεRI cross-linking except _____. a. heparin b. eicosanoids c. neutral proteases d. histamine e.

TNF-α.

14–15 Lipid mediators produced by activated mast cells include which of the following? (Select all that apply.) a. platelet-activating factor b. cathepsin G c. chymase d. leukotrienes e. carboxypeptidase f. prostaglandins.

14–16 All of the following are biological effects mediated by the products of mast cells except _____. a. chemotaxis of neutrophils, eosinophils, and effector T cells b. growth factor secretion c. smooth muscle contraction d. connective tissue remodeling e.

All of the above are mediated by mast cells.

14–17 Identify the mismatched pair. a.

TNF-α: immediate release from mast cells b. mucosal mast cell production: T-cell immunodeficiencies c. connective tissue mast cells: chymotryptase d. lipid mediator: prostaglandins e. leukotrienes: increase vascular permeability.

14–18 Prostaglandin D2 (PGD2) enhances all of the following except _____.

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a. b. c. d.

smooth muscle contraction chemotaxis of neutrophils increased vascular permeability vasodilation.

14–19 Which of the following directly inhibits the cyclooxygenase pathway by inhibiting the activity of prostaglandin synthase? a.

ADAM10 b. experimental anti-IgE c. aspirin (acetyl salicylate) d. chymotryptase e.

ADAM33.

14–20 _____ released by TH2 cells promotes an elevated level of eosinophils in the circulation. a.

IL-4 b.

IL-13 c.

TNF-α d.

FcγRII e.

IL-5.

14–21 A. Explain the importance of allergens having protease activity in the context of antigenspecific T-cell activation.

B. Provide a specific example of a major allergen that has protease activity.

14–22 Match the physical effects of IgE-mediated mast-cell degranulation in column A with the tissue exposed to the allergen in column B. Column A Column B ___ a. decrease in blood pressure 1. respiratory tract ___ b. diarrhea

2. heart and vascular system

___ c. swelling of tissues

3. gastrointestinal tract

___ d. constriction of the throat ___ e. wheezing ___ f. vomiting ___ g. violent bursts of sneezing

14–23 Explain briefly how penicillin initiates a type I hypersensitivity response.

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14–24 A. Explain how erythrocytes become coated with complement component C3b during an allergic reaction to penicillin.

B. Why is this important to the mechanism by which IgE antibodies are produced?

14–25 Why are antihistamines used to treat allergic rhinitis and allergic asthma? What symptoms of each disease, respectively, do they alleviate.

14–26 A. Describe two ways in which the immunoglobulins acting as antigen receptors on the surface of a mast cell differ from the immunoglobulins acting as the antigen receptors on the surface of a B cell.

B. What is the essential difference in response of these two cell types when antigen binds to these surface immunoglobulins.

12–27 Some allergies can be treated by a procedure called desensitization.

A. Explain two current approaches to desensitization.

B. Explain the main disadvantage associated with each.

14–28 Give three ways in which a susceptible person can help to minimize the risk of having an allergic reaction.

14–29 How do mast cells contribute to innate immunity?

14–30 What are the effects of histamine binding to the H1 receptor on smooth muscle, mucosal epithelia, and the endothelial cells of blood vessels.

14–31 The antigens that provoke hypersensitivity reactions are referred to as a.

T-independent antigens b. superantigens c. subunit vaccines d. attenuated vaccines e. allergens.

14–32 Which of the following allergens is not likely to be encountered through inhalation? a. plant pollen b. metals c. animal dander d. mold spores e. house dust mite feces.

14–33 _____ express FcεRI and contain granules containing inflammatory mediators. (Select all that apply.) a. macrophages b. activated eosinophils c. mast cells 213

d. e.

natural killer cells basophils.

14–34 Match the mast cell product in column A with its biological effect in column B. Column A Column B ___ a. IL-4 1. activates endothelium ___ b. CCL3 2. amplifies TH2-cell response ___ c. TNF-α 3. increases vascular permeability ___ d. histamine 4. connective tissue matrix remodeling ___ e. tryptase 5. chemotaxis 14–35 Aspirin (acetyl salicylate) inhibits prostaglandin synthesis by binding irreversibly to prostaglandin synthase, the first enzyme in the _____ pathway. a. cyclooxygenase b. carboxypeptidase c. metalloprotease d. lipooxygenase e. peroxidase.

14–36 Which of the following is associated with eosinophilia? (Select all that apply.) a.

IL-5-induced proliferation b. endocardium damage c. neuropathy d.

B-cell lymphoma e. decreased bone marrow function.

14–37 Which of the following genetic polymorphisms is associated with a predisposition to asthma? (Select all that apply.) a. promoter variants of IL-5 b. structural variant of IgG receptor c.

HLA class II allotypes d. β2-adrenergic receptor variant e.

ACOX5 (5-lipoxygenase).

14–38 The wheal-and-flare inflammatory reaction is an example of a. an immediate type I allergic response b. a late-phase type I allergic response c. a late-phase type IV allergic response d. an immediate type III allergic response e. a late-phase type III allergic response.

14–39 Which of the following tests is used to determine whether a particular allergen is responsible for asthma? a. measure wheal-and-flare diameter after intradermal injection of allergen b. measure Arthus reaction diameter after intradermal injection of allergen c. inject a controlled amount of allergen intradermally and observe urticaria 214

d. e.

measure peak expiratory flow rate (PEFR) following inhalation of allergen measure eosinophils in nasal secretions following inhalation of allergen.

14–40 Which of the following are consequences of anaphylactic shock? (Select all that apply.) a. smooth muscle contraction b. immune complex deposition on blood vessels c. loss of blood pressure d. constriction of airways e. complement activation.

14–41 During the course of a successful desensitization process, the patient’s antibodies will change from an _____isotype to an _____ isotype. a.

IgG4:IgE b.

IgE:IgM c.

IgA:IgM d.

IgG1:IgG4 e.

IgE:IgG4.

14–42 Which of the following are potential means by which type I allergic reactions can be managed or treated? (Select all that apply.) a.

Use antihistamines to block histamine binding to H1 histamine receptors. b.

Use corticosteroids to suppress inflammation. c.

Desensitize the patient by feeding them allergen and skewing the immune response from an IgE to an IgA response. d.

Anergize allergen-specific T cells through vaccination with allergen-derived peptides. e.

Administer Il-4, IL-5, or IL-1β to promote TH1 responses. f.

Block high-affinity IgE receptors to prevent mast-cell degranulation.

14–43 Anita Garcia, 17 years old, and her roommate Rosa Rosario were celebrating a friend’s birthday at a dessert buffet at a local restaurant when Anita developed acute dyspnea, and angioedema. She complained of an itchy rash, and then had difficulty swallowing. Rosa drove Anita to the emergency room two blocks away rather than wait for an ambulance. As they approached the hospital, Anita lost consciousness. This medical emergency would most probably result in immediate _____ before any subsequent treatment. a. subcutaneous injection of epinephrine b. intravenous injection of corticosteroids c. intravenous injection of antihistamine d. intravenous injection of antibiotics e. intravenous injection of a nonsteroidal anti-inflammatory drug.

14–44 Look again at Question 14–43. What do you think Anita was suffering from? Given the circumstances in which the episode occurred, suggest a likely cause.

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ANSWERS 14–1 a, b, c, e 14–2 a, c, d, e 14–3 a—2; b—5; c—3; d—4; e—1 14–4 d 14–5 d 14–6 b 14–7 (i) Inhalation: house dust mite feces, animal dander. (ii) Injection: drugs administered intravenously, wasp venom. (iii) Ingestion: peanuts, drugs administered orally. (iv) Contact with skin: poison ivy, nickel in jewelry.

14–8 A. If an individual becomes sensitized to antigen by making antibodies of the IgE isotype during first exposure, then a type I hypersensitivity reaction may result if antigen is encountered again. The IgE made initially binds stably via its Fc region to very high-affinity FcεRI receptors on mast-cell surfaces. When antigen binds to this IgE, cross-linking of FcεRI occurs, delivering an intracellular signal that activates the mast cell.

B. Mast cells contain preformed granules containing a wide range of inflammatory mediators that are triggered to be released extracellularly through an exocytic mechanism called degranulation. The inflammatory mediators contained in the granules and released immediately include histamine, heparin, TNF-α, and proteases involved in the remodeling of connective tissue matrix. The proteases include tryptase and chymotryptase (expressed by mucosal and connective mast cells, respectively), cathepsin G, and carboxypeptidase. Additional inflammatory mediators are generated after mast-cell activation, including IL-3, IL-4, IL-5, IL-13, GM-CSF, CCL3, leukotrienes C4 and D4, and platelet-activating factor.

14–9 a, g 14–10 d 14–11 b 14–12 A. Armed mast cells and basophils become activated when IgE molecules bound to FcεRI on their cell surface become cross-linked. Normally this occurs when antigen is bound to IgE. If IgE were able to bind to FcεRI using one domain, and at the same time bind to FcεRII using a different domain, then IgE itself would mediate cross-linking of FcεRI and cause cellular activation in the absence of antigen.

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B. This does not occur because IgE has two distinct binding sites for FcεRI and FcεRII, and when one or the other of these binding sites is occupied, the conformation of IgE is altered so that it is unable to bind to the other receptor.

14–13 e 14–14 b 14–15 a, d, f 14–16 e 14–17 b 14–18 a 14–19 c 14–20 e 14–21 A. Particles containing proteins that stimulate allergic responses will be more easily broken down by proteolysis, enabling more effective release of the allergen. Proteolytic degradation results in the formation of peptides that will bind to MHC class II molecules and consequently stimulate TH2 cells.

B. Present in the feces of the house dust mite Dermatophagoides pteronyssimus is a cysteine protease that is an allergen responsible for 20% of human allergies in North America.

14–22 a—2; b—3; c—2; d—1; e—1; f—3; g—1 14–23 The reactive bond in the β-lactam ring of penicillin reacts with proteins on the surface of human cells, with erythrocytes most commonly being involved. This modification generates a foreign epitope to which TH2 cells and B cells respond.

14–24 A. C3b becomes deposited on the cell surface of penicillin-modified erythrocytes because a bacterial infection is ongoing (the reason that penicillin was administered in the first place). The erythrocyte becomes coated as a bystander effect of complement activation.

B. C3b on the penicillin-modified erythrocyte binds to CR1 on macrophages in the spleen, which facilitates receptor-mediated endocytosis and the subsequent processing and presentation of the penicillin–protein conjugate peptide. Then TH2 cells interact with the peptide:MHC class II complexes, become activated, and provide help to B cells with IgE B-cell receptors specific for the penicillin–protein conjugate.

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14–25 Mast cells activated by inhaled allergens in the type I hypersensitivity reaction that causes allergic rhinitis or asthma release histamine. Histamine binding to its receptors on smooth muscle causes the bronchial constriction typical of asthma and the difficulty in breathing.

Histamine binding to receptors on vascular endothelium causes increased permeability of the epithelium and inflammation of nearby tissue, causing the runny nose and swollen eyes typical of allergic rhinitis, and also an accumulation of mucus and fluid in the bronchi typical of allergic asthma. By blocking histamine action, antihistamines help alleviate these symptoms.

14–26 A. (i) The immunoglobulin on a mast cell is an IgE antibody that has become bound to the mast cell’s FcεRI receptor, whereas the immunoglobulin on a B cell is a transmembrane form made by the cell itself. (ii) A B cell might have any class of immunoglobulin on its surface, whereas mast cells have only IgE. (iii) IgE molecules of many different antigen specificities can be bound to the surface of an individual mast cell, whereas an individual B cell carries immunoglobulin molecules of only one specificity.

B. After binding to antigen, mast cells become operational as effector cells without the need to undergo proliferation or differentiation. In contrast, after antigen binds to a surface immunoglobulin on a B cell, the cell must proliferate and differentiate to produce effector cells (antibody-secreting plasma cells).

14–27 A. (i) One approach to desensitization is the subcutaneous injection of the allergen itself into sensitized individuals with the aim of skewing the immune response from an IgE to an IgG4 isotype. This is achieved by gradually increasing the subcutaneous allergen concentration over time, which favors IgG over IgE production. When antigen is encountered subsequently, IgG will compete with IgE for binding and inhibit IgE cross-linking on mast-cell surfaces. (ii) The second approach involves vaccination with allergen-derived peptides designed to be bound by HLA class II molecules and presented to allergen-specific TH2 cells with the aim of inducing anergy in these T cells. This would prevent them from giving help to allergen-specific naive B cells, thus preventing the production of more IgE antibody on repeated exposures to the environmental allergen.

B. (i) A risk of the first approach is the possibility of activating a systemic anaphylactic response after mast-cell activation. Because the patient was previously sensitized, IgE antibodies against allergen are present and, if bound to mast cells, will induce mast-cell degranulation. In the event of an anaphylactic response to an allergy shot, the patient will have epinephrine administered immediately by the attending physician or nurse practitioner. (ii) With the peptide vaccination approach, allergen-specific T cells are rendered anergic and there is no risk of triggering an anaphylactic reaction. However, the disadvantage of this approach is that because the HLA class II genes are highly polymorphic, the vaccine would have to include sufficient peptides able to bind to most HLA class II allotypes, or it would need to be custom made for each individual on the basis of their HLA class II type.

14–28 (i) Avoid contact with allergens as much as possible by modifying their behavior and their home environment. (ii) Use pharmacological agents that inhibit allergic responses. (iii) Undergo desensitization therapy to divert immune responses from IgE to IgG4 isotype.

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14–29 Mast cells express Toll-like receptors, which can bind to pathogen-associated molecules and stimulate the production of cytokines and chemokines that participate in innate immune responses.

14–30 When smooth muscle cells bind histamine using H1 receptors, they contract. In combination with increased mucus production by mucosal epithelium this produces a variety of effects, for example, wheezing due to bronchial constriction, coughing, sneezing, watery eyes, nasal discharge, itchiness, and, if the reaction occurs in the gut, vomiting and diarrhea. When endothelial cells of blood vessels bind histamine, an increase in vascular permeability enables the entry of fluid (edema) and leukocytes into affected tissues.

