Chapter 1 Elements of the Immune System and Their Roles in Defense
The small intestine is the major site in the human body that interacts with microorganisms. Immunology is the study of the physiological mechanisms that humans and other mammals use to defend their bodies from invasion by other organisms. The origins of the subject lie in the practice of medicine, with historical observations that people who survived an epidemic disease were untouched when faced with that disease again—they had become immune to infection. Infectious diseases are caused by microorganisms, which reproduce and evolve more rapidly than their human hosts. During an infection, the microorganism pits a vast population of its species against an individual Homo sapiens. In response, the human body invests heavily in cells that are dedicated to defense and collectively form the immune system. An immune system is crucial to human survival. In the absence of a working immune
system, even minor infections take hold and prove fatal. Without intensive treatment, children born without an immune system die in early childhood from common infections. However, all humans suffer infectious diseases, especially when young. To provide an immunity that gives long-lasting future protection, the immune system must first do battle with the causative microorganism. This places children at highest risk during their first infection with a microorganism and, without modern medicine, leads to substantial child mortality, as occurs in the developing world. When entire populations face a new infection, the outcome can be catastrophic, as experienced by indigenous peoples who were killed in large numbers by European diseases that were imported with the arrival of Europeans in the Americas in 1492 and the subsequent initiation of transatlantic trade. New diseases are still emerging. The coronavirus SARS-CoV-2, which causes the respiratory disease COVID-19, was first detected in Wuhan, China, in December 2019, although the virus is thought to have been circulating for a few months
before that, according to both retrospective testing of earlier samples collected for other purposes and variations in the genome sequences of viruses from different samples. Within a few weeks, infected individuals had carried the virus around the globe along the modern trading routes of the jet airliner and cruise ship, resulting in a pandemic. By early September 2020, more than 27 million people had been infected with SARS-CoV-2 and nearly 900,000 of them had perished. In many countries, normal life and commerce ground to a standstill as people stayed at home to reduce the spread of the virus. In medicine, the greatest triumph of immunology is vaccination, a procedure that prevents severe disease by exposing healthy infants to the infectious agent in a form that does not cause disease. Vaccination provides human immune systems with the experience they need to make a strong response, but one with little risk to health and life. Vaccination was first used against smallpox, a viral scourge that for centuries decimated human populations and disfigured the faces of the survivors. In Asia, a small dose of smallpox virus was
used to induce immunity long before 1721, when Lady Mary Wortley Montagu introduced the method to Europeans. In 1796, Edward Jenner, a doctor in rural England, showed how inoculation with cowpox virus protected against the related smallpox virus, but with less risk of causing disease than the earlier method. Jenner called his procedure vaccination, vaccinia being the name of the mild disease caused by cowpox. Since Jenner’s time, vaccination progressively reduced the incidence of smallpox worldwide, until it was eventually eliminated in the 1970s (Figure 1.1). Figure 1.1 Vaccination led to the eradication of smallpox. The modern era of smallpox vaccination began in 1796. By December 1979, after 2 years during which no case of smallpox was recorded, the World Health Organization announced the eradication of the virus. Since then, the proportion of the human population that has either been vaccinated against smallpox or acquired immunity by being infected with smallpox virus has steadily decreased. The result is that the human population has become increasingly vulnerable should the virus emerge again,
