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Hypersensitivity diseases: disorders caused by immune responses

Hypersensitivity Hypersensitivity is a term that is used to identify situations in which some type of substance or medication triggers an unusually strong and adverse reaction from the immune system. In some instances, hypersensitivity reactions can be extremely uncomfortable, cause permanent damage or even result in death. There are four commonly accepted types of this condition, with variations of these four supported by different schools of medical thought. Allergies are normally classified as Type 1 hypersensitivity. These involve allergic reactions that produce an almost immediate effect. The individual may begin to have difficulty breathing, experiencing what amounts to an asthma attack. In more extreme situations, anaphylaxis may occur. An antibody-dependent or cytotoxic reaction defines define Type 2 situations. Within this category, the hypersensitive reaction manifests with the development of particular conditions such as Goodpasture’s Syndrome, Myasthenia Gravi or Graves disease. A Type 2 hypersensitivity type has more long range implications. Type 3 hypersensitivity is classified as an immune complex disease. Within this category, conditions such as Arthus reaction or Serum sickness occur. Along with Type 2, patients diagnosed with Type 3 often require ongoing monitoring in order to keep the triggered condition under control. DTH or delayed type hypersensitivity is known as Type 4. Within this category, patients may develop various


dermatological issues that are extremely uncomfortable, experience fluctuation in T-cell levels and possibly develop conditions such as multiple sclerosis. As with other hypersensitivity types, it is important to identify the substance or medication causing the hypersensitive reaction and prevent any further ingestion of that substance. One of the best ways to get an idea of how painful hypersensitivity can be is to consider the momentary sharp pain that is often experienced when extremely cold beverages come in contact with a tooth filling. The sudden and intense wave of pain created can often seem unbearable for a brief moment before leveling off. For people with hypersensitive reactions to medicine, food or some factor in their environment, that level of pain does not subside within a moment but can last for an extended period of time. Physicians can often identify what is causing the severe reaction and help the patient learn to avoid the irritant1. This may involve changes of prescription medication, avoiding certain spices, herbs or foods or altering some aspect of the home or work environment. While hypersensitivity can be extremely debilitating and even fatal, it can be managed in most cases.

Immunity Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide range of pathogens irrespective of antigenic specificity. Other components of the immune system adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity. Innate immunity or nonspecific immunity is the natural resistance with which a person is born. It provides resistance through several physical, chemical and cellular approaches. Microbes first encounter the epithelial layers, physical barriers that line our skin and mucous membranes. Subsequent general defenses include secreted chemical signals (cytokines), antimicrobial substances, fever and phagocytic activity associated with the inflammatory response. The phagocytes express cell surface receptors that can bind and respond to common molecular


patterns expressed on the surface of invading microbes. Through these approaches, innate immunity can prevent the colonization, entry and spread of microbes. Adaptive immunity is often sub-divided into two major types depending on how the immunity was introduced. Naturally acquired immunity occurs through contact with a disease causing agent, when the contact was not deliberate, whereas artificially acquired immunity develops only through deliberate actions such as vaccination. Both naturally and artificially acquired immunity can be further subdivided depending on whether immunity is induced in the host or passively transferred from an immune host. Passive immunity is acquired through transfer of antibodies or activated T-cells from an immune host and is short lived usually lasting only a few months, whereas active immunity is induced in the host itself by antigen and lasts much longer, sometimes life-long. The diagram below summarizes these divisions of immunity-

Figure 1: Divisions of Immunity A further subdivision of adaptive immunity is characterized by the cells involved, humoral immunity is the aspect of immunity that is mediated by secreted antibodies, whereas the protection provided by cell mediated immunity involves T-lymphocytes alone2. Humoral immunity is active when the organism generates its own antibodies and passive when antibodies are transferred between individuals. Similarly, cell mediated immunity is active when the organisms’ own T-cells are stimulated and passive when T cells come from another organism.