14–31 e 14–32 b 14–33 b, c, e 14–34 a 2; b 5; c 1; d 3; e 4 14–35 a 14–36 a, b, c 14–37 c, d, e 14–38 a 14–39 d 14–40 a, c, d 14–41 e 14–42 a, b, d, f 14–43 Rationale: The correct answer is a. This is a case of anaphylactic shock caused by a food allergy. Anita‘s sudden onset of shortness of breath, swelling of mucosal tissues causing difficulty in breathing, and rash are characteristic of a type I hypersensitivity reaction after the rapid absorption of allergen into the bloodstream and systemic activation of mast cells in the connective tissue of blood vessels. Given the life-threatening nature of this medical emergency, where asphyxiation due to constriction of the airways and swelling of the epiglottis may occur, immediate suppression of Anita‘s hyperactive response is warranted. Subcutaneous injection of epinephrine will bring the most immediate effect, not corticosteroids, antihistamines, antibiotics, or nonsteroidal anti-inflammatory agents. Epinephrine will relax bronchial constriction, stimulate the heart, and induce the reformation of tight junctions between vascular endothelial cells, which will alleviate swelling and restore blood pressure.

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14–44 Anita was suffering from acute anaphylactic shock almost certainly caused by an allergic reaction to something she had just eaten at the buffet. Given that it was a dessert buffet, nuts or peanuts would be one of the most likely suspects, because they or their oils are ingredients or contaminants in many prepared foods, and they are well known to provoke severe anaphylactic reactions in susceptible people.

CHAPTER 15: TRANSPLANTATION OF TISSUES AND ORGANS 15–1 All of the following are characteristics of blood donations and transfusions that enable their extensive use for transplantation purposes except _____. a. individuals can donate on a regular basis without any deleterious effects b. erythrocytes do not express MHC class I or class II molecules c. the blood components only need to function for a few weeks d. only the ABO antigens need to be compatible between donor and recipient e. blood transfusion is a straight forward and inexpensive process.

15–2 In routine blood transfusions, which of the following must be matched correctly? (Select all that apply.) a.

A and B antigens b.

O antigens c.

Rhesus D antigen d.

MHC class I molecules e.

MHC class II molecules.

15–3 The underlying molecular basis for distinguishing blood-group antigens A, B and O is _____ at the erythrocyte surface. a. the presence or absence of fucose in glycolipids b. differences in the oligosaccharide attached to the lipid ceramide c. structural polymorphisms in the Rhesus D antigen d. the levels of MHC class I and class II molecules.

15–4 _____ results from alloreactions mediated by donor T cells in the graft subsequent to hematopoietic stem-cell transplantation. a.

Acute rejection b.

Chronic rejection c.

Graft-versus-host disease (GVHD) d.

Serum sickness e.

Hyperacute rejection.

15–5 Blood transfusions mismatched for ABO and/or rhesus antigens are associated with _____. (Select all that apply.) a. type III hypersensitivity reactions b. alloreactive immune responses 220

c. d. e.

lysis of recipient red blood cells laboratory errors in the cross-matching procedure activation of host complement and destruction of donor cells.

15–6 a. b. c. d. e.

Alloantibodies to blood-vessel endothelium on solid organ grafts _____. are specific for HLA class I and class II antigens cause hyperacute rejection cause acute rejection target endothelium for attack by NK cells are IgA and do not fix complement.

15–7 Which of the following is a permissible match between a blood donor and a recipient (donor: recipient)? (Select all that apply.) a.

O –: AB + b.

O +: AB – c.

AB +: O – d.

A –: A + e.

AB –: O +.

15–8 a. b. c. d.

All of the following are commonly used sources of hematopoietic stem cells except ____. skin cells bone marrow umbilical cord blood peripheral blood.

15–9 Match the term in Column A with its description in Column B. Column A ___a. chronic rejection

___b. myeloablative therapy ___c. ischemia ___d. mixed lymphocyte reaction

___e. transfusion effect

Column B 1. assessment of degree to which recipient‘s T cells would respond to a transplanted organ 2. annihilation of the immune system 3. a form of type III hypersensitivity 4. improved outcome of organ transplantation if previous blood transfusions containing shared HLA-DR allotypes with organ was given to recipient 5. blood deprivation often accompanying organ collection

15–10 The direct pathway of allorecognition involves interaction of _____, whereas the indirect pathway of alloreaction involves interaction of _____. a. donor T cells with allogeneic HLA molecule on recipient dendritic cells; recipient T cells with allogeneic HLA molecules on donor dendritic cells

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b. recipient T cells with allogeneic HLA molecules on donor dendritic cells; donor T cells with allogeneic HLA molecule on recipient dendritic cells c. recipient T cells with allogeneic HLA molecules on donor dendritic cells; recipient T cells with peptides of allogeneic HLA molecules on recipient dendritic cells d. recipient T cells with peptides of allogeneic HLA molecules on recipient dendritic cells; donor T cells with peptides of allogeneic HLA molecules on donor dendritic cells.

15–11 _____ is a monoclonal antibody administered to transplant patients before and after transplantation in order to induce lymphopenia. a.

Rabbit antithymocyte globulin (rATG) b.

Tacrolimus c.

Alemtuzumab d.

Belatacept e.

Basiliximab.

15–12 Which of the following is mismatched? a. methotrexate: dihydrofolate reductase b. prednisolone: NFκB c. cyclosporin: calcineurin d. basiliximab: IL-2 receptor e.

OKT3: CD52 f. corticosteroid: Hsp90.

15–13 Which of the following is classified as a pro-drug? (Select all that apply.) a. azathioprine b. cyclophosphamide c. cyclosporin d. prednisone e. rapamycin f. mycophenolate mofetil.

15–14 All of the following culminate in complement fixation and removal of T cells by phagocytes except _____ which instead causes the T-cell receptors to be internalized and unavailable for antigen recognition. a. alemtuzumab b.

OKT3 c. rabbit antithymocyte globulin (rATG).

15–15 In the context of allogeneic transplantation, identify the mismatched pair. a. inhibition of inflammation: prednisone b. inhibition of co-stimulation: daclizumab c. inhibition of cytokine signaling: basiliximab d. inhibition of calcineurin: tacrolimus (FK506) e. inhibition of T-cell proliferation: azathioprine.

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15–16 _____ is not a drug that targets replication and proliferation of alloantigen-activated T cells. a.

Rapamycin b.

Methotrexate c.

Mycophenolate mofetil d.

Azathioprine e.

Cyclophosphamide.

15–17 Which of the following exerts its effect by inhibiting the activation of calcineurin by calcium and thereby interferes with nuclear translocation of NFAT? (Select all that apply.) a. tacrolimus (FK506) b. mycophenolic acid c. cyclophosphamide d. belatacept e. cyclosporin A. 15–18 Hematopoietic stem cell transplantation is appropriate for all of the following conditions except _____. a. thalassemia major b.

Wiskott–Aldrich syndrome c.

Fanconi‘s anemia d. cirrhosis of the liver e. sickle-cell anemia f. non-Hodgkin‘s lymphoma.

15–19 What explains the increased incidence of bone marrow graft failure and cancer relapse when mature T cells are depleted from donor bone marrow before engraftment?

15–20 _____ describes the process by which transplanted pluripotent stem cells find their way to the bone marrow spaces in the bones of the body and begin to produce new blood cells. a.

Myeloablation b.

Engraftment c.

Relapse d.

Graft-vesus-leukemia e.

Chemotherapy.

15–21 _____ is/are a disease or genetic defect that can be treated by bone marrow transplantation. (Select all that apply.) a.

A leukocyte defect b.

Multiple myeloma c.

Hemoglobin defects d.

Celiac disease e.

Acquired immune deficiency syndrome (AIDS).

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15–22 Myeloablative therapy is carried out in bone marrow transplantation in order to _____.

(Select all that apply.) a. prevent graft-versus-host disease b. prevent host-versus-graft disease c. suppress autoreactive T cells in the graft d. disable the patient‘s hematopoietic stem cells but not their circulating leukocytes e. provide space for colonization of transplanted stem cells in bone marrow stroma f. destroy tumors of immune-system cells.

15–23 For the patient‘s new immune system to function effectively in bone marrow recipients, some HLA allotypes must be shared because _____. (Select all that apply.) a. professional antigen-presenting cells are host-derived b. professional antigen-presenting cells are donor-derived c. otherwise an autoimmune disease would develop d. newly generated T cells are positively selected on the recipient‘s thymic epithelium e. if all HLA molecules were mismatched, acute rejection of the grafted cells would occur.

15–24 The risk of _____ is the primary complication in bone marrow transplants. a. acute host-versus-graft disease b. hyperacute rejection c. chronic rejection d. acute graft-versus-host disease e. cancer.

15–25 _____ from a bone marrow transplant facilitate alloreactive responses, causing the condition defined as acute graft-versus-host disease. a.

Natural killer cells b.

Mature T cells c.

Dendritic cells d.

Thymocytes e.

Mature B cells.

15–26 A patient diagnosed with grade IV of graft-versus-host disease would most probably exhibit _____. (Select all that apply.) a. serum bilirubin levels of 2-3mg/dl b. jaundice c. skin blistering and desquamation d. severe abdominal pain e. maculopapular rash on less than 25% of body surface.

15–27 Autologous bone marrow transplantation used to treat cancer patients involves reinfusing a(n) _____-depleted stem-cell population into the patient after their cancer treatment has been completed. a. mature T cell b. antibody c. tumor cell 224

d. e.

dendritic cell NK cell.

15–28 Leukapheresis is used in hematopoietic stem-cell transplantation where stem cells from a suitable donor are fractionated on the basis of their expression of _____. a.

CD3 b. the same major histocompatibility antigens as the recipient c. the same minor histocompatibility antigens as the recipient d. the same inhibitory KIR receptors as the recipient e.

CD34.

15–29 Donors treated with _____ can donate bone marrow-derived stem cells from a less invasive peripheral blood draw instead of the more invasive bone marrow aspiration. (Select all that apply.) a. anti-CD3 b. cyclophosphamide c. anti-CD34 d. granulocyte colony-stimulating factor (G-CSF) e. granulocyte–macrophage colony-stimulating factor (GM-CSF).

15–30 Despite a slower engraftment, cord blood as a source of transplanted hematopoietic stem cells is better than bone marrow or than stem cells derived from peripheral blood in that _____.

(Select all that apply.) a. the recipient does not need to undergo myeloablative therapy b. there is a higher degree of tolerance for HLA disparity c. there is a lower incidence of graft-versus-host disease d. cord blood can be infused directly into the bone marrow of recipients e. a larger number of stem cells express CD34.

15–31 Males engrafted with HLA-identical bone marrow from their sisters develop graft-versushost disease because _____. a.

T cells develop in the male thymus that are not tolerant to minor histocompatibility antigens expressed by the sister b. mature T cells in the graft have specificity for male-specific minor histocompatibility antigens c. there are differences between the sexes in how self proteins are modified posttranslationally d.

NK-cell alloreactions occur e. residual female hormones in the graft cause upregulation of HLA class I on male dendritic cells presenting minor histocompatibility antigens.

15–32 Residual leukemia cells persisting in a patient after they have received chemotherapy, irradiation, and a bone-marrow transplant are sometimes eliminated by a _____ effect which involves the action of _____. (Select all that apply.) a. graft-versus-leukemia; alloreactive T cells b. haploidentical; regulatory T cells 225

c. d. e.

acute minor histocompatibility; recipient NK cells myeloablation; mature T cells graft-versus-leukemia; alloreactive NK cells.

15–33 Family members who donate their bone marrow to a transplant patient and who share one out of the two HLA haplotypes are providing a(n) _____ transplant. a. autologous b.

HLA-matched c. haploidentical d. chimeric e. cross-matched.

15–34 What is the term used to describe the condition of an individual who possesses two sets of hematopoietic cells, one derived from the individual‘s own bone marrow and one derived from a different source, for example, an organ transplant or blood transfusion that has not been rejected? a. haploidentical b. chimeric c. cross-protected d. dimorphic e. mixed lymphocyte reaction.

15–35 Following a hematopoietic stem cell transplant, T-cell responses will be activated by dendritic cells of _____ origin. a. donor b. recipient c. both donor and recipient.

15–36 Match the term in Column A with its description in Column B. Column A Column B ___a. minor histocompatibility antigens

1. allotypic differences that arise from polymorphisms in human proteins

___b. haploidentical transplant

2. cells

___c. autologous hematopoietic cell transplantation

3. only one HLA haplotype is shared but not both

___d. graft-versus-tumor effect

4. removal of harmful cells from one‘s own bone marrow before reinfusion 5. residual leukemic cells eliminated by alloreactive T cells or NK cells in a graft.

___e. CD34

on the surface of hematopoietic stem

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15–37 George Cunningham was diagnosed with Crohn‘s disease when 23 years old. He was experiencing acute abdominal pain, diarrhea, rectal bleeding, anemia and weight loss. He did not respond to conventional immunosuppressive therapies and was given a course of infliximab, an anti-TNF-α monoclonal antibody that suppresses inflammation by blocking TNF-α activity. On day 12 after receiving his first infusion, he developed a mild fever, generalized vasculitis, swollen lymph glands, swollen joints and joint pain. Traces of blood and protein were detected in his urine. Which of the following is the most likely cause of these recent symptoms? a.

Type I hypersensitivity involving anaphylaxis. b.

Type II hypersensitivity leading to hemolytic anemia. c.

Type III hypersensitivity caused by immune complex deposition in blood vessels. d.

Type IV hypersensitivity involving CD8 T-cell cytotoxicity. e.

Type II hypersensitivity leading to thrombocytopenia.

15–38 How do the clinical objectives of transplantation differ from those of vaccination?

15–39 Explain why, in principle, an organ transplanted from any donor other than an identical twin is almost certain to be rejected in the absence of any other treatment.

15–40 The term _____ is used to describe polymorphic antigens that vary between individuals of the same species. a. xenoantigens b. immunoantigens c. alloantigens d. histoantigens e. autoantigens.

15–41 Contrast acute rejection and chronic rejection.

15–42 A. Explain why an organ transplant made between a donor of blood group AB and a recipient of blood group O will always be rejected, even if it is perfectly HLA-matched and the recipient has been given immunosuppressant drugs. What is this type of rejection called?