either naturally or as a deliberate act of human malevolence. The 3-year-old girl in the photograph was the last recorded person in the world to be naturally infected with the variola major strain of the smallpox virus; this occurred in Bangladesh in October 1975. She recovered fully. The last case of the variola minor strain of smallpox was recorded in Somalia in 1977. Effective vaccines have been made for only a fraction of the infectious diseases, and for some vaccines the application has been limited by cost. The widely used vaccines were developed by trial and error, in an era when little was known of the immune system’s components and how they work. That approach is no longer successful in vaccine development; all the easily won vaccines seem to have been made. Today’s greater knowledge and deeper understanding of the mechanisms of immunity are spawning new ideas for vaccines against infectious diseases, and also for noninfectious diseases such as cancer. All these new ideas and technology are being applied to the development and manufacture of vaccines and therapeutics for the
purpose of ending the SARS-CoV-2 pandemic. To that end, 52,000 papers on SARS-CoV-2 were published in the biomedical journals in the 6 months from January to June 2020, and many more have been published since then. The casualties of SARS-CoV-2 include vaccination programs in 23 African countries that were suspended because of the chaos. In 2020, 13.5 million children missed out on vaccinations against polio, measles, human papilloma virus, yellow fever, cholera, and meningitis. In this chapter, we consider the microorganisms that infect human beings and the defenses the microorganisms must overcome to start and propagate an infection. The individual cells and tissues of the immune system and how they integrate with the rest of the human body are described. The first line of defense is innate immunity, which combines physical and chemical barriers with rapid responses that eliminate infecting microorganisms before they disrupt human tissue. These mechanisms stop most infections, but when they fail, the targeted and forceful defenses of adaptive immunity are brought into play. These adapt to the particular
microorganism and are continually refined in the course of infection. Usually successful, the adaptive immune response clears the infection and has a longlasting memory that prevents its recurrence. 1-1
Numerous commensal microorganisms inhabit healthy human bodies The remit of the immune system is to protect the human body from infectious disease. Most infectious diseases of humans are caused by microorganisms, which are smaller than a human cell. For both benign and dangerous microorganisms, the human body constitutes an extensive resource-rich environment in which to feed, live, and reproduce. More than 1000 different microbial species dwell in a healthy adult human’s gut, and they constitute about 4.5 kg of the body’s weight. They are called commensal microorganisms because they ‘eat at the same table’ as their human host. The entire community of microbial species that inhabits the human body—skin, mouth, gut, or vagina—is called the microbiota. Different ecological niches within the body have distinctive microbiota and are described as the ‘gut microbiota,’ the ‘oral
microbiota,’ and so on. The biology of many commensal species has yet to be studied in any depth because they cannot yet be grown in the laboratory. We know they are there, because their distinctive nucleic acid sequences were discovered from analyses of human feces. Animals coevolve with their commensal species and become both tolerant of them and dependent on them. Commensal organisms enhance human nutrition by processing digested food and making some of our essential vitamins. They also protect against disease, because their presence helps to prevent colonization by disease-causing microorganisms. For example, as well as competing for space, the bacterium Escherichia coli, a major component of the healthy human gut microbiota, secretes antibacterial proteins called colicins that incapacitate other bacterial species and prevent their colonization of the human gut. When a person with a bacterial infection is treated with antibiotics, much of the gut microbiota is killed along with the diseasecausing bacteria. After such treatment, the body recolonizes with a new population of commensal
bacteria, a situation in which opportunistic bacteria, such as Clostridium difficile, can become established and cause disease. Clostridium difficile is present in small numbers in healthy individuals, but in patients treated with antibiotics it can proliferate (Figure 1.2). It secretes a toxin that inflames the colon. This causes diarrhea and bleeding and can lead to the serious and potentially fatal condition of pseudomembranous colitis. Figure 1.2 Antibiotic treatments disrupt the natural ecology of the colon. When antibiotics are taken orally to counter infection with pathogenic bacteria, symbiotic populations of commensal bacteria in the colon are also exterminated. With completion of the treatment, there is an opportunity for potentially disease-causing strains of bacteria to populate the colon and cause further disease.