Immune System The immune system is a network of cells, tissues and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily microbes—tiny organisms such as bacteria, parasites and fungi that can cause infections. Viruses also cause infections but are too primitive to be classified as living organisms. The human body provides an ideal environment for many microbes. It is the immune system’s job to keep them out or failing that, to seek out and destroy them. When the immune system hits the wrong target however, it can unleash a torrent of disorders, including allergic diseases, arthritis and a form of diabetes. If the immune system is crippled, other kinds of diseases result. The immune system is amazingly complex. It can recognize and remember millions of different enemies and it can produce secretions (release of fluids) and cells to match up with and wipe out nearly all of them. The secret to its success is an elaborate and dynamic communications network. Millions and millions of cells, organized into sets and subsets, gather like clouds of bees swarming around a hive and pass information back and forth in response to an infection. Once immune cells receive the alarm, they become activated and begin to produce powerful chemicals. These substances allow the cells to regulate their own growth and behavior, enlist other immune cells and direct the new recruits to trouble spots. Although scientists have learned much about the immune system, they continue to study how the body launches attacks that destroy invading microbes, infected cells and tumors while ignoring healthy tissues. New technologies for identifying individual immune cells are now allowing scientists to determine quickly which targets are triggering an immune response. Improvements in microscopy are permitting the first-ever observations of living B cells, T cells and other cells as they interact within lymph nodes and other body tissues. In addition, scientists are rapidly unraveling the genetic blueprints that direct the human immune response as well as those that dictate the biology of bacteria, viruses and parasites. The combination of new technology and expanded genetic information will no doubt reveal even more about how the body protects itself from disease3.


Figure 2: Immune System

The Organs of the Immune System Bone Marrow All the cells of the immune system are initially derived from the bone marrow. They form through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere 4. The bone marrow produces B cells, natural killer cells, granulocytes and immature thymocytes.

Thymus The function of the thymus is to produce mature T cells 5. Immature thymocytes, also known as prothymocytes, leave the bone marrow and migrate into the thymus. Through a remarkable maturation process sometimes referred to as thymic education, T cells that are beneficial to the immune system are spared, while those T cells that might evoke a detrimental autoimmune response are eliminated. The mature T cells are then released.

Spleen The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages, dendritic cells, natural killer cells and red blood cells. In addition to capturing foreign materials (antigens) from the blood that passes through the spleen, migratory macrophages and dendritic


cells bring antigens to the spleen via the bloodstream 6. An immune response is initiated when the macrophage or dendritic cells present the antigen to the appropriate B or T cells. This organ can be thought of as an immunological conference center. In the spleen, B cells become activated and produce large amounts of antibody. Also, old red blood cells are destroyed in the spleen7.

Lymph Nodes The lymph nodes function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are found throughout the body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most of our tissues 8. Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation. In a similar fashion as the spleen, the macrophages and dendritic cells that capture antigens present these foreign materials to T and B cells, consequently initiating an immune response9.

Figure 3: Organs of the Immune System

Immune response An immune response to foreign antigen requires the presence of an antigen-presenting cell (APC), (usually either a macrophage or dendritic cell) in combination with a B cell or T cell. When an APC presents an antigen on its cell surface to a B cell, the B cell is signalled to proliferate and produce antibodies that specifically bind to that antigen. If the antibodies bind to antigens on bacteria or parasites it acts as a signal for macrophages to engulf (phagocytose) and


kill them. Another important function of antibodies is to initiate the "complement destruction cascade." When antibodies bind to cells or bacteria, serum proteins called complement bind to the immobilized antibodies and destroy the bacteria by creating holes in them. Antibodies can also signal natural killer cells and macrophages. If the APC presents the antigen to T cells, the T cells become activated. Activated T cells proliferate and become secretory in the case of CD4+ T cells or if they are CD8+ T cells, they become activated to kill target cells that specifically express the antigen presented by the APC. The production of antibodies and the activity of CD8+ killer T cells are highly regulated by the CD4+ helper T cell subset. The CD4+ T cells provide growth factors or signals to these cells that signal them to proliferate and function more efficiently. This multitude of interleukins or cytokines that are produced and secreted by CD4+ T cells are often crucial to ensure the activation of natural killer cells, macrophages, CD8+ T cells and macrophages.