B. Give another example of ABO incompatibility between donor and recipient that would lead to this type of rejection.

C. What other antigen incompatibilities, other than those of blood group, are most likely to provoke this type of rejection?

D. Which pre-surgical laboratory test should be performed to prevent this type of rejection?

15–43 We learned in Chapter 5 that the benefit of having and expressing multiple MHC class I and class II genes is that it increases the number and variety of pathogen-derived peptide antigens that can potentially be presented to T cells. If more is better, then why has natural selection not favored the evolution of more than three genes each for MHC class I and MHC class II? 15–44

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A. Identify three general classes of drug that are used to suppress acute transplant rejection, and provide examples of each class.

B. What side-effects and toxic effects are associated with each class of drug?

15–45 Explain how cyclosporin A acts as an immunosuppressant drug.

15–46 Graft-versus-host disease (GVHD) is a consequence of _____. a. mature T lymphocytes from the donor mounting an immune response against tissue of the recipient b. mature T lymphocytes from the recipient mounting an immune response against tissue of the donor c. mismatching A, B, and O antigens between donor and recipient d. mismatching Rhesus antigen between donor and recipient e. antibodies of the donor stimulating NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of tissues of the recipient.

15–47 A. Explain how mouse monoclonal antibodies (MoAbs) can be used to suppress acute graft rejection.

B. What feature of these mouse antibodies compromises their effectiveness in vivo and limits their use?

15–48 Which of the following best explains why a bone marrow donor needs to be HLAmatched to the recipient? a.

The bone marrow transplant contains enough mature T cells to reconstitute the recipient and the recipient provides the antigen-presenting cells. b.

The recipient‘s MHC molecules mediate positive selection of thymocytes in the thymus that interact with donor-derived MHC molecules in the periphery. c.

Reconstituted T cells are restricted by donor, not recipient, HLA allotypes. d.

Without an HLA match, the donor-derived thymocytes undergo negative selection. e.

If the donor is not HLA matched, the reconstituted T cells will be autoreactive.

15–49 A. Explain why a boy with leukemia who receives a bone marrow transplant from his sister that is perfectly matched for MHC class I and class II is still likely to get graft-versus-host disease.

B. Which effector T cells are usually involved in this reaction, and why?

15–50 A. Are the criteria for selecting suitable donors the same for liver and bone marrow transplants?

B. Why or why not?

15–51 From a clinical perspective explain how the logistics of organ transplantation differ from those for a bone marrow transplant.

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15–52 Indicate whether each of the following statements is true (T) or false (F). ___a. ABO or Rhesus antigen mismatches stimulate cytotoxic T-cell responses. ___b. There are polymorphic antigens other than ABO and Rhesus antigens that can cause type II hypersensitivity reactions. ___c. Cross-matching has now been replaced with routine use of DNA-based methods. ___d. Lymphocytes and erythrocytes express HLA class I and II molecules. ___e. Platelet transfusions are used to replace fluid and prevent bleeding.

15–53 Richard French, 53 years old, was diagnosed with chronic myelogenous leukemia. His elder brother Don is HLA-haploidentical and will donate bone marrow. Richard‘s oncologist has recommended him to a medical center that favors using bone marrow depleted of mature T cells prior to infusion. The most likely rationale for employing the practice of T-cell depletion is that _____. a.

T-cell depletion will remove alloreactive T cells from the donor and prevent the potential for graft-versus-host disease (GVHD) b. mature T-cell chimerism is required to establish long-term tolerance c. because Don is HLA-haploidentical and male, there is no risk of alloreactivity toward major or minor histocompatibility antigens d. because of Don‘s age, the expected bone marrow harvest is already marginal for successful engraftment, and depletion measures would compromise the yield of stem cells e. the benefit of using a cocktail of immunosuppressive drugs outweighs the risk of contaminating the bone marrow during T-cell depletion.

15–54 Forty-four-year old Danielle Bouvier is on the waiting list for a kidney transplant and is receiving weekly dialysis. Her HLA type is: HLA-A: 0101/0301; HLA-B: 0702/0801; HLADRB1: 0301/0701. Today, Danielle‘s physician informed her that several potential kidney donors are available. Which of the following would be the most suitable? a.

A: 0301/0201; B: 4402/0801; DRB1: 0301/0403 b.

A: 0301/2902; B: 1801/0801; DRB1: 0301/0701 c.

A: 2902/0201; B: 0702/0801; DRB1: 0301/13011 d.

A: 0101/0101; B: 5701/0801; DRB1: 0701/0701 e.

A: 0101/0301; B: 0702/5701; DRBA: 0403/0301.

15–55 Explain why it is necessary to match at least some of the HLA allotypes between donor and recipient in a bone marrow transplant given to remedy SCID. 15–56 (A) What is a cross-match test? (B) Why is it carried out? (C) How is it carried out?

15–57 Match each of the following blood groups with the type(s) of blood a person with the first blood group can safely receive in a transfusion.

1. group O; 2. group A; 3. group B; 4. group AB a. group O; b. group A; c. group B, d. group AB. 15–58 What type of hypersensitivity reaction would result from a mismatched blood transfusion? a. Type I 229

b. Type II c. Type III d. Type IV 15–59 What is the name of the clinical test used to determine the compatibility between a donor and recipient requiring a blood transfusion? a. desensitization b. cross-match test c. Arthus reaction d. HLA typing e. delayed-type hypersensitivity reaction 15–60 _____ is associated with a type III hypersensitivity reaction. (Select all that apply.) a. Allergen binding to cell-surface components and creating foreign epitopes. b. Cross-linking of IgE on mast cells c. Formation of small immune complexes that are deposited in blood vessel walls d. Complement fixation e. Hemorrhaging f. Antibody excess 15–61 When an individual receives a kidney transplant, the main concern will be to control the development of _____. a. graft-versus-host disease b. transplant rejection c. xenorecognition d. allergic reactions e. lymphoproliferative disorders.

15–62 In the context of organ transplantation, what is the increased risk associated with an individual‘s having received previous blood transfusions on multiple occasions?

15–63 Which of the following are correctly matched? (Select all that apply.) a. allograft: same person b. autograft: to treat damage caused by autoimmune processes c. isograft: syngeneic d. antithymocyte globulin: xenogeneic e. same species: allogeneic.

15–64 Alloantibodies specific for HLA class I molecules can mediate hyperacute rejection of kidney transplants. Explain under what conditions an individual would possess preexisting antibodies against HLA class I polymorphisms.

15–65 In general the higher the patient‘s panel reactive antibody (PRA), _____. a. the higher the number of suitable transplant donors b. the less likely it is that a hyperacute reaction will occur c. the higher the risk of developing hemolytic disease of the newborn 230

d. e.

the more limited the number of suitable transplant donors the higher the risk of developing autoimmunity.

15–66 If _____ occurs in an organ to be transplanted, endothelial activation, leukocyte infiltration, inflammatory cytokine production, and complement activation may occur. a. a mixed lymphocyte reaction b. the transfusion effect c. kidney dialysis d. ischemia e. myeloablative therapy.

15–67 Which of the following are correctly matched? (Select all that apply.) a. hyperacute rejection: preexisting antibodies against cell-surface antigens b. acute rejection: anti-HLA antibodies c. chronic rejection: alloreactive T-cell clones specific for HLA allotypes of donor d. acute rejection: direct pathway of allorecognition e. transfusion effect: indirect pathway of allorecognition.

15–68 Acute rejection of a kidney graft involves the activation of recipient T cells by _____ of _____ origin. a. dendritic cells; recipient b.

B cells; recipient c. dendritic cells; donor d. macrophages; recipient e.

B cells; donor.

15–69 Effector mechanisms of _____ rejection resemble those responsible for type IV hypersensitivity reactions. a. xenogeneic b. acute c. chronic d. hyperacute e. blood transfusion.

15–70 When donor MHC:donor self-peptide complexes activate recipient T cells, _____. a. acute rejection of transplanted organs occurs b. suppression occurs and transplanted organs are tolerated c. hyperacute rejection of transplanted organs occurs d. complement pathways are activated e. an indirect pathway of allorecognition occurs.

15–71 The extent to which an individual‘s T cells respond to allogeneic HLA expressed on irradiated donor cells can be measured in vitro using _____. a. a cross-match test b. a superantigen recognition test 231

c. d. e.

the mixed lymphocyte reaction the transfusion effect assay the panel reactive antibody test.

15–72 In a mixed lymphocyte reaction the donor cells are irradiated to ensure that they do not _____. a. stimulate recipient cells b. become anergic c. alter their level of expression of HLA molecules d. proliferate e. undergo apoptosis.

15–73 As the number of expressed MHC isoforms in the thymus increases beyond a certain value, the T-cell repertoire _____. a. becomes smaller b. becomes more diverse c. is unaffected.

15–74 In chronic rejection, effector T cells respond to _____ complexes on _____-derived dendritic cells. a. donor MHC class I:donor self peptide; donor b. donor MHC class II:donor self peptide; donor c. recipient MHC class I:donor MHC peptide; recipient d. recipient MHC class II:donor MHC peptide; recipient e. recipient MHC class II:donor MHC peptide; donor.

15–75 Alloantibody production after organ transplantation involves _____. a. a mixed lymphocyte reaction b. the indirect pathway of allorecognition by CD4 T cells c. activation of regulatory CD4 T cells d. the transfusion effect e. a switch from a chronic to an acute state of organ rejection.

15–76 As time progresses following an organ transplant, the alloreactive T-cell response shifts from a(n) _____ pathway to a(n) _____ pathway of allorecognition. a. exogenous; endogenous b. inflammatory; cytotoxic c. hyperacute; suppressive d. autologous; heterologous e. direct; indirect.

15–77 Patients who have previously received a blood transfusion that has HLA-DR allotypes in common with their kidney transplant are _____. a. less likely to reject the graft owing to the presence of regulatory CD4 T cells b. more likely to reject the graft owing to the presence of HLA alloantibodies c. less likely to reject the graft owing to negative selection of alloreactive T-cell clones 232

d. e.

at risk of developing a hyperacute rejection at risk of developing graft-versus-host disease.

15–78 The outcome of organ transplantation improves when _____. (Select all that apply.) a. the patient has been transfused with blood sharing HLA allotypes with the transplanted organ b.

HLA-A, HLA-B and HLA-DR are matched c. a thymectomy is performed at the time of transplantation d. plasmapheresis is carried out before transplantation e. immunosuppressive drugs are used to prevent the activation and proliferation of T cells.

15–79 Which of the following are correctly matched? (Select all that apply.) a. prednisone: pro-drug b. rapamycin: calcineurin c. azathioprine: cytotoxicity d. methotrexate: NFB e. cyclophosphamide: microbial products.

15–80 _____ is a nitrogen mustard compound converted to a DNA-alkylating agent in the body that is used to inhibit cell proliferation after transplantation. a.

Methotrexate b.

Rapamycin c.

FK506 d.

Cyclophosphamide e.

Mycophenolate mofetil.

15–81 Prednisone is a steroid used in transplantation that _____. (Select all that apply.) a. binds to a cell-surface receptor and inhibits the function of NFB b. is combined with cytotoxic drugs to improve its efficacy c. decreases the synthesis of IB d. causes a decrease in production of inflammatory cytokines e. can lead to bone demineralization as an unwanted side-effect.

15–82 Which of the following immunosuppressive drugs functions by inhibiting DNA synthesis? (Select all that apply.) a. cyclophosphamide b. prednisone c. azathioprine d. methotrexate e. mycophenolate mofetil f. cyclosporin A g. tacrolimus.

15–83 _____ decreases the activity of the transcription factor NFAT by inhibiting calcineurin.

(Select all that apply.) a.

Tacrolimus 233

b. c. d. e.

Azathioprine Mycophenolic acid Cyclosporin A Rapamycin.

15–84 Indicate whether each of the following statements is true (T) or false (F). ___ a. Dosage of immunosuppressive drugs is often decreased in transplant patients to minimize toxic side-effects, but there is a risk of rejection. ___ b. Antithymocyte globulin (ATG) is a monoclonal antibody specific for T-cell surface antigens. ___ c. Immunosuppressive xenogeneic antibodies can be used repeatedly for multiple episodes of transplant rejection without complication. ___ d. Daclizumab, an anti-CD3 humanized antibody, is used to treat and prevent acute rejection. ___ e. A possible side-effect of using antilymphocyte globulin (ALG) is serum sickness.

15–85 Steroid receptors are complexed with _____. a.

Hsp90 in the cytoplasm b.

Hsp90 on the cell surface c. calcineurin in the cytoplasm d. calcineurin in the nucleus e.

NFκB in the cytoplasm.

15–86 Corticosteroids interfere with chemotaxis of leukocytes by _____. a. decreasing the production of GM-CSF and IL-1 b. inducing apoptosis c. inhibiting the expression of adhesion molecules on endothelial vessels d. suppressing the activity of phospholipase A2 e. reducing nitrogen oxide synthase (NOS) activity.

15–87 Tacrolimus causes which of the following effects? (Select all that apply.) a. reduced T-cell proliferation b. decreased production of nitric oxide c. decreased production of IL-3, IL-4, GM-CSF, and TNF- d. decreased activity of cyclo-oxygenase type 2 e. serum sickness.

15–88 Which of the following is an effect of both tacrolimus and corticosteroids? a. reduced T-cell proliferation b. decreased production of nitric oxide c. decreased production of IL-3, IL-4, GM-CSF, and TNF- d. decreased activity of cyclo-oxygenase type 2 e. serum sickness.

15–89 Which of the following human molecules would be candidates for genetic modification of pigs to make these animals more suitable as organ donors for humans? (Select all that apply.)

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a. b. c. d. e.

membrane co-factor protein (MCP) decay-accelerating factor (DAF) HLA class II HLA class I CD59.

15–90 A characteristic of the human eye that enables the cornea to be transplanted with a 90% success rate is that _____. (Select all that apply.) a. antigen-presenting cells in the eye do not express the co-stimulatory molecule B7 b. the cornea is not vascularized c. anterior-chamber-associated immune deviation (ACAID) establishes a state of tolerance in the eye d. only regulatory T cells express the adhesion molecules necessary to enter the cornea e. the aqueous humor of the anterior chamber contains TGF-, which downregulates CD40 and inhibits IL-12 secretion.