Clostridium difficile is an example of such a bacterium; it produces a toxin that can cause severe diarrhea in patients treated with antibiotics. In hospitals, acquired C. difficile infections are the cause of death for many elderly patients. 1-2 Pathogens are infectious organisms that cause
disease Any microorganism that causes disease is termed a pathogen. This definition includes microbes such as the influenza virus and the typhoid bacillus that habitually cause disease, and also microorganisms that are usually harmless but cause disease if a person’s immune system and other defenses of the body are weakened. The latter category comprises the opportunistic pathogens. In the early years of the human immunodeficiency virus (HIV) pandemic, when there was no effective therapy, almost all people who became infected died. Their immune systems became worn out by the HIV infection, but their deaths were caused by various opportunistic pathogens. Pathogens are of four kinds. The viruses, bacteria, and fungi are all groups of related microorganisms. The internal parasites are a heterogeneous group of unicellular protozoa and multicellular invertebrates, mainly worms. In this book we consider the functions of the human immune system principally in the context of controlling infection. For some pathogens this necessitates their complete elimination, but for others it is sufficient to
limit the size of the pathogen population and its anatomical location within the human host. Figure 1.3 illustrates the variety in shape and form of the four kinds of pathogen. Figure 1.4 lists common or wellknown infectious diseases and the pathogens that cause them. Reference to many of these diseases and the problems they pose for the immune system are made throughout this book. Figure 1.3 Numerous microorganisms have evolved to be human pathogens. (a) The coronavirus SARS-CoV-2 is the cause of a worldwide pandemic of an acute respiratory disease (COVID-19) that started late in 2019 (×70,000). (b) Human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS) (×80,000). (c) Staphylococcus aureus, a bacterium that colonizes human skin, is the common cause of pimples and boils and also causes food poisoning (×5000). (d) Streptococcus pneumoniae is the major cause of bacterial pneumonia and a cause of meningitis in children and the elderly (×5800). (e) Salmonella enterica serovar Enteritidis, a bacterium that commonly causes food
poisoning (×6500). (f) Mycobacterium tuberculosis, the bacterium that causes tuberculosis (×19,200). (g)
A human cell (colored green) containing Listeria monocytogenes (colored yellow), a bacterium that can contaminate processed food, causing disease (listeriosis) in pregnant women and immunosuppressed individuals (×1160). (h)
Pneumocystis jirovecii, an opportunistic fungus that infects people with AIDS and other immunosuppressed individuals. The fungal cells (colored green) are in lung tissue (×720). (i)
Epidermophyton floccosum, the fungus that causes ringworm (×500). (j) Candida albicans, a normally commensal fungus, which occasionally causes thrush and more severe systemic infections (×1270). (k)
Trypanosoma brucei (colored orange) is the protozoan that causes African sleeping sickness. It is seen here in a blood sample with erythrocytes (×2000). (l)
Schistosoma mansoni, the helminth worm that causes schistosomiasis. The adult intestinal blood fluke forms are shown: the male is thick and bluish, the female thin and white (×8). All photos are false-
colored electron micrographs, the exception being (l), a light micrograph. Figure 1.4 Diverse microorganisms cause human disease. Pathogenic organisms are of four main types—viruses, bacteria, fungi, and parasites. The latter are mostly protozoans and worms. Some important pathogens in each category are listed along with the diseases they cause. *The classifications are a guide and are not taxonomically consistent: family names are given for the viruses; general groupings used in medical bacteriology are given for the bacteria; and higher taxonomic divisions are given for the fungi and parasites. Bacteria are classed as either Gram-positive or Gram-negative according to whether they stain purple or pink using the Gram staining procedure. Type Disease Pathogen
General classification* Route of infection Viruses
Coronavirus disease 2019 (COVID-19) SARS-CoV-2
Coronaviruses Oral/respiratory/ocular mucosa Severe acute respiratory syndrome SARS-CoV Coronaviruses
Oral/respiratory/ocular mucosa West Nile encephalitis West Nile virus Flaviviruses Bite of an infected mosquito Type Disease Pathogen General
classification* Route of infection Yellow fever Yellow
fever virus Flaviviruses Bite of infected mosquito
(Aedes aegypti) Hepatitis B Hepatitis B virus
Hepadnaviruses Sexual transmission; infected blood
Chickenpox Varicella-zoster Herpesviruses
Oral/respiratory Mononucleosis Epstein–Barr virus
Herpesviruses Oral/respiratory Influenza Influenza
virus Orthomyxoviruses Oral/respiratory Measles
Measles virus Paramyxoviruses Oral/respiratory