Figure 4: Immune Response to Self or Foreign Antigens

Cells of the Immune System


Macrophages Macrophages are involved in both in vivo and in vitro immune responses and have certain functional properties. In the process of Phagocytosis, macrophages function as effector cells as they recognize engulf and destroy foreign (antigenic) substances. Macrophages are accessory cells in the immune response. They are the major antigen-presenting cells of the body that interact with antigen as a primary step in the induction of an immune response. B cells can also present antigen10. Antigen presentation involved: 1. Binding and uptake of antigen by the macrophage surface membrane, which creates a tightly bound antigen that is more immunogenic than free antigen. 2. Processing and later re-expression of antigen on the antigen-presenting cell surface in association with MHC (class II)-encoded glycoproteins. 3. Release of soluble mediators, such as the monokine (macrophage-derived hormone) which stimulate the maturation and proliferation of T cells (the result of this sequence of events is the activation of antigen-specific B cells and T cells).

Lymphocytes Lymphocytes are both precursor cells of immunologic function as well as regulators and effectors of immunity. Smaller lymphocytes (T cells) have a long life span of months or years, whereas larger lymphocytes (B cells) have a shorter life span of 5 to 7 days. A general method for detection and quantitation of T cells and B cells depends on the differential reactivity of the two cell types with appropriately prepared red blood cells. These two types of cells are: 1. T cells accumulate sheep red blood cells (SRBCs) around their surfaces and form clusters referred to as erythrocyte (E) rosettes.


2. There is no such reaction between B cells and SRBCs, unless the red blood cells (indicated as E for erythrocytes) are coated with hemolysin-antibody (A) and special nonhemolytic preparations of guinea pig complement (C), thus called EAC rosettes.

T-Lymphocytes Surface markers: CD1, CD3 and CD11 are found on most peripheral blood T cells. CD3 is associated with, but distinct from the T-cell receptor for antigen; CD11, with the SRBC rosette receptor. CD4 is present on T helper cells, effector cells for delayed hypersensitivity and CD2 cell inducers. CD8 is present on cytotoxic and T suppressor cells. CD10 is present on stem cells, some B cells and activated peripheral blood T cells. Subpopulations: 1. Effector T (Te) cell also called TDTH cells are the peripheral lymphocytic cells responsible for delayed type hypersensitivity (DTH) reactions. 2. Cytotoxic T (Tc or CTL) cells are induced artificially by immunization with allogeneic tissue and naturally by tumors and virus. To be induced to the killer function, the precursor cells must be stimulated by antigen in association with class II MHC molecules. 3. Memory T (Tm) cells are induced during primary immunization; they recognize the specific antigen and participate in the anamnestic response. 4. Helper T (Th) cells are lymphocytes that recognize a specific antigen in association with a homologous class II MHC molecule and collaborate with B cells and macrophages in the induction of the humoral immune response. Similar cells collaborate with other T cells to facilitate the production of Te cells. 5. Suppressor T (Ts) cells are lymphocytes that recognize a specific antigen and interfere with the development of an immune response either directly or via suppressor factors. These cells


may be involved in the prevention of Autoimmunity. Ts cell precursors are activated by antigens in association with a particular type of class II MHC molecule

B-Lymphocytes Subpopulations: B cells are divided into subpopulations according to the immunoglobulin class they synthesize: D, M, G, A, and E B-cells respectively. Surface markers: Surface immunoglobulin binds specific antigens and functions as an antigen recognition site that initiates the differentiation of the B cell, resulting in antibody synthesis. Contact between the antigen epitope and the immunoglobulin in the B-cell membrane triggers cell division. As this process continues, the B cell matures into a plasma cell with abundant rough endoplasmic reticulum, actively secreting large amounts of the antibody specifically reactive with its homologous epitope.


Hypersensitivity diseases disorders caused by immune responses