15–91 Which of the following are transplanted with a relatively high success rate despite major differences in HLA class I and II between donor and recipient? (Select all that apply.) a. bone marrow b. heart c. cornea d. kidney e. liver.

15–92 Liver transplantation requires that _____ be matched between donor and recipient.

(Select all that apply.) a.

HLA class I b.

HLA class II c.

ABO antigens d. rhesus antigen.

15–93 What is the probability that a sibling will be able to provide a HLA-haploidentical kidney for transplantation? a.

100% b.

75% c.

50% d.

25% e.

0%.

15–94 What explains the observation that mixed lymphocyte reactions carried out between some dizygotic twins have a negligible stimulation index?

ANSWERS 15–1 d 235

15–2 a, c 15–3 b 15–4 c 15–5 b, d, e 15–6 b 15–7 a, d 15–8 a 15–9 a—3; b—2; c—5; d—1; e—4 15–10 c 15–11 c 15–12 e 15–13 a, b, d, f 15–14 b 15–15 b 15–16 a 15–17 a, e 15–18 d 15–19 Mature T-cell depletion of bone marrow reduces GVHD, but graft failure and disease recurrence in cancer patients is an associated risk with this procedure. Apparently, alloreactive T-cell responses benefit engraftment by suppressing remnants of the recipient‘s immune system and removing residual cancer cells through a graft-versus-leukemia (GVL) effect.

15–20 b 15–21 a, b, c 15–22 b, e, f

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15–23 b, d 15–24 d 15–25 b 15–26 b, c, d 15–27 c 15–28 e 15–29 d, e 15–30 b, c 15–31 b 15–32 a, e 15–33 c 15–34 b 15–35 a 15–36 a—1; b—3; c—4; d—5; e—2.

15–37 Rationale: The correct answer is c. This is an example of serum sickness, a type III hypersensitivity reaction. George has made antibodies against infliximab, which is a chimeric monoclonal antibody made of human and mouse (foreign) components. Because this is an adaptive immune response, it takes time before sufficient levels of anti-infliximab antibody are made and cause the formation of immune complexes. Deposition of the immune complexes in blood vessels, joints, and glomeruli are causing George‘s symptoms. These symptoms are typically self-limiting, because as anti-infliximab antibody levels increase into the zone of antibody excess, the size of immune complexes will increase and they will then be cleared effectively by splenic macrophages, Kupffer cells of the liver, and mesangial cells of the kidney.

15–38 Vaccination is used to stimulate a very specific, long-lasting immune response against a pathogen that provides protection in the event of subsequent encounter. The objective of transplantation, however, to suppress the immune response to eliminate the rejection of a graft that bears foreign epitopes.

15–39 Acute rejection is due chiefly to immune responses made by the recipient‘s T cells against HLA class I and II molecules of the graft that are different from those of the recipient and that the recipient‘s immune system perceives as ‗foreign.‘ The differences can be due to the HLA 237

molecules, the self peptides they bind, or both. Transplantation between identical twins and transplantation of autografts are the only situations in which the graft and the recipient are genetically identical and in which there are no differences in either the HLA molecules or the bound peptides. In these situations, graft rejection does not occur. Transplantation between donors and recipients who have identical HLA class I and II molecules, usually HLA-identical siblings, almost always involves differences in the peptides that are bound by the HLA molecules. These differences trigger peptide-specific alloreactive T cells to cause graft rejection through the direct pathway of allorecognition. Although it is possible to match donor and recipient for many HLA class I and II allotypes, in practice most clinical transplants involve one or more mismatched HLA loci. For these differences in HLA type, alloreactive T-cell clones activated by either the direct or indirect pathway of allorecognition cause graft rejection.

Destruction of the grafted organ is effected through a type IV delayed-type hypersensitivity response.

15–40 c 15–41 Acute rejection occurs within a few days of transplantation and is mediated by an alloreactive CD4 and CD8 T cell-mediated adaptive immune response by the recipient against the ‗foreign‘ HLA molecules on the graft and involves the direct pathway of recognition. In contrast, chronic rejection occurs months to years after transplantation; it is mediated by antiHLA class I and anti-HLA class II alloantibodies and involves the indirect pathway of recognition. CD4 T cells are first activated by recipient dendritic cells presenting donor-derived HLA class II allotypes of the recipient. These activated CD4 T cells in turn activate B cells, which are also presenting donor-derived allogeneic HLA peptides. This cognate interaction results in the production of anti-HLA class I (and also anti-HLA class II) antibodies.

15–42 A. The organ would be rejected immediately by the process of hyperacute rejection as a result of the presence in the recipient‘s blood of preformed antibodies against the A and B blood group antigens present on the tissues of the graft. Such antibodies are made early in life as a result of exposure to common bacteria that carry surface carbohydrates similar to those on human cells. A person of blood group O would have made antibodies against bacterial ‗A‘ and ‗B‘ antigens, because the person does not have these antigens on their own cells and is thus not tolerant to them. These preexisting anti-A and anti-B antibodies in the recipient‘s blood will immediately attack the endothelium of blood vessels throughout the transplant, which expresses the A and B blood group antigens. Blood vessels become occluded through thrombus formation.

The graft is deprived of oxygen and becomes engorged with blood hemorrhaging from leaky blood vessels. Hyperacute rejection occurs almost immediately after transplantation and cannot be treated once it has started.

B. Other examples of combinations that will induce hyperacute rejection: O recipient, A donor; O recipient, B donor; A recipient, B donor; B recipient, A donor; A recipient, AB donor; and B recipient, AB donor.

C. A recipient‘s preformed antibodies against an HLA class I antigen expressed on the endothelial cells of the transplant can also cause hyperacute rejection. Such antibodies can be generated in pregnancies in which the fetus expresses a paternal HLA allotype different from the

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maternal HLA allotype. These antibodies can also arise from HLA-incompatible blood transfusions or previous transplants.

D. Hyperacute rejection can be prevented by typing and cross-matching donor and recipient for the A, B, and O blood groups and HLA antigens. The recipient‘s serum antibodies are assayed in vitro for their ability to bind to donor white blood cells.

15–43 Beyond a certain number of isotypes, the T-cell repertoire will be decreased, owing to the disproportionate increase in negative selection events as the number of different isotypes increases. Each additional isotype will decrease the number of T cells exported to the periphery, compromising the diversity of the T-cell population.

15–44 A. Class 1: corticosteroids. Examples: hydrocortisone and prednisone.

Class 2: cytotoxic drugs. Examples: azathioprine, cyclophosphamide, and methotrexate.

Class 3: T-cell activation inhibitors. Examples: cyclosporin A, tacrolimus (FK506), and rapamycin.

B. Class 1: side-effects/toxic effects: fluid retention, weight gain, diabetes, bone demineralization, and thinning of the skin.

Class 2: side-effects/toxic effects: nonspecifically prevent DNA replication in all mitotic cells causing, for example, diarrhea or hair loss. More specific effects are liver damage caused by azathioprine, and bladder damage caused by cyclophosphamide.

Class 3: side-effects/toxic effects: nephrotoxicity and suppression of B-cell and granulocyte activation.

15–45 Cyclosporin A prevents the production of IL-2 and its high-affinity receptor, and thus prevents the activation of T cells and their proliferation and differentiation. It acts by inactivating the protein calcineurin. Calcineurin is a serine/threonine protein phosphatase that is activated by the first part of the T-cell receptor signaling pathway and dephosphorylates the transcription factor NFAT. This modification is necessary for NFAT, which normally resides in the cytoplasm, to enter the nucleus and stimulate transcription of the genes for IL-2 and the IL-2 receptor α chain. Inactivation of calcineurin by cyclosporin thus prevents the production of IL-2 and its high-affinity receptor.

15–46 a 15–47 A. Anti-CD3 MoAbs are often administered to patients to suppress T-cell activity when signs of graft rejection are observed. Because CD3 is expressed only on T lymphocytes, this therapy is extremely specific. Anti-CD3 antibodies cross-link CD3:T-cell receptor complexes, leading to a reduction in the number of these complexes on the cell surface and a reduction in the number of T cells in the circulation. Suppression of effector T-cell activity protects the graft.

B. Mouse MoAbs are antigenic in species other than mice and stimulate anti-MoAb responses. Repeated doses will exacerbate this situation and lead to the formation and clearance of MoAb:anti-MoAb immune complexes before the antibody can bind to the T cells, thus rendering the mouse antibody ineffective. A type III hypersensitivity reaction resembling serum 239

sickness can also result when small immune complexes are formed; that is, when MoAb levels exceed anti-MoAb levels. Hence, repeated doses are discouraged, and physicians must restrict this form of immunosuppressive therapy to one episode of rejection.

15–48 b 15–49 A. Graft-versus-host disease is caused by T cells in the transplanted bone marrow making an immune response against antigens on the recipient‘s tissues. This can happen even though donor and recipient are HLA matched, because there are proteins other than HLA antigens that can differ between people and provoke an immune response. Such antigens are known as minor histocompatibility antigens. In a bone marrow transplant from a female to a male, the minor histocompatibility antigens most likely to cause a problem are male-specific proteins (which are encoded on the Y chromosome) that a female‘s T cells will not be tolerant to and will see as ‗foreign‘ or non-self.

B. CD8 cytotoxic T cells. The proteins that act as minor histocompatibility antigens are mainly intracellular proteins. Intracellular proteins of the recipient‘s cells are processed into peptides by proteasomes as part of normal protein degradation and turnover. These peptides are transported into the endoplasmic reticulum and thus are eventually presented on the surface of the recipient‘s cells by HLA class I molecules. Any peptides that are different from those in the donor may be recognized as non-self by the donor‘s cytotoxic T cells, which recognize peptides bound to HLA class I molecules. The naive CD8 T cells in the bone marrow can be activated to effector status by the presentation of minor histocompatibility peptides by dendritic cells in secondary lymphoid organs.

Because the brother and sister share HLA class I type, the sister‘s T cells will be able to recognize non-self peptides presented by her brother‘s HLA molecules.

15–50 A. No. B. Unlike bone marrow, in which a successful outcome is compromised by HLA mismatches, the liver can be transplanted even if there are major differences in HLA class I and class II between donor and recipient. The liver is more refractory to hyperacute or acute rejection than other vascularized organs such as the kidney; low expression levels of HLA class I and the absence of HLA class II contribute to this refractory state. Donor and recipient still need to be matched for ABO, and transplant patients receive immunosuppressive therapy to control chronic rejection.

15–51 First, the medical specialists involved in carrying out the transplant and overseeing the post-transplant regimen are different for organ transplantation and for bone marrow transplantation. Patients receiving organ transplants will have transplant surgeons and physicians, whereas bone marrow recipients will consult with hematologists, oncologists, and radiologists. Second, the requirement for HLA matching and immunosuppressive therapy in organ transplantation depends on which organ is being transplanted. The success of a bone marrow transplant is much more sensitive to HLA mismatches, and the recipient‘s immune system is not simply immunosuppressed; rather, it is destroyed by myeloablative therapy involving chemotherapy and irradiation. Third, the pool of potential bone marrow donors is 240

larger than the demand, unlike organ donations, for which thousands of patients are on waiting lists. Finally, the bone marrow donor is alive and healthy, whereas organ donors are on life support or have experienced a fatal accident.

15–52 a—F; b—T; c—F; d—F; e—F 15–53 Rationale: The correct answer is a. An HLA haploidentical donor has one HLA haplotype in common with the recipient and one that is different. A bone marrow sample from a haploidentical donor contains numerous alloreactive T cells that can respond to the HLA class I and class II molecules encoded by the HLA class I and II genes of the recipient‘s HLA haplotype that is not shared with the donor. These alloreactive T cells have the potential to cause a severe and life-threatening graft-versus-host-disease. To prevent such an outcome, bone marrow grafts from haploidentical donors are purged of T cells before being infused into the recipient.

Haploidentical transplants are only given to patients who are unable to find an HLA-matched donor. Family members are good candidate donors because all parents and 50% of siblings (on average) have one HLA haplotype in common and one that is different from a patient such as Richard. Unlike Don, who is HLA-haploidentical to Richard, his other sibling Margaret could not be a donor because neither of her HLA haplotypes is shared with Richard.

15–54 Rationale: The correct answer is d. The better the match in HLA class I and class II allotypes between the donor and the recipient, the better the outcome of the transplantation.

Donor ‗d‘ has five out of six alleles in common for HLA-A, HLA-B, and DRB. Donors ‗b‘ and ‗e‘ share only four, and donors ‗a‘ and ‗c‘ only three.

11–55 After the bone marrow transplant, the patient‘s entire immune system, including T cells and dendritic cells, will become reconstituted from hematopoietic stem cells in the donor bone marrow. Donor-derived T cells developing in the recipient‘s thymus will, however, be positively selected on the recipient‘s HLA molecules, and will only recognize antigen in that context. If the donor and recipient do not share any HLA molecules, these T cells will not be able to recognize antigen presented by the donor-derived dendritic cells or macrophages and will not be activated in response to pathogens. Because T-cell activation is central to all adaptive immune responses, the recipient will remain severely immunodeficient and unable to make adaptive immune responses to pathogens. In addition, HLA matching reduces the severity of graft-versus-host disease (GVHD), in which mature T cells in the donor graft respond to the allogeneic MHC class I and II molecules of the recipient and attack host tissue.

15–56 A. A cross-match test assesses the compatibility between a potential donor and a recipient for blood transfusion.

B. A cross-match test is carried out to ensure that hypersensitivity reactions, such as type II hypersensitivity, do not occur as a result of antibodies in the recipient's blood reacting against blood group antigens on the donor erythrocytes, thus triggering destruction of the transfused red cells.

C. To carry out a cross-match test, blood serum from the recipient (the blood fraction containing antibodies) is mixed with erythrocytes from the donor.

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15–57 1—a; 2—a, c; 3—a, b; 4—a, b, c, d.

15–58 b 15–59 b 15–60 c, d, e 15–61 b 15–62 There is a possibility of incompatibility between erythrocytes and leukocytes involving ABO, Rhesus antigens, HLA class I and class II molecules, and other polymorphic alloantigens.