Mumps Mumps virus Paramyxoviruses
Oral/respiratory Poliomyelitis Polio virus
Picornaviruses Oral Jaundice Hepatitis A virus
Picornaviruses Oral Smallpox Variola Poxviruses
Oral/respiratory AIDS Human immunodeficiency virus
Retroviruses Sexual transmission, infected blood Type
Disease Pathogen General classification* Route of infection Rabies Rabies virus Rhabdoviruses Bite of an
infected animal Common cold Rhinoviruses
Rhinoviruses Nasal Diarrhea Rotavirus Rotaviruses
Oral Rubella Rubella Togaviruses Oral/respiratory
Bacteria Trachoma Chlamydia trachomatis
Chlamydias Oral/respiratory/ocular mucosa Bacillary
dysentery Shigella flexneri Gram-negative bacilli Oral
Food poisoning Salmonella enterica serovar
Enteritidis, S. Typhimurium Gram-negative bacilli Oral
Plague Yersinia pestis Gram-negative bacilli Infected
flea bite, respiratory Tularemia Francisella tularensis
Gram-negative bacilli Handling infected animals
Typhoid fever Salmonella Typhi Gram-negative bacilli
Oral Type Disease Pathogen General classification*
Route of infection Gonorrhea Neisseria gonorrhoeae
Gram-negative cocci Sexually transmitted
Meningococcal meningitis Neisseria meningitidis
Gram-negative cocci Oral/respiratory Meningitis, pneumonia Haemophilus influenzae Gram-negative
coccobacilli Oral/respiratory Legionnaire’s disease
Legionella pneumophila Gram-negative coccobacilli
Inhalation of contaminated aerosol Whooping cough
Bordetella pertussis Gram-negative coccobacilli
Oral/respiratory Cholera Vibrio cholerae Gramnegative vibrios Oral Anthrax Bacillus anthracis Grampositive bacilli Oral/respiratory by contact with spores
Diphtheria Corynebacterium diphtheriae Grampositive bacilli Oral/respiratory Tetanus Clostridium
tetani Gram-positive bacilli (anaerobic) Infected
wound Boils, wound infections Staphylococcus
aureus Gram-positive cocci Wounds; oral/respiratory
Type Disease Pathogen General classification* Route
of infection Pneumonia, scarlet fever Streptococcus
pneumoniae Gram-positive cocci Oral/respiratory
Tonsillitis Streptococcus pyogenes Gram-positive
cocci Oral/respiratory Leprosy Mycobacterium leprae
Mycobacteria Infected respiratory droplets
Tuberculosis Mycobacterium tuberculosis
Mycobacteria Oral/respiratory Respiratory disease
Mycoplasma pneumoniae Mycoplasmas
Oral/respiratory Typhus Rickettsia prowazekii
Rickettsias Bite of infected tick Lyme disease Borrelia
burgdorferi Spirochetes Bite of infected deer tick
Syphilis Treponema pallidum Spirochetes Sexual
transmission Fungi Aspergillosis Aspergillus species
Ascomycetes Opportunistic pathogen, inhalation of spores Type Disease Pathogen General classification*
Route of infection Athlete’s foot Trichophyton species
Ascomycetes Physical contact Candidiasis, thrush
Candida albicans Ascomycetes (yeasts) Opportunistic
pathogen, resident microbiota Pneumonia
Pneumocystis jirovecii Ascomycetes Opportunistic pathogen, resident lung microbiota Protozoan
parasites Leishmaniasis Leishmania major Protozoa
Bite of an infected sand fly Malaria Plasmodium
falciparum Protozoa Bite of an infected mosquito
Toxoplasmosis Toxoplasma gondii Protozoa Oral, from infected material Trypanosomiasis Trypanosoma
brucei Protozoa Bite of an infected tsetse fly Helminth
parasites (worms) Common roundworm Ascaris
lumbricoides Nematodes (roundworms) Oral, from infected material Schistosomiasis Schistosoma
mansoni Trematodes Through skin by bathing in infected water Over evolutionary time, the relationship between a pathogen and its human host can change in ways that affect disease severity. Pathogenic organisms evolve adaptations that enable them to invade their hosts, replicate within them, and be propagated through a human population. Rapid death of the human host is rarely in a microbe’s interest, because this destroys its home and source of sustenance. Consequently, those organisms with
potential to inflict severe and fatal disease often evolve an accommodation with their host. In complementary fashion, human populations evolve a genetic resistance to common disease-causing organisms; the diseases they cause are known as endemic diseases. These diseases, such as measles, chickenpox, and malaria, are ubiquitous in a given population, with most people being exposed during childhood. Because of the interplay between host and pathogen, the nature and severity of infectious diseases in human populations are always changing. Influenza is an example of a common viral disease that has severe symptoms but is usually overcome by the human immune system. The fever, aches, and lassitude that accompany infection can seem overwhelming, and it is difficult to imagine overcoming foes or predators at the peak of a bout of influenza. Nevertheless, despite the severity of the symptoms, most strains of influenza pose no great danger to healthy people in populations where influenza is endemic. Warm, well-nourished, and otherwise healthy people usually recover within 2 weeks and