Each transfusion will stimulate alloantibody production to these polymorphic determinants, which, if present in the blood of a subsequent transfusion, will stimulate a type II hypersensitivity reaction in the recipient. Each blood transfusion increases the alloantibody pool, making it more difficult to find donors who will not cause a hypersensitivity reaction.

15–63 c, d, e 15–64 If the individual has received a previous solid organ graft or blood transfusion that was not matched for HLA class I, a primary alloantibody response would have been mounted.

Priming can also occur naturally during pregnancy when fetal cells bearing paternal HLA molecules enter the maternal circulatory system at birth. If the paternal HLA isoforms are different from the maternal isoforms, the mother will mount an anti-HLA alloantibody response.

If a woman has multiple pregnancies with the same partner, her anti-HLA titer and memory Bcell population will increase. If a woman has multiple pregnancies with different partners who have disparate HLA allotypes, the diversity of anti-HLA antibody will also increase. Both scenarios restrict the number of possible donors for transplantation; unsuitable donors are eliminated from the list after cross-matching.

15–65 d 15–66 d 15–67 a, d, e 15–68 c 15–69 b 15–70 a 15–71 c 15–72 d

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15–73 a 15–74 d 15–75 b 15–76 e 15–77 a 15–78 a, b, e 15–79 a, c 15–80 d 15–81 b, d, e 15–82 a, c, d, e 15–83 a, d 15–84 a—T; b—F; c—F; d—F; e—T 15–85 a 15–86 c 15–87 a, c 15–88 c 15–89 a, b, e 15–90 b, c, e 15–91 c, e 15–92 c, d 15–93 c 15–94 In about 8% of dizygotic twins, the blood circulation is joined and the twins are born chimeric with hematopoietic cells of both twins present in both circulatory systems. A state of tolerance is induced to disparate major and minor histocompatibility antigens, explaining the absence of stimulation in a mixed lymphocyte reaction. These twins would also be expected to 243

be able to donate organs or bone marrow to each other without the development of GVHD or the need for immunosuppressive drugs.

CHAPTER 16: DISRUPTION OF HEALTHY TISSUE BY THE ADAPTIVE IMMUNE RESPONSE 16–1 Autoimmune diseases, which are classified on the basis of the effector mechanism that causes the symptoms, include all of the following types of hypersensitivity reaction except _____. a. type I b. type II c. type III d. type IV. 16–2 a. b. c. d. e.

Which type of autoimmune disease is correctly matched with its cause? type I: IgE-mediated type II: effector T cells type III: immune complex deposition in tissues type IV: extracellular matrix-associated autoantigens type V: cell-surface components.

16–3 Match the type of hypersensitivity in column A with its description in column B. Column A Column B ___ a. type I 1. antibodies directed against extracellular matrix on the cell surface ___ b. type II 2. T cell-mediated ___ c. type III 3. deposition of soluble immune complexes in tissues ___ d. type IV 4. IgE-mediated

16–4 Which of the following is an example of a type II autoimmune response? (Select all that apply.) a. subacute bacterial endocarditis b.

Goodpasture‘s syndrome c. multiple sclerosis d. systemic lupus erythematosus e. myasthenia gravis.

16–5 Which of the following is an example of a type III autoimmune response? (Select all that apply.) a. mixed essential cryoglobulinemia b. acute thrombocytopenia purpura c. systemic lupus erythematosus d. rheumatoid arthritis e. insulin-resistant diabetes.

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16–6 Which of the following is an example of a type IV autoimmune response? (Select all that apply.) a. pemphigus vulgaris b. autoimmune thrombocytopenia purpura c. subacute bacterial endocarditis d. type 1 diabetes e. multiple sclerosis.

16–7 Explain why splenectomy is sometimes carried out in patients with persistent type II autoimmune diseases that affect leukocytes.

16–8 If autoantibodies of the IgG or IgM isotype were produced with specificity for components found on the surface of erythrocytes, which of the following would occur? (Select all that apply.) a. formation of membrane-attack complex b. immune-complex deposition in renal glomeruli c. anemia d. hypothyroidism e. receptor-mediated phagoytosis via Fc receptors on phagocytes.

16–9 Which of the following is the cause of red blood cell deficiency in autoimmune hemolytic anemia? (Select all that apply.) a. inability of red blood cells to develop normally in the bone marrow b. loss of red blood cells due to widespread pinpoint hemorrhages c. hemolysis by assembly of membrane-attack complexes d. phagocyte-mediated clearance in the spleen e. rapid turnover of red blood cells due to CD8 T-cell killing.

16–10 All of the following are associated with Goodpasture‘s syndrome except _____. (Select all that apply.) a. α chain of type IV collagen b. inflammation c. extracellular matrix antigen d. neutropenia e. renal tubules and glomeruli f. type III hypersensitivity reaction.

16–11 _____ is a highly variable type III autoimmune disease in which immune complexes form and may cause glomerulonephritis of the kidney, arthritis of the joints, and vasculitis of the face. a. pemphigus vulgaris b. systemic lupus erythematosus c. rheumatoid arthritis d. multiple sclerosis e.

Goodpasture‘s syndrome.

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16–12 Individuals who have two defective alleles of the AIRE gene _____. a. exhibit symptoms of autoimmunity at a young age b. are unable to activate regulatory T cells c. exhibit decreased predisposition to autoimmune disease d. are very effective at inducing anergy of circulating autoreactive B and T cells e. are more likely to be women of African or Asian origin.

16–13 All of the following autoimmune diseases are correctly matched with their HLA disease associations except _____. a.

HLA-B27: ankylosing spondylitis b.

HLA-DQ2: type 1 diabetes in Africans and Asians c.

HLA-B35: birdshot retinopathy d.

HLA-DR4: rheumatoid arthritis e.

HLA-DQ6: narcolepsy.

16–14 The haplotype A1–B8–DR3–DQ2 is associated with several common autoimmune diseases including all of the following except _____. a. ankylosing spondylitis b. systemic lupus erythematosus c. autoimmune hepatitis d. myasthenia gravis e. type 1 diabetes f. primary biliary cirrhosis.

16–15 With the exception of ______, these autoimmune diseases are more prevalent in women than in men. a. rheumatoid arthritis b. multiple sclerosis c. ankylosing spondylitis d.

Sjögren‘s syndrome e.

Graves‘ disease.

16–16 Which of the following is not a characteristic of Graves‘ disease? a. weight loss b. enlarged thyroid gland c. elevated thyroid-stimulating hormone d. heat intolerance e. overproduction of T3 and T4.

16–17 All of the following are true regarding thyroglobulin except _____. a. its tyrosine residues are iodinated and cross-linked b. it is broken down to produce thyroid hormones c. it is stored in follicles of the thyroid d. it signals the pituitary gland to stop releasing thyroid-stimulating hormone e. it is synthesized initially as a glycoprotein by thyroid epithelial cells.

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16–18 Which of the following describes myasthenia gravis? a.

Ectopic lymphoid tissue forms and impairs endocrine function. b.

Disruption of adhesion molecules of cellular junctions. c.

Autoimmune response to proteins of anterior chamber of the eye. d.

Chronic inflammation of the gut mucosa. e.

The neuromuscular junction is compromised.

16–19 Which of the following is associated with antagonistic autoantibodies against cell-surface receptors or adhesion molecules? (Select all that apply.) a. myasthenia gravis b. rheumatoid arthritis c. insulin-resistant diabetes d.

Graves‘ disease e. pemphigus vulgaris.

16–20 The reason why babies born to mothers with Graves‘ disease suffer passively from the disease for only a short while after birth is that _____. a. very little IgM is transported across the placenta b. only antibodies, and not the B cells making the autoantibodies, cross the placenta c. the newborn‘s regulatory T cells suppress autoantibody production d. the newborn‘s thyroid gland develops resistance to the effects of maternal autoantibodies e. thyroglobulin synthesis does not commence until months after birth.

16–21 The formation of ectopic lymphoid tissues occurs in all of the following conditions except _____. a. pemphigus foliaceus b. chronic hepatitis C infection c.

Hashimoto‘s disease d. rheumatoid arthritis e. multiple sclerosis f.

Graves‘ disease.

16–22 A(n) _____ binds to the antigen-binding site of another antibody. a. cryptic epitope b. anti-idiotypic antibody c. molecular mimic d. receptor antagonist e. autoantibody.

16–23 All of the following are linked to the development of rheumatoid arthritis or are associated with its treatment except _____. (Select all that apply.) a. anti-immunoglobulin autoantibodies b. adalumumab c. leukocyte infiltration in synovial tissue d. joint inflammation e. pulmonary hemorrhage 247

f. g. h. i. j.

rituximab increased susceptibility if the person possesses the HLA-DRB1*04:01 or 04:04 allotypes. peptidyl arginine deiminases smoking rheumatic fever.

16–24 It is believed that the allotype DRB1*_____ may confer protection against rheumatoid arthritis because it contains _____ amino acid residues at positions 70 and 71 that bind to different subsets of peptides compared with the allotypes that confer susceptibility to this disease. a.

04:01; acidic b.

04:02; acidic c.

04:04; basic d.

04:05; basic e 04:08; acidic.

16–25 Celiac disease exhibits all of the following symptoms except _____. a. villous atrophy b. anemia c. diarrhea d. tissue ulceration e. malabsorption f. increased susceptibility to intestinal cancer.

16–26 All of the following are characteristics of tissue transglutaminase except ____. a. generation of negatively charged peptides that bind well to the positively charged pockets of the DQ2 and DQ8 allotypes b. conversion of glutamine to glutamate by deamination c. upregulation during tissue inflammation d. stimulation of IgG or IgA autoantibodies in celiac disease e. predisposition to celiac disease if individual possesses particular polymorphic variants.

16–27 Describe three types of unwanted and potentially harmful immune response.

16–28 Which of the following describes processes by which self-reactive lymphocytes are rendered incapable of mounting an autoimmune response? (Select all that apply.) a. sequestration of autoantigens in immunologically privileged sites b. induction of anergy in peripheral compartments c. positive selection of autoimmune T lymphocytes in secondary lymphoid tissues d. negative selection of T lymphocytes in the thymus e. suppression by regulatory T cells f. negative selection of B lymphocytes in the bone marrow g. expression of AIRE in the bone marrow h. induction of alloreactive responses it the thymus i. somatic hypermutation to an alternative antigen specificity j. apoptosis in primary lymphoid tissue 248

k.

deprivation of T-cell help.

16–29 From Table 16–29 below, match the autoimmune disease in column A with the corresponding antigen in column B and the consequence in column C. Use each answer only once. Then indicate whether the autoimmune disease is categorized as type II, III, or IV. Table Q16–29 Column A

Column B

Column C

a. Rheumatoid arthritis

1. Myelin basic protein, proteolipid protein

A. Destruction of red blood cells by complement and phagocytosis, anemia

b. Subacute bacterial endocarditis

2. DNA, histones, ribosomes, snRNP, scRNP

B. Joint inflammation and destruction

c. Autoimmune hemolytic anemia

3. Thyroid-stimulating hormone receptor

C. Pancreatic β cell destruction

d. Mixed essential cryoglobulinemia

4. Bacterial antigen

D. Glomerulonephritis

e. Multiple sclerosis

5. Rheumatoid factor IgG complexes

E. Hyperthyroidism

f. Systemic lupus erythematosus 6. Epidermal cadherin

F. Blistering of skin

g. Type 1 diabetes

7. Synovial joint antigen

G. Glomerulonephritis, vasculitis, arthritis

h. Graves‘ disease

8. Rh blood group antigens

H. Systemic vasculitis

i. Pemphigus vulgaris

9. Pancreatic β cell antigen

I. Brain degeneration, paralysis

16–30 Describe the three immunological mechanisms responsible for the destruction of red blood cells in autoimmune hemolytic anemia.

16–31 Characterize two properties of endocrine glands that render them susceptible to autoimmune attack.

16–32 Hashimoto‘s and Graves‘ diseases both impair normal functioning of the thyroid gland but do so using different immunopathological mechanisms. Compare and contrast these mechanisms.

16–33 Indicate whether each of the following statements is true (T) or false (F). ___a. During pregnancy, IgG antibodies and activated lymphocytes can cross the placenta and enter the circulatory system of the fetus. ___b. Blood plasma exchange (plasmapheresis) can be used to remove maternal IgG from the newborn. ___c. All autoimmune diseases involve a breach of T-cell tolerance.

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___d. Newborns of mothers with T cell-mediated autoimmune diseases exhibit the same symptoms as their mothers. ___e. Autoimmune diseases can be induced after an infection.

16–34 A. What mechanism of self-tolerance is broken in the autoimmune syndrome APECED? B. What is the underlying genetic defect in APECED? Explain why it leads to a reduction in self-tolerance.

16–35 You have isolated a subset of CD25+ CD4+ T cells from the blood that have T-cell receptors specific for a self antigen but do not proliferate when challenged with the antigen in vitro. What is the name given to these T cells, and what role are they thought to have in preventing autoimmunity?

16–36 People who are heterozygous for HLA-DQ2 and HLA-DQ8 allotypes are at greater risk of developing type 1 diabetes than those who are homozygous for HLA-DQ2 or HLA-DQ8.

A. Explain the reason for this increased susceptibility.

B. Why is the above statement true mainly for people of northern European origin but not for some other ethnic groups?

16–37 A. Which patients affected by Goodpasture‘s syndrome also succumb to pulmonary hemorrhage?

B. Explain the reason for this complication.

16–38 Explain the relationship between HLA-DRB1*04, smoking, the expression of peptidyl arginine deaminase, and rheumatoid arthritis.

16–39 In the context of autoimmunity: (A) define molecular mimicry; and (B) provide an example.

16–40 A recent therapy developed for the treatment of rheumatoid arthritis includes the use of _____ monoclonal antibodies that suppress the autoimmune response. (Select all that apply.) a. anti-TNF-α b. anti-C-reactive protein c. anti-CD20 d. anti-rheumatoid factor e. anti-CD3.

16–41 Chronic diseases in which the immune response is targeted toward autologous entities of one‘s body are known as _____. a. hypersensitivity reactions b. innate immune reactions c. allergic reactions d. autoimmune diseases e. anergic reactions.

250

16–42 Discuss why splenectomy is a viable treatment for chronic autoimmune diseases targeted at circulating neutrophils.

16–43 Indicate whether each of the following statements is true (T) or false (F). ___ a. Autoimmune diseases are rarely resolved. ___ b. Autoimmune responses are the result of innate immune responses directed toward self antigens. ___ c. Some forms of autoimmune disease involve IgE autoantibodies. ___ d. During pregnancy the fetus is exposed to maternal leukocytes. ___ e. Ectopic lymphoid tissue resembling secondary lymphoid tissue may develop under the influence of lymphotoxin (LT).

16–44 Match the autoimmune disease in column A with the consequence in column B. Column A Column B ___ a. type 2 diabetes 1. skin blistering ___ b. rheumatoid arthritis 2. joint deterioration ___ c. mixed essential cryoglobulinemia 3. keotacidosis ___ d. acute rheumatic fever 4. heart valve scarring ___ e. pemphigus vulgaris 5. systemic vasculitis 16–45 Match the autoimmune disease in column A with the autoantigen in column B. Column A Column B ___ a. mixed essential cryoglobulinemia 1. thyroid-stimulating hormone receptor ___ b. myasthenia gravis 2. cell wall components of Streptococcus ___ c. Graves‘ disease 3. myelin basic protein ___ d. acute rheumatic fever 4. acetylcholine receptor ___ e. multiple sclerosis 5. rheumatoid factor IgG 16–46 Which of the following would be consistent with a diagnosis of Goodpasture‘s syndrome? (Select all that apply.) a. pulmonary hemorrhage b. joint inflammation c. glomerulonephritis d. anti-collagen IgG deposition in renal glomeruli e. hyperglycemia.

16–47 Thyroid-stimulating hormone is made in the _____ and induces the release of thyroid hormones after proteolytic processing of _____. a. pituitary gland; thyroglobulin b. hypothalamus; thyroxine c. pancreas; thyroglobulin d. pituitary gland; thyroid-stimulating hormone receptor e. thyroid gland; thyroid peroxidase.

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16–48 Graves‘ disease causes _____, whereas Hashimoto‘s disease causes _____. a. hypothyroidism; hyperthyroidism b. hyperthyroidism; hypothyroidism c. hypoglycemia; hyperglycemia d. hyperglycemia; hypoglycemia e. glomerulonephtitis; systemic vasculitis.

16–49 A. What is ectopic lymphoid tissue?

B. Give four examples where this type of tissue forms in autoimmune disease.

16–50 How do the treatments for Hashimoto‘s and Graves‘ diseases differ, and why?

16–51 Which of the following are correctly matched? (Select all that apply.) a. exocrine tissue: islets of Langerhans b. type 2 diabetes: insulin-dependent diabetes mellitus c. β cells of pancreas: insulin production d. α cells of pancreas: somatostatin production e. insulitis: lymphocyte infiltration in islets of Langerhans.

16–52 Examples of rheumatic diseases caused by autoimmune responses include _____. (Select all that apply.) a. rheumatoid arthritis b. acute rheumatic fever c. multiple sclerosis d. autoimmune hemolytic anemia e.

Sjögren‘s syndrome f. systemic lupus erythematosus.

16–53 Another name for anti-immunoglobulin autoantibodies is _____. a.

C-reactive protein b. rheumatoid factor c. rituximab d. thyroglobulin e. ectopic antibodies f. infliximab.

16–54 Rituximab, used in the treatment of rheumatoid arthritis, depletes _____ through a process involving the cross-linking of _____ on the surface of NK cells and the induction of antibody-dependent cell-mediated cytotoxicity. a.

NK cells; NKG2D b.

T cells: NKG2D c. inflammatory cytokines; TNF-alpha d.

C-reactive protein; FcγRIII e.

B cells; FcγRIII.

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16–55 Which of the following autoimmune diseases affect the nervous system? (Select all that apply.) a. myasthenia gravis b. mixed essential cryoglobulinemia c.

Graves‘ disease d. pemphigus vulgaris e. multiple sclerosis.

16–56 _____ autoantibodies enhance receptor function. a. neutralizing b. opsonizing c. agonist d. complement-fixing e. antagonist.

16–57 Antagonistic autoantibodies made against the insulin receptor cause _____. (Select all that apply.) a. type 1 diabetes b. hypoglycemia c. hyperglycemia d. insulin-resistant diabetes e. light-headedness.

16–58 Deficiency in the production of AIRE results in _____. (Select all that apply.) a. normal expression of tissue-specific proteins in the bone marrow and thymus b. incomplete negative selection of developing T cells c. the development of autoimmune B-cell and T-cell responses against endocrine glands and other tissues d. death in infancy e. the development of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED).

16–59 Describe two different ways in which infection with bacteria or viruses compromises Tcell tolerance, leading to the production of effector T cells specific for self antigens.

16–60 Ankylosing spondylitis has a strong association with polymorphisms found in _____. a.

HLA-B27 b.

AIRE c.

CTLA-4 d.

HLA-DQ6 e.

HLA-Cw6 f.

FoxP3 g.

TNF-α.

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16–61 Autoantibody specificities are affected by HLA class II polymorphisms. In the case of systemic lupus erythematosus, indicate which of the following associations between HLA-class II and autoantigens have been observed in these patients. a.

HLA-DR3; nuclear ribonucleoprotein complex b.

HLA-DR5; small cytoplasmic ribonucleoprotein complex c.

HLA-DR2; double-stranded DNA d.

HLA-DR4; single-stranded RNA e.

HLA-DQ8; double-stranded RNA. 16–62 Explain the mechanism that gives rise to a broadening B-cell response during the course of systemic lupus erythematosus.

16–63 _____ is an example in which physical trauma provides access of lymphocytes to an otherwise immunologically privileged site. (Select all that apply.) a. rheumatoid arthritis b. multiple sclerosis c. type 1 diabetes d. myasthenia gravis e. sympathetic ophthalmia.

16–64 Bacterial infections are associated with which of the following autoimmune diseases?

(Select all that apply.) a.

Reiter‘s syndrome b. pemphigus vulgaris c. reactive arthritis d. rheumatic fever e. myasthenia gravis.

16–65 _____ is the term used to describe how pathogen antigens resemble host antigens and can sometimes trigger autoimmune disease. a. intramolecular epitope spreading b. molecular mimicry c. intermolecular epitope spreading d. sympathetic senescence e. linkage equilibrium.

16–66 A. What is meant by the term ‗epitope spreading‘?

B. Name one autoimmune disease affecting the skin in which epitope spreading is involved, and explain how.

16–67 The upregulation of _____ by IFN-γ can contribute to antigen-specific T-cell activation on thyroid epithelium. a.

CD4 b.

CD8 c.

HLA class I 254

d. e.

HLA class II CD28.

16–68 A(n) _____ is an epitope that is typically not accessible to the immune system but is revealed under inflammatory or infectious states. a. cryptic epitope b. molecular mimic c. regulatory peptide d. carrier e. adjuvant.

16–69 The process by which the human thymus gradually decays is known as _____. a. apoptosis b. senescence c. involution d. the hygiene hypothesis e. self-tolerance.

16–70 The autoreactive CD4 T cells of elderly people with rheumatoid arthritis _____. (Select all that apply.) a. express high levels of CD28 b. are predominantly anergic c. express KIR2DS2 d. are highly susceptible to apoptosis in inflamed joints e. produce IFN-γ.

16–71 Amanda Chenoweth, 21 years of age, returned from a summer job as a pianist on a cruise ship where she was exposed daily to excessive sun; she developed a rash on her cheeks. She complained that her finger joints were stiff and painful, which made it difficult to play the piano, and that her hips became painful after sitting at the piano for long periods. Her blood sample tested positive for anti-nuclear antibodies and had decreased serum C3 levels. A urine albumin test showed elevated protein levels. A course of prednisone (an anti-inflammatory steroid) in combination with naprosyn (a nonsteroidal anti-inflammatory agent) was begun and her condition improved rapidly. What is the most likely cause and clinical name of her condition? a. deterioration of the central nervous system; multiple sclerosis b. cartilage destruction by bone-cell enzymes; rheumatoid arthritis c. immune complexes fixing complement in kidney, joints, and blood vessels; systemic lupus erythematosus d. autoantibodies against acetylcholine receptor at the neuromuscular junction; myasthenia gravis e. consumption of seafood to which she was allergic; acute systemic anaphylaxis.

16–72 At 42 years old, Stephanie Goldstein developed occasional blurred and double vision, numbness and ‗pins and needles‘ in her arms and legs (paresthesia), and bladder incontinence.

After a month of these symptoms she went to her doctor, who sent her to the neurology specialist. An MRI scan revealed areas of demyelination in the central nervous system (CNS), 255

and Stephanie was diagnosed with the autoimmune disease multiple sclerosis (MS). Which of the following best explains why some people are susceptible to the development of MS? a.

Negative selection of autoreactive T cells occurs during T-cell development. b.

Apoptosis of autoreactive B cells occurs in the bone marrow during B-cell development. c.

An inability to produce immunological tolerance toward CNS-derived constituents results in the generation of self-reactive lymphocytes. d.

An immunodeficiency inhibiting somatic recombination of immunoglobulins and T-cell receptors results in impaired lymphocyte development. e.

Regulatory T cells fail to activate autoreactive T cells in secondary lymphoid organs.

16–73 Anders Anderson, was seen by his pediatrician at 24 months old after a recent bout of diarrhea and vomiting. He had lost his appetite and complained that his stomach hurt. Anders was in the 5% centile for weight, had slender limbs, wasted buttocks, and a protuberant abdomen. Jejunal biopsy revealed abnormal surface epithelium, and villous atrophy with hyperplasia of the crypts. Which of the following would be a likely clinical finding in this patient? a. glomerulonephritis b. urticarial rash c. anti-gliadin IgA antibodies d. chronic wheezing e. low blood pressure.

16–74 Seventeen-year-old Lisa Montague practiced piano for 3–4 hours each day while preparing for music college auditions. Some of her pieces required sustained arm-muscle activity and she began to find them hard to play, even though she had previously played them easily.

When she also started to have difficulty swallowing and chewing, she told her mother, who took her to the emergency room, where the physician noticed drooping eyelids and limitation of ocular motility. An electromyogram detected impaired nerve-to-muscle transmission.

Administration of pyridostigmine rapidly improved Lisa‘s symptoms. Which of the following blood-test results would be most consistent with her condition? a. elevated rheumatoid factor b. elevated anti-myelin basic protein antibodies c. elevated anti-acetylcholine receptor antibodies d. elevated anti-nuclear antibodies e. elevated anti-Rh antibodies.

ANSWERS 16–1 a

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16–2 c 16–3 a—4; b—1; c—3; d—2 16–4 b, e 16–5 a, c 16–6 d, e 16–7 When autoantibodies directed toward leukocyte surface antigens bind to the cell surface, complement fixation and deposition of C3b occurs. The membrane-attack complex usually does not form on leukocytes because of complement regulatory proteins. Their elimination from the circulation, however, occurs by a different mechanism involving splenic macrophages that bear FcR and CR1, receptors for antibodies and C3b, respectively. The macrophages carry out phagocyte-mediated clearance of these leukocytes, leading to a deficiency of these cells in the circulation. Removal of the spleen spares the elimination of these leukocytes. The presence of antibody and C3b on their cell surface does not affect their ability to functional normally.

16–8 a, c, e 16–9 c, d 16–10 d, f 16–11 b 16–12 a 16–13 c 16–14 a 16–15 c 16–16 c 16–17 d 16–18 e 16–19 a, c, e 16–20 b 16–21 a

257

16–22 b 16–23 e, j 16–24 b 16–25 d 16–26 e 16–27 (i) Allergy. IgE antibodies made against normally innocuous environmental antigens trigger widespread mast-cell activation. This can lead to allergic diseases such as asthma or to a potentially fatal anaphylactic reaction. (ii) Autoimmune disease. Chronic immune responses by B cells or T cells to self antigens can cause tissue damage and chronic illnesses such as diabetes, multiple sclerosis, and myasthenia gravis. Autoimmunity is sometimes provoked as a consequence of an immune response to pathogen-derived antigen that cross-reacts on healthy host cells or tissue. (iii) Transplant rejection. A person‘s immune system will make an immune response against the foreign MHC molecules on transplanted tissue that is MHC-incompatible.

16–28 a, b, d, e, f, j, k 16–29 a.

Rheumatoid arthritis: 7, B IV b.

Subacute bacterial endocarditis: 4, D III c.

Autoimmune hemolytic anemia: 8, A II d.

Mixed essential cryoglobulinemia: 5, H III e.

Multiple sclerosis: 1, I IV f.

Systemic lupus erythematosus: 2, G III g.

Type 1 diabetes: 9, C IV h.

Graves‘ disease: 3, E II i.

Pemphigus foliaceus: 6, F II 16–30 (i) Red blood cells coated with antibodies against red blood cell-surface components bind to splenic macrophages via Fc receptors, inducing phagocytosis of the red blood cell by receptormediated endocytosis. (ii) Red blood cells bound by antibodies against red blood cells fix complement, which causes deposition of C3b on the surface of the red blood cell. C3b then binds to the receptor CR1 on splenic macrophages, inducing phagocytosis of red blood cells. (iii) Antibody against red blood cells triggers the complement cascade and the formation of membrane-attack complexes on the red blood cell, leading to cell lysis.

16–31 First, endocrine glands synthesize tissue-specific proteins unique to that gland. These proteins are not normally found in primary lymphoid organs where lymphocyte maturation occurs. Hence, the population of T and B lymphocytes is not tolerant to some endocrine glandspecific proteins, and these self proteins are thus recognized as foreign antigens. Second, 258

endocrine glands are highly vascularized because their products need to gain access to the circulation. This feature gives leukocytes relatively easy access to endocrine tissue.

16–32 Both Hashimoto‘s and Graves‘ diseases disrupt the normal production of the thyroid hormones tri-iodothyronine (T3) and thyroxine (T4), which are derived from thyroglobulin in thyroid follicles. The formation of T3 and T4 requires engagement of the thyroid-stimulating hormone receptor (TSHR) with thyroid-stimulating hormone (TSH) secreted from the pituitary gland, a key step in the regulation of thyroid hormone production. This step malfunctions for these two diseases.