assume that their immune system will accomplish this task. Contrasting with influenza is Ebola virus, a pathogen new to human populations and which causes a high mortality of 60– 75% among those infected. The effects of SARS-CoV-2 on human populations are less severe than those of Ebola but much greater than those of seasonal influenza and the common colds caused by other strains of coronavirus. COVID-19 is killing large numbers of people, but most of them were vulnerable because of other, preexisting conditions. 1-3 Skin and mucosal surfaces are barrier defenses against infection The skin gives the human body a formidable defense against infection. It is an epithelium protected by a tough, impenetrable outer barrier of layers of keratinized cells. Epithelium is a general name for the layers of cells that line the outer surface and the inner cavities of the body. However, the skin can be breached by physical damage, such as wounds, burns, or surgical procedures, which exposes soft tissues and renders them vulnerable to infection. Until the adoption of antiseptic procedures in the 19th century, surgery was a risky business,
largely because of the life-threatening infections that the procedures introduced. Consequently, far more soldiers died from infected wounds than from the direct effects of enemy action. Ironically, the need to conduct increasingly sophisticated and wide-ranging warfare has been the major force driving improvements in surgery and medicine. As an example from immunology, the horrific burns suffered by fighter pilots during the Second World War stimulated the study and application of skin transplantation, which directly led to knowledge of the cellular basis of the immune response. Continuous with the skin are the epithelia that line the respiratory, gastrointestinal, and urogenital tracts (Figure 1.5). On these internal surfaces, the impermeable skin gives way to specialized tissues that communicate with the environment and are vulnerable to microbial invasion. These tissues, the mucosal surfaces, or mucosae, are coated with the mucus they constitutively secrete. This thick fluid layer contains glycoproteins, proteoglycans, and enzymes that protect the epithelial cells from damage and contribute to limiting
infection. In the respiratory tract, mucus is continually removed through the beating action of the cilia that characterize this epithelium. The mucus bathing the epithelium is replenished by goblet cells, specialized in the synthesis and secretion of mucus. In this way the respiratory mucosa is continually cleansed of unwanted material, particularly infectious microorganisms. Epithelial surfaces also secrete antimicrobial substances. Sebum secreted by the sebaceous glands associated with hair follicles contains fatty acids and lactic acids, which cooperate to inhibit bacterial growth at the skin surface. All epithelia produce antimicrobial peptides that kill bacteria, fungi, and enveloped viruses by the common mechanism of perturbing their membranes. Tears and saliva contain lysozyme, an enzyme that kills bacteria by degrading their cell walls. Also deterring microorganisms are the acidic environments of the stomach, vagina, and skin. The fixed defenses of skin and mucosa provide well-maintained mechanical, chemical, and microbiological barriers that prevent most pathogens from gaining access to the cells and
tissues of the body. When those barriers are breached and pathogens gain entry to the body’s soft tissues, the defense mechanisms of innate immunity are aimed at the invaders. 1-4 The innate immune response produces a state of inflammation at sites of infection Cuts, abrasions, bites, and wounds provide routes for pathogens to get through the skin. Touching, rubbing, picking, and poking the eyes, nose, and mouth help pathogens breach mucosal surfaces, as does breathing polluted air, eating contaminated food, and being around infected people. With few exceptions, the infections remain localized and are extinguished within a few days without incapacitation or illness. Such infections are controlled and terminated by the innate immune response, which is always ready to react. The response consists of two phases (Figure 1.6). The first is recognition that a pathogen is present. This involves soluble proteins and cell-surface receptors that bind either to the pathogen or to human cells and plasma proteins that have been altered by the pathogen’s presence. Once the pathogen has been recognized, the second phase
of the response recruits effector mechanisms that kill or eliminate the pathogen. Mediating the effector mechanisms are effector cells that engulf bacteria, kill virus-infected cells, and attack protozoa. Guiding the effector cells is complement, a system of plasma proteins that commands the effector cells by tagging pathogens with molecular flags. Complement proteins can also kill pathogens without assistance from effector cells by perturbing the integrity of the pathogens’ membranes. Collectively, these defenses comprise innate immunity, a genetically programmed set of responses that can act immediately when an infection occurs. Numerous families of receptor proteins contribute to pathogen recognition in the innate immune response. They are of many different structural types and have binding specificities for chemically diverse ligands. These ligands include peptides, proteins, glycoproteins, proteoglycans, peptidoglycans, carbohydrates, glycolipids, phospholipids, nucleic acids, small molecules, and metabolites. Figure 1.6 Immune defense involves pathogen recognition followed by pathogen