In Hashimoto‘s disease, anti-thyroid antigen antibodies and TH1 effector cells are involved. Large numbers of lymphocytes take up residence in the gland tissue, establishing germinal centers that resemble those in lymph nodes. Eventually the thyroid tissue is destroyed and thyroid follicles are no longer able to respond to TSH and make T3 or T4, a condition called hypothyroidism.

Graves‘ disease, in contrast, results in hyperthyroidism. Anti-TSHR antibodies act agonistically, mimicking TSH even in its absence. The thyroid follicle is chronically overstimulated by these antibodies and overproduces T3 and T4. The effector T cells are of the TH2 type, and the absence of lymphocyte infiltration retains the thyroid gland in operable condition. Therefore T3 and T4, no longer regulated by TSH, are secreted continuously in excess of concentrations required by the body.

16–33 a—F; b—T; c—T; d—F; e—T 16–34 A. The negative selection of developing autoreactive T cells in the thymus.

B. The underlying genetic defect is in a gene encoding a protein called AIRE (autoimmune regulator). This is a transcription factor that, when working normally, causes several hundreds of proteins otherwise expressed only in particular peripheral tissues to be expressed by medullary epithelial cells in the thymus. This induces the negative selection of T cells specific for these proteins and their deletion from the T-cell repertoire. The T cells emerging from the thymus are therefore tolerant to a large number of antigens found primarily on organs and tissues elsewhere in the body. When AIRE is defective and these proteins are not expressed in the thymus, the population of naive T cells that develops will contain T cells reactive against these antigens of peripheral tissues.

16–35 These cells are called regulatory T cells (Treg). When activated by encounter with their corresponding self antigen, they become able to suppress the activation of naive autoreactive T cells. This active suppression of autoreactive T cells in the periphery is now thought to be an important method of preventing autoimmune reactions.

16–36 A. Increased risk of developing type 1 diabetes is associated with the formation of a heterozygote-specific heterodimer composed of the HLA-DQ8α chain DQA1*03 and the HLADQ2β chain DQB1*02:01.

B. In northern Europeans this combination of α and β chains is never encoded in the same haplotype, so it can be produced only in heterozygotes. Haplotypes containing both susceptibility 259

alleles can, however, be present in Africans, and similarly confer susceptibility to type 1 diabetes.

16–37 A. Habitual cigarette smokers with Goodpasture‘s syndrome develop not only glomerulonephritis but also pulmonary hemorrhage.

B. Unlike non-smokers, whose basement membranes are in general not compromised in pulmonary alveoli, smokers have alveoli that are damaged as a result of chronic exposure to cigarette smoke. Damage provides a gateway by which autoantibodies can gain access to basement membranes, where they become deposited, activate complement, and cause rupture of alveolar blood vessels.

16–38 Peptidyl arginine deaminase (PAD) is an enzyme induced in the respiratory tract after smoke-induced damage. PAD converts arginine residues in self proteins to citrulline residues, thus creating epitopes to which the T-cell repertoire is not tolerant. Citrullinated proteins are subject to proteolysis, and the resulting peptides bind to HLA-DRB1*04 and stimulate autoreactive CD4 T cells and antibodies against citrullinated self proteins. If a joint becomes infected or is wounded, inflammation of joint tissue activates PAD, which generates the same citrullinated epitopes. HLA-DRB1*04-restricted effector and memory T cells are recruited and activated and an immune response follows, initiating the development of rheumatoid arthritis.

16–39 A. Molecular mimicry refers to the phenomenon in which a pathogen expresses an antigen that bears a chemical similarity to a host-cell antigen. Once pathogen-specific antibodies or effector T cells are generated, they have the potential to cross-react with self antigen.

B. An autoimmune disease involving molecular mimicry is rheumatic fever.

Infection with Streptococcus pyogenes (for example ‗strep throat‘) results in the production of antibodies specific for the bacterial cell-wall proteins. These antibodies cross-react with chemically similar (but not identical) self antigen expressed on heart tissue. This is followed by complement activation and the production of inflammatory mediators, which cause damage to heart tissue and valves and the formation of scar tissue, which can lead to cardiovascular complications later in life. This type of immunological aftermath can be avoided if antibiotics are administered early during infection.

16–40 a, c 16–41 d 16–42 Neutrophils targeted by autoantibodies are predominantly destroyed in the spleen through uptake by splenic macrophages via Fc receptors and the complement receptor CR1. Splenectomy would thus reduce the rate at which neutrophils are destroyed. By themselves, antibodies and complement bound to the neutrophil surface do not impair the normal function of neutrophils. In addition, white blood cells are far less susceptible to the formation of membrane-attack complement complexes, owing to the continual production of complement regulatory proteins in these nucleated cells.

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16–43 a—T; b—F; c—F; d—F; e—T 16–44 a—3; b—2; c—5; d—4; e—1 16–45 a—5; b—4; c—1; d—2; e—3 16–46 a, c 16–47 a 16–48 b 16–49 A. Ectopic lymphoid tissue, also known as tertiary lymphoid tissue, is found as a result of infiltration of immune-system cells, such as lymphocytes, dendritic cells, macrophages, and follicular dendritic cells, into endocrine tissue. The cells then organize through a process known as lymphoid neogenesis to form structures that functionally resemble secondary lymphoid tissues, except that ectopic lymphoid tissue lacks a capsule and does not associate with the lymphatics.

B. Ectopic lymphoid tissue is characteristic of Hashimoto‘s thyroiditis and has also been associated with rheumatoid arthritis, Graves‘ disease, and multiple sclerosis.

16–50 Hashimoto‘s and Graves‘ diseases are treated differently because, although they both affect the thyroid gland, they exert opposing effects on the production of thyroid hormones— inhibition and overproduction, respectively. Hashimoto‘s disease is treated by administering synthetic thyroid hormones orally to replace the deficiencies in T3 and T4. Graves‘ disease is treated either by suppressing thyroid function with inhibitory drugs or by thyroidectomy combined with thyroid hormone replacement therapy.

16–51 c, e 16–52 a, e, f 16–53 b 16–54 e 16–55 a, e 16–56 c 16–57 c, d 16–58 b, c, e 16–59 261

(i) Inflammatory cytokines induced by infection can activate autoreactive T cells nonspecifically, and interfere with the ability of regulatory T cells to maintain peripheral tolerance. (ii) T-cell cross-reactivity can occur when pathogen peptides have related amino acid motifs compared with self peptides and, when bound to the same or similar MHC allotype, can lead to the activation of self-reactive T cells. In some cases the only requirement is a common peptide:MHC structural conformation and neither peptide nor MHC relatedness is actually required. In both cases, however, molecular mimicry is operating.

16–60 a 16–61 c 16–62 In SLE, the protein epitopes recognized by autoreactive T cells are part of large macromolecular complexes composed of aggregates of histone proteins and DNA, or aggregates of ribosomal proteins and RNA. Accessible epitopes on the external surface of the complex can bind easily to antigen receptors on the surface of different neighboring B cells that possess different epitope specificities (for example histone-specific antigen receptors as well as DNAspecific antigen receptors). If these B cells are presenting peptides to which the original autoreactive CD4 T cells is specific, then help is provided to both types of B cell and antibodies are generated to both accessible epitopes. Alternatively, if the B cell internalizes and degrades the complex and presents peptides derived from inaccessible interior proteins to CD4 T cells, then T cells with specificities to all protein components of the complex, both accessible and inaccessible, become activated and the immune response broadens.

16–63 a, e 16–64 a, c, d 16–65 b 16–66 A. Epitope spreading is the phenomenon in which the immune response, having initially targeted a particular epitope on an antigen molecule, progressively involves other crossreactive epitopes on the same molecule.

B. Pemphigus foliaceus. Autoantibody production against the protein desmoglein, a component of desmosomes, initially involves epitopes that do not result in any tissue damage or symptoms. Only when additional desmoglein epitopes become involved, as a result of epitope spreading, does the autoimmune response cause damage to desmosomes and give rise to lesions in the skin (the disease pemphigus).

16–67 d 16–68 a 16–69 c 262

16–70 c, e 16–71 Rationale: The answer is c. This is a case of systemic lupus erythematosus (SLE). The vascular rash on the face, and the painful finger joints and hips, suggest that Amanda has developed a systemic inflammatory condition. The decreased levels of C3 are consistent with increased complement fixation by the classical pathway mediated by the anti-nuclear antibodies typical of SLE. Elevated levels of protein in the urine are suggestive of glomerulonephritis, another common complication of SLE. When immune complexes of antibody, complement, and antigen are deposited in the synovia of joints, in blood vessel walls, and in kidney glomeruli rather than being cleared from the circulation, inflammation results.

16–72 Rationale: The correct answer is c. One mechanism for achieving immunological tolerance to self proteins is negative selection in the thymus. Developing T cells bearing T-cell receptors that bind too strongly to self MHC or to self-peptide:self-MHC complexes are signaled to die by apoptosis, which eliminates self-reactive T cells. Self proteins not presented to developing T cells in the thymus, such as proteins sequestered in the central nervous system, would not be scrutinized during negative selection, and self-reactive T cells would result.

16–73 Rationale: The correct answer is c. This is a case of celiac disease, also known as glutensensitive enteropathy. An inflammatory response involving CD4 T cells is made against gluten proteins (including gliadins and glutenins) in gut-associated lymphoid tissues. Anti-gliadin and anti-glutenin IgA antibodies are secreted into the lumen of the gut. Atrophy of intestinal villi compromises absorption and, as seen in this case, affected children fail to thrive.

16–74 Rationale: The correct answer is c. This is a case of myasthenia gravis, a type II autoimmune disease caused by antagonist antibodies against acetylcholine receptors, which impede the binding of the neurotransmitter acetylcholine. Lisa experienced muscle weakness and impairment of neuromuscular signaling, which affected the strength in oral, ocular, and upper extremity muscles, hallmarks of this disease. Pyridostigmine is an inhibitor of cholinesterase, an enzyme that normally degrades acetylcholine after neuromuscular transmission. That Lisa demonstrated rapid recovery when treated with this drug shows that acetylcholine was associated with her symptoms, and by increasing the acetylcholine concentration her symptoms were alleviated.

CHAPTER 17: CANCER AND ITS INTERACTIONS WITH THE IMMUNE SYSTEM 17–1 Which of the following is mismatched? a. oncology: diagnosis and treatment of tumors b. carcinoma: characteristic cell types found in benign tumors c. mutation: changes in DNA involving substitutions, deletions, insertions, recombinations, and translocations 263

d. e.

leukemia: cancer of the immune system affecting circulating cells malignant transformation: gain of ability to form a cancer.

17–2 Which of the following is mismatched? a. tumor suppressor genes: mutated in over 50% of human cancer cases b.

HTLV-1: an RNA retrovirus associated with adult T-cell leukemia c.

Helicobacter pylori: bacterial infection associated with colon cancer d. sipuleucel-T cell vaccine: treatment for late-stage metastatic prostate cancer e. cancer immunosurveillance: recognition and elimination of cancer cells by defense mechanisms.

17–3 a. b. c. d. e.

Mutagens that increase one‘s predisposition to developing cancer are called _____. carcinogens tumor antigens neoplastic mutagens oncogenes proto-oncogenes.

17–4 Match the infectious agent in column A with the associated cancer in column B. Column A Column B ___ a. human T-cell leukemia virus 1 (HTLV1)

1. liver cancer

___ b. human papillomavirus

2. stomach cancers arising from ulcers

___ c. Epstein–Barr virus

3. genital cancer

___ d. hepatitis B or C viruses

4. adult T-cell leukemia

___ e. Helicobacter pylori

5. Burkitt‘s lymphoma

___ f. human immunodeficiency virus (HIV-1)

6. Kaposi‘s sarcoma

17–5 Human papillomaviruses express proteins that bind to _____ and block its function.

(Select all that apply.) a.

MIC glycoproteins b. p53 c.

CT antigens d.

TLR4 e.

Rb. 17–6 In domestic dogs and Tasmanian devils, successful passage and growth of tumors through copulation and biting, respectively, are attributed to _____. a. absence of quiescent cancer stem cells in the tumor 264

b. c. d. e.

limited MHC diversity between animals repression of tumor-specific antigen expression repression of tumor-associated antigen expression lack of regulatory T cells.

17–7 _____ is/are commonly associated with the fusion between the BCR gene and the ABL proto-oncogene. a.

Non-small cell lung carcinoma b.

Bladder tumors c.

Melanoma d.

Head and neck squamous cell carcinoma e.

Chronic myelogenous leukemia.

17–8 Explain how decreased levels of HLA class I on variant cancer cells can (A) enhance or (B) reduce tumor growth.

17–9 Which of the following cell types in a tumor biopsy would not be associated with a promising prognosis? a.

B cells b. memory T cells c.

TFH cells d. regulatory T cells e. cytotoxic T cells.

17–10 Match the treatment in column A with its target in column B. Column A Column B ___ a. vemurafenib 1. programmed death 1 (PD-1) ___ b. elotuzumab 2. CD20 ___ c. ipilimumab

3. CD30

___ d. nivolumab

4. CD319

___ e. lirilumab

5. CTLA-4

___ f. brentuximab

6. BRAF

___ g. ibritumomab

7. HLA-C-specific inhibitory KIRs

17–11 Match the term in column A with its description in column B. Column A Column B ___ a. lenalidomide

1. promotes shedding of FcγRIII from NK-cell surfaces

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___ b. bortezomib

2. proteasome inhibitor

___ c. phosphoantigen

3. opsonizes tumor cells

___ d. elotuzumab

4. blocks new blood vessel formation

___ e. ADAM33 metalloproteinase

5. activates γ:δ T cells

___ f. dexamethasone

6. immunosuppressive steroid

17–12 Bortezomib has all of the following effects except _____. a. reducing the supply of peptides needed for MHC class I transport to the cell surface b. inhibiting tumor-cell proliferation c. inducing tumor-cell apoptosis d. inhibiting proteasome activity e. blocking inhibitory KIRs. 17–13 Adoptive transfer of sipuleucel-T-primed dendritic cells is a form of immunotherapy currently used for the treatment of _____. a. late-stage metastatic prostate cancer b. multiple myeloma c. chronic myelogenous leukemia d. melanoma e. cervical cancer.

17–14 Provide an example of a monoclonal antibody that can be modified differently to either detect or eradicate a tumor.

17–15 Which of the following is not a human monoclonal antibody that is directed at a cellsurface component? a. rituximab b. alemtuzumab c. ibritumomab d. bevacizumab e. ipilimumab.

17–16 A. What are tumor-specific antigens?

B. How do they originate?

C. Give two examples, together with the type of tumor they come from.

17–17 A. What are tumor-associated antigens?

B. How do they originate?

C. Give two examples together with the type of tumor they come from.

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17–18 Indicate whether each of the following statements is true (T) or false (F). ___ a. A mutation in only one copy of a tumor suppressor gene can cause malignant transformation. ___ b. A neoplasm is characterized by abnormal cell division, which can cause disruption to organ function. ___ c. Malignant tumors are often encapsulated and are limited in size. ___ d. Most cancers develop in tissues that are actively undergoing division. ___ e. Cancers of immune system cells that form solid tumors are known as sarcomas. ___ f. Individuals with Li–Fraumeni syndrome who have been treated successfully for cancer are likely to develop another primary malignancy at a later time.

17–19 A. What are the two main classes of gene that, if not expressed correctly, can lead to malignant transformation?

B. What are the gene products made by each class?

17–20 Explain why the incidence of cancer is higher in the elderly than in young people.

17–21 A. What is Li–Fraumeni syndrome?

B. What is the underlying cause?

17–22 Explain how the immune mechanisms for the detection of cancer cells are (A) similar to and (B) different from those that detect virus-infected cells.

17–23 Provide examples where tumor cells transferred between a donor and a recipient are either (A) rejected and do not cause cancer, or (B) not rejected and cause cancer.

17–24 When the immune system is involved in _____, an appraisal for cancer cells is occurring. a. malignant transformation b. apoptosis c. antineoplasia d. immunosurveillance e. immunosuppression.

17–25 A. How is it possible for a tumor-specific antigen to be composed of a unique sequence of amino acids not encoded in the genome of the tumor cell?

B. Give a specific example.

17–26 Epithelial tumors express MIC proteins on their cell surfaces.

A. Why does this make the tumor cells susceptible to attack by NK cells, γ:δ T cells, and cytotoxic CD8 T cells?

B. How do the tumor cells evade such attack?

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17–27 A benign tumor of glandular tissue is known as a(n) _____. a. sarcoma b. myeloma c. adenoma d. adenocarcinoma e. lymphoma.

17–28 A malignant tumor is characterized by which of the following features? (Select all that apply.) a. encapsulation b. localized c. restricted in size d. metastasizes to distant sites e. results from multiple mutations affecting cell division or survival.

17–29 Which of the following pairs are matched correctly? (Select all that apply.) a. myeloma: bone marrow b. benign tumor: encapsulation c. lymphoma: bone marrow d. tumor-associated antigens: proteins expressed only by tumor cells e. sarcoma: epithelial cell.

17–30 Examples of tumor suppressor genes include _____. (Select all that apply.) a.

APC b.

RAS c. p53 d.

ABL e.

DCC. 17–31 _____ describes the condition in which a cell becomes able to cause cancer. a.

Malignant mutation b.

Malignant recombination c.

Malignant neoplasm d.

Malignant transformation e.

Malignant suppression.

17–32 A protein expressed in response to damage to DNA that results in death to the cell is _____. a.

Ras b. p53 c.

Rb d.

Abl 268

e.

MAGEA1.

17–33 Human herpesvirus 8 (HHV8) is associated with the development of _____ in immunocompromised patients. a.

Burkitt‘s lymphoma b. chronic myeloid leukemia c. melanoma d. myeloma e.

Kaposi‘s sarcoma.

17–34 Li–Fraumeni syndrome is linked to a greater risk of cancer as a result of the inheritance of a germline mutation in one copy of _____. a.

TLR-9 b. p53 c.

CTLA4 d. heat-shock protein e.

Rb. 17–35 Chemical and physical agents that increase mutation rates by damaging DNA and increase the likelihood of developing cancer are known as _____. a. oncogens b. malignant transformers c. antitumor suppressor agents d. carcinogens e. tumor-associated agents.

17–36 _____ agents usually cause single nucleotide substitutions in DNA, whereas _____ agents produce more significant damage to DNA. a. mutagenic; carcinogenic b. chemical; physical c. benign; malignant d. tumor-associated; tumor-specific e. benign; oncogenic.

17–37 An example of a physical agent that increases an individual‘s predisposition to developing cancer is_____. (Select all that apply.) a. cigarette smoke b.

X-rays c. ultraviolet radiation d. asbestos e. exposure to radioactive sources.

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17–38 Burkitt‘s lymphoma is a tumor associated with _____ infection, which causes _____ to divide uncontrollably. a.

Epstein–Barr virus; B cells b. hepatitis B virus; epithelial c. human T-cell leukemia; hepatocytes d. human herpesvirus; T cells e. papillomavirus; uterine cells.

17–39 DNA viruses associated with cancer development include _____. (Select all that apply.) a. human papillomavirus (HPV) b. human immunodeficiency virus (HIV-1) c. human herpesvirus 8 (HHV8) d.

Epstein–Barr virus (EBV) e. malignant transformation.

17–40 Cancers develop their own blood supply and become vascularized through _____. a. apoptosis b. neoplasia c. angiogenesis d. metastasis e. malignant transformation.

17–41 Systemic distribution of cancer cells to other sites of the body through the bloodstream or lymph is a process known as _____. a. apoptosis b. neoplasia c. angiogenesis d. metastasis e. malignant transformation.

17–42 The efficacy of treating bladder cancer is increased by introducing the BCG vaccine. The vaccine component attributing this antitumor effect is _____, which induces a state of chronic inflammation. a. mycolic acid b. unmethylated CpG-containing DNA c. lipopolysaccharide d. teichoic acid e. peptidoglycan.

17–43 270

Which of the following are true for cancer stem cells? (Select all that apply.) a.

They are self-renewing. b.

They are highly susceptible to radiation. c.

They are resistant to toxins used in chemotherapy. d.

They may be present in low numbers without causing relapse. e.

They may cause cancer if donated in organ transplants.

17–44 Proteins not expressed on normal cells but found on tumor cells are called _____. a. cancer stem cell antigens b. oncogenic antigens c. tumor-associated antigens d. tumor-specific antigens e. proto-oncogene products.

17–45 Tumor-specific antigens are derived from _____. (Select all that apply.) a. peptide antigens encoded by fused portions of recombined genes b. peptide antigens containing point mutations c. proteins modified by abnormal post-translational processes d. reactivated embryonic genes e. viral proteins f. overexpression of normal genes g. non-contiguous peptides spliced together by peptide bonds in the proteasome.

17–46 Which of the following describe types of tumor-associated antigens? (Select all that apply.) a.

They are derived from self proteins to which the immune system is not tolerant. b.

They are derived from proteins encoded by mRNAs that have undergone abnormal posttranscriptional splicing. c.

They are proteins normally expressed in immunologically privileged sites. d.

They are proteins expressed at unusually high levels. e.

They are derived from viral proteins to which the immune system is not tolerant.

17–47 A tumor-associated antigen normally expressed only in the testis is called a _____ antigen. a.

MIC b.

CT c. male-specific d. sex chromosome-encoded e. privileged.

17–4 s8 A mechanism by which cancer cells can evade an immune response involves an alteration in the amount of MIC on the cell surface by a. decreasing the level of MIC transcription 271

b. cleavage of MIC at the cell surface by a protease c. switching from a transmembrane form of MIC to a secreted form d. cytosolic degradation of MIC in proteasomes e. alternative mRNA splicing resulting in a truncated form of MIC that is no longer able to bind to NKG2D. 17–49 Which of the following is a mechanism by which tumors can evade immune detection? (Select all that apply.) a. reduction in levels of HLA class I b. recruitment of regulatory T cells c. enhancement of inflammatory responses d. lowering of levels of MIC on the cell surface e. increase in levels of CT antigens.

17–50 Which cytokines are associated with tumor-induced suppression of the immune response?

(Select all that apply.) a.

IL-12 b.

IL-2 c.

TGF-β d.

IL-4 e.

IL-10.

17–51 One of the side effects of treating tumor patients with anti-CTLA4 monoclonal antibodies is _____. a. the development of autoimmune disease b. lymphoproliferative disorder c. increased levels of mutation in tumor cells d. upregulation of CT antigens e. reactivation of embryonic genes.

ANSWERS IS4 Chapter 17 Testbank answers

17–1 b 17–2 c 17–3 a 17–4 a—4; b—3; c—5; d—1; e—2; f—6 272

17–5 b, e 17–6 b 17–7 e 17–8 A. Enhancement of tumor growth occurs when cancer cells stop expressing HLA class I because these cells are no longer presenting tumor antigens to cytotoxic T cells. Variant cells are consequently able to escape immune detection.

B. Tumor cells that lack HLA class I are more susceptible to attack by NK cells. The inhibitory receptor on NK cells fails to engage normally, and this causes tumor cell killing after the activation and release of cytotoxic molecules by the NK cell.

17–9 d 17–10 a—6; b—4; c—5; d—1; e—7; f—3; g—2 17–11 a—4; b—2; c—5; d—3; e—1; f—6 17–12 e 17–13 a 17–14 Ibritumomab, an anti-CD20 antibody, is used in cases of non-Hodgkin‘s lymphoma.

When conjugated to indium-111, it aids in the identification of the location and size of primary tumors and the degree of metastasis. When conjugated to yttrium-90, it precisely targets and kills tumor cells with its β-radiation.

17–15 d 17–16 A. Tumor-specific antigens are antigens found exclusively on tumor cells and are not expressed by normal cells.

B. They can originate from the following: (1) as the result of mutations in normal genes in the tumor cell that cause changes in amino acid sequence that generate new epitopes; (2) by the generation of hybrid genes through genetic recombination, with the consequent production of a new protein unique to the tumor cell; or (3) from viral proteins expressed as a result of viral infection or integration into the host-cell genome.

C. Examples are MART2 (melanoma) and BCR–ABL fusion protein (chronic myeloid leukemia) and human papillomavirus (cervical carcinoma).

17–17 A. Tumor-associated antigens are antigens expressed in tumor cells as well as some normal cells, but often at higher levels in tumor cells.

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B. They can originate from the following: (1) proteins involved in mitosis that are produced at higher concentrations because the cells are continually dividing; (2) proteins expressed during embryogenesis that have become deregulated and reactivated transcriptionally; or (3) proteins expressed continuously at high levels in tumor cells that are normally expressed at low levels or transiently.

C. Examples are MAGEA1 and MAGEA3 (melanoma).

17–18 a—F; b—T; c—F; d—T; e—F; f—T 17–19 A. Proto-oncogenes and tumor suppressor genes.

B. Proto-oncogenes encode proteins that participate in cell division, such as growth factors, growth factor receptors, signal transduction proteins, and activators of gene expression.

Tumor suppressor genes encode proteins that inhibit the division of mutant cells; examples are p53, APC, and DCC. 17–20 For a cell to become cancerous and undergo malignant transformation, at least five or six mutations (depending on the cell type) must accumulate independently. Because of the low frequency of mutation, significant time is needed for a single cell to accrue this number of mutations. As a person ages, the prevalence of cells bearing the required mutations increases.

17–21 A. Li–Fraumeni syndrome is a condition in which there is a strong predisposition to developing multiple types of cancer, even at a young age.

B. Progression to cancer is related to the inheritance of a mutation in one of the copies of p53, a tumor suppressor gene, which facilitates the apoptosis of cells with DNA damage. Individuals with Li–Fraumeni syndrome need accrue only one new mutation in the functional copy of the p53 gene to develop a cell with loss of p53 activity, in contrast with other people, who must acquire mutations on both copies.

17–22 A. NK cells and cytotoxic T cells detect cancer cells and virus-infected cells through the alteration of MHC class I. B. Unlike virus detection, which involves inflammatory responses that stimulate immediate innate immune responses, cancer cells can often grow for long periods before they induce an inflammatory state and a consequent immune response.

17–23 A. If primary tumor cells are donated between MHC-disparate mice, the cytotoxic T cells of the recipient recognize differences in MHC class I and kill the tumor cells.

B. (i) The marsupial known as the Tasmanian devil can pass tumor cells between individuals when fighting and biting each other‘s faces. Because of limited MHC diversity in the 274

species, there is a lack of allograft rejection, and the tumor cells establish themselves at the site of facial injury. (ii) In humans, residual tumor cells in an HLA-matched transplanted organ will not be rejected because the recipient is immunosuppressed and unable to mount an antitumor immune response.

17–24 d 17–25 A. The proteasome not only degrades proteins into peptide fragments, but it also has the potential to splice peptides together to form a novel peptide. The new peptide is derived from short sequences from different parts of the polypeptide that is undergoing proteolysis.

B. An example of proteasome splicing has been demonstrated for a glycoprotein (gp100) expressed in melanocytes. A unique fused peptide sequence made up of amino acids 40– 42 and 47–52 of gp100 was shown to be formed and to be presented by HLA-A32, stimulating cytotoxic T-cell responses.

17–26 A. MIC proteins are ligands for the activating receptor NKG2D, which is expressed

by NK cells, γ:δ T cells, and cytotoxic CD8 T cells, and activates these cells to kill the tumor cells.

B. Some of the tumor cells evade being killed by expressing a protease that cleaves MIC from the cell surface. When the soluble MIC product binds to the NKG2D receptors on NK cells, γ:δ T cells, and cytotoxic T cells it induces receptor-mediated endocytosis, thus reducing the level of NKG2D on the surface of these cells. Together with the removal of MIC from tumorcell surfaces, this helps the tumor cells evade cell-mediated killing.

17–27 c 17–28 d, e 17–29 a, b 17–30 a, c, e 17–31 d 17–32 b 17–33 e 17–34 b 17–35 d 17–36 b

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17–37 b, c, e 17–38 a 17–39 a, d 17–40 c 17–41 d 17–42 b 17–43 a, c, d, e 17–44 d 17–45 a, b, c, e, g 17–46 a, c, d 17–47 b 17–48 b 17–49 a, b, d 17–50 c, e 17–51 a

276