destruction. A common strategy used to counter microbial pathogens is shown. A protein of the complement system (turquoise) is cleaved in two by a protease (not shown). The large fragment attaches to the bacterium (red) with a covalent bond. The attached piece of complement is a flag that marks the pathogen as dangerous. The small complement fragment activates a phagocyte, an effector cell bearing a receptor that engages the complement fragment attached to the bacterium. The phagocyte engulfs the complex of bacterium, complement, and receptor and delivers it to the phagosome. This acidic intracellular vesicle contains enzymes that degrade and destroy the bacterium. A phagocyte is a cell that eats, ‘phago’ derived from the Greek word for eat. During play and exploration of the local environment, small wounds to the skin can be a daily occurrence for many children. On returning home, the grazes are washed, which removes most of the dirt and the bacteria associated with soil, plants, and wild and domesticated animals, including other humans. Of the bacteria that remain, some divide and start an
infection. The receptors of cells in the damaged tissue detect the bacteria, and the cells send out small messenger proteins called cytokines that bind receptors on the effector cells of innate immunity to trigger the innate immune response. The overall effect of the innate immune response is to induce a state of inflammation in the infected tissue. An ancient concept in medicine, inflammation was defined by calor, dolor, rubor, and tumor: the Latin words for heat, pain, redness, and swelling. These symptoms are not caused by the infecting pathogen but by the human innate immune response to the pathogen. Cytokines induce dilation of nearby blood capillaries, which increases the blood flow, causing the skin to warm and redden. Vascular dilation (vasodilation) creates gaps between the cells of the endothelium, the thin layer of specialized epithelium that lines the interior of blood vessels. This makes the endothelium more permeable, increasing the leakage of blood plasma into connective tissue. Expansion of the local fluid volume, or edema, causes swelling, putting pressure on nerve endings and causing pain.
Cytokines alter the adhesive properties of the vascular endothelium, permitting white blood cells to leave the blood and enter the inflamed tissue (Figure 1.7). White blood cells recruited to the infected tissue contribute to the inflammation and in this context are called inflammatory cells. Infiltration of cells into the inflamed tissue increases the swelling, and the cells release chemicals that cause pain. The upside of the discomfort and disfigurement caused by inflammation is that it enables an army of immune-system cells and soluble effector molecules to be brought rapidly and in quantity to the infected tissue. Figure 1.7 Innate immune mechanisms establish a state of inflammation at sites of infection. Illustrated here are the events following an abrasion of the skin. Bacteria invade the underlying connective tissue and stimulate the innate immune response. Historically, the study of immunology (adaptive immunity) and the study of inflammation (innate immunity) were separate medical disciplines, and they began to merge only in the 1980s. Today, the terms inflammation and innate immunity are used interchangeably. The mechanisms
of innate immunity are considered in Chapters 2 and 3. 1-5 The adaptive immune response builds on the innate immune response Everybody is exposed to pathogens every day. The intensity of exposure and the diversity of the encountered pathogens increase with crowded city living and the daily exchange of people and pathogens in international airports and other transport hubs. Despite the exposure, innate immunity keeps most people healthy for most of the time. Nevertheless, some infections outrun the innate immune response, an event more frequent in people who are poor, malnourished, badly housed, deprived of sleep, or stressed and insecure in other ways. When this occurs, the innate immune response works to minimize the spread of infection while enlisting white blood cells called lymphocytes to increase the strength and focus of the immune response. The unique contribution that lymphocytes make to the defense of the human body is the adaptive immune response. This is organized around the existing infection and the innate immune response and adapts that response to the unique characteristics of the
infecting pathogen. Consequently, the adaptive immunity that is directed at the pathogen is powerful, long lasting, and specific to that pathogen. Adaptive immunity has evolved only in vertebrate animals, where it complements the mechanisms of innate immunity that vertebrates and invertebrates have in common. The effector mechanisms of adaptive immunity are largely those used in innate immunity. The important differences between innate immunity and adaptive immunity are in the receptors that lymphocytes use to recognize pathogens (Figure 1.8). The receptors of innate immunity are structurally of many different types. Each receptor recognizes molecular features shared by groups of pathogens, and none is specific for a particular pathogen. Conversely, the lymphocytes of adaptive immunity recognize pathogens using only one type of cellsurface receptor, but this is made in billions of different versions. The adaptive immune response becomes specific for a particular pathogen by including only lymphocytes expressing a receptor that recognizes the pathogen. Lymphocyte receptors are
not encoded by conventional genes, but by genes that are cut, spliced, and modified during lymphocyte development. By these mechanisms, each lymphocyte is programmed to make one variant of the basic receptor type. Billions of different receptor variants are represented in the lymphocytes of a person’s immune system, which enables all possible pathogens to be recognized by the immune system.
Figure 1.8 Principal characteristics and distinguishing features of innate immunity and adaptive immunity. During infection, only lymphocytes bearing receptors that recognize the infecting pathogen are recruited to the adaptive immune response. They then proliferate and differentiate to form an army of pathogen-specific effector cells (Figure 1.9). The processes that select pathogenspecific lymphocytes for proliferation and differentiation are called clonal selection and clonal expansion. Because of the time it takes to expand a few selected lymphocytes into an army, the benefit of the adaptive immune response cannot be felt until 7–10 days after the onset of infection. Figure 1.9
Selection of lymphocytes by a pathogen. Top panel:
during its development from a progenitor cell (gray), a lymphocyte is programmed to make one form of cellsurface receptor that recognizes a particular molecular structure. Each lymphocyte makes a receptor of different specificity, and the population of circulating lymphocytes includes billions of different receptors, all recognizing different structures. This arrangement enables all possible pathogens to be recognized. Lymphocytes with different receptor specificities are represented by different colors. Center panel: upon infection by a particular pathogen, only a few lymphocytes (represented by the yellow cell) have receptors that bind to the pathogen or one of its components. Bottom panel: these lymphocytes are selected for stimulation, proliferation, and differentiation. This produces an expanded population of effector cells. The ‘flu’ is a global disease that most people have experienced. It starts when epithelial cells in the lower respiratory tract become infected with influenza virus. The debilitating symptoms emerge 3 or 4 days after the start of infection, when the spread of the virus outruns the innate immune
response. The disease persists for 5–7 days while an adaptive immune response is developed and then put to work. As the adaptive immune response gains the upper hand, fever subsides and a gradual convalescence begins in the second week after infection. Some of the lymphocytes that contributed to a successful adaptive immune response persist in the body and are selected to provide long-term immunological memory of the pathogen. These memory cells enable subsequent encounters with the same pathogen to elicit a stronger and faster adaptive immune response; one that terminates infection before there are any significant symptoms of disease. The adaptive immunity based on immunological memory is also called acquired immunity, or protective immunity. For some pathogens, such as measles virus, one full-blown infection provides immunity for decades, whereas for influenza virus the protection is less effective. This is not due to faulty memory but to the rapid evolution of the virus, which allows it to escape the immunity acquired by its human hosts. The first time that a person makes an
adaptive immune response to a pathogen is called the primary immune response. During the primary response, the person acquires the immunological memory that enables subsequent encounters with the pathogen to be met with a faster and stronger secondary immune response. The purpose of vaccination is to provide people with a good immunological memory of the pathogen without them having to experience the disease. To do this, any vaccine must stimulate strong innate and adaptive immune responses against the pathogen (Figure 1.10). Immunological memory and vaccination are considered in Chapter 11.
Link of the original textbook (pdf):