Immunology Dr.M.

Kannan

2012-13

III B.Sc., Microbiology

Immunology Immuno tolerance

One of the remarkable characteristics of the normal immune system is that it is capable of reacting to an enormous variety of microbes, but it does not react against each individual's own (self) antigens. This unresponsiveness to self antigens, also called immunologic tolerance, is maintained despite the fact that the mechanisms by which lymphocyte receptors are expressed are not inherently biased to produce receptors for nonself antigens. In other words, lymphocytes with the ability to recognize self antigens are constantly being generated during the normal process of lymphocyte maturation. Immunologic Tolerance Significance and Mechanisms Immunologic tolerance is a lack of response to antigens that is induced by exposure of lymphocytes to these antigens. When lymphocytes with receptors for a particular antigen are exposed to this antigen, any of three outcomes is possible (Fig. 1). The lymphocytes may be activated, leading to an immune response; antigens that elicit such a response are said to be immunogenic. The lymphocytes may be functionally inactivated or killed, resulting in tolerance; antigens that induce tolerance are said to be tolerogenic. Immunologic tolerance to different self antigens may be induced when developing lymphocytes encounter these antigens in the generative lymphoid organs, called central tolerance, or when mature lymphocytes encounter self antigens in peripheral tissues, called peripheral tolerance (Fig. 2). The Central tolerance is a mechanism of tolerance only to self antigens that are present in the generative lymphoid organs, namely, the bone marrow and thymus. Tolerance to self antigens that are not present in these organs must be induced and maintained by peripheral mechanisms.

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Figure 1 Consequences of the encounter of lymphocytes with antigens. Naive lymphocytes may be activated to proliferate and differentiate by immunogenic antigens. Tolerance is induced when tolerogenic antigens induce functional anergy (unresponsiveness) or apoptosis. Leading to an inability of the cells to again respond to the same antigen even in an immunogenic form. Some antigens are ignored by lymphocytes, resulting in no response, but the lymphocytes are capable of responding to the same antigen in an immunogenic form

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Figure 2 Central and peripheral tolerance to self antigens. Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and are deleted (central tolerance). Mature self-reactive lymphocytes may be inactivated or deleted by encounter with self antigens in peripheral tissues (peripheral tolerance) lymphocytes are shown here, but the same processes occur with T lymphocytes as well.

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Primary and Secondary Responses to Antigens The immune system reacts to an antigen by studying the levels of antibodies in serum over time (figure 3). This level is expressed quantitatively as the titer, or concentration of antibodies. Upon the first exposure to an antigen, the system undergoes a primary response. The earliest part of this response, the latent period, is marked by a lack of antibodies for that antigen, but much activity is occurring. During this time, the antigen is being concentrated in lymphoid tissue, and is being processed by the correct clones of B lymphocytes. As plasma cells synthesize antibodies, the serum titer increases to a certain plateau and then tapers off to a low level over a few weeks or months. When the class of antibodies produced during this response is tested, an important characteristic of the response is uncovered. It turns out that, early in the primary response, most of the antibodies are the IgM type, which is the first class to be secreted by naive plasma cells. Later, the class of the antibodies (but not their specificity) is switched to IgG or some other class (IgA or IgE). When the immune system is exposed again to the same immunogen within weeks, months, or even years, a secondary response occurs. The rate of antibody synthesis, the peak titer, and the length of antibody persistence are greatly increased over the primary response. The rapidity and amplification seen in this response are attributable to the memory B cells that were formed during the primary response. Because of its association with recall, the secondary response is also called the anamnestic response. The advantage of this response is evident: It provides a quick and potent strike against subsequent exposures to infectious agents. This memory effect forms the basis for giving boosters additional doses of vaccine to increase the serum titer.

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Figure 3 THE STAGES IN ORIGIN, DIFFERENTIATION, MATURATION, ACTIVATION AND DIFFERENTIATION OF B CELL Development generally follows a similar general pattern in both types of lymphocytes (figure 4). Starting in embryonic and fetal stages, stem cells in the yolk sac, liver, and bone marrow give rise to immature lymphocytes that are released into the circulation. Because these undifferentiated cells cannot yet react with antigens, they must first undergo developmental changes at some specific anatomical location. This maturation occurs along two separate lines that will characterize all future responses. The fully mature B and T lymphocytes are released and ultimately take up residence in various lymphoid organs. Lymphocyte differentiation and

immunocompetence are basically complete by the late fetal or early neonatal period.

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Specific Happenings in B-Cell Maturation The site of B-cell maturation was first discovered in birds, which have an organ in the intestine called the bursa. In human certain bone marrow sites that harbor stromal cells. These huge cells nurture the lymphocyte stem cells and provide hormonal signals that initiate B-cell development. As a result of gene modification and selection, hundreds of millions of distinct B cells develop. These naive lymphocytes home to specific sites in the lymph nodes, spleen, and gut-associated lymphoid tissue (GALT), where they adhere to specific binding molecules. Here they will come into contact with antigens throughout life. In addition to having immunoglobulins as surface receptors, a fully differentiated B cell has a distinctively rough appearance under high magnification, with numerous microvillus projections.

Figure 4

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Specific Happenings in T-Cell Maturation The maturation of T cells and the development of their specific receptors are directed by the thymus gland and its hormones. Due to the complexity of T-cell function, there are at least seven classes of T-cell receptors or markers, termed the CD cluster (abbreviated from cluster of differentiation CD1, CD2, etc.). Some receptors recognize antigen molecules bound to cells on MHC receptors; others recognize receptors on B cells, other T cells, and macrophages.

Like B cells, T cells also migrate to lymphoid organs and occupy specific sites. Additional characteristics typical of mature T cell are smaller and fewer microvilli under high magnification and the property of rosette formation when mixed with normal sheep red blood cells. It has been estimated that 25X109 T cells pass between the lymphatic and general circulation per day.

ENTRANCE AND PROCESSING OF ANTIGENS AND CLONAL SELECTION Antigen Processing and Presentation Reorganization of foreign protein antigens by a T cell requires that peptides derived from the antigen be displayed within the cleft of an MHC molecule on the membrane of a cell. The formation of these peptide-MHC complexes requires that a protein antigen be degraded into peptides by a sequence of events called antigen processing. The degraded peptides then associate with MHC molecules within the cell interior, and the peptide-MHC complexes are transported to the membrane, where they are displayed (antigen presentation). Class I and class II MHC molecules associate with peptides that have been processed in different intracellular compartments. Class I MHC molecules bind peptides derived from endogenous antigens that have been processed within the cytoplasm of the cell (e.g., normal cellular proteins, tumor proteins, or viral and bacterial proteins produced within infected cells). Class II MHC molecules bind peptides derived from exogenous antigens that are
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internalized by phagocytosis or endocytosis and processed within the endocytic pathway. Having reviewed the characteristics of lymphocytes, let us now examine the properties of antigens, the substances that cause them to react. An antigen (Ag) is a substance that provokes an immune response in specific lymphocytes. The property of behaving as an antigen is called antigenicity. The term immunogen is another term of reference for a substance that can elicit an immune response. To be perceived as an antigen or immunogen, a substance must meet certain requirements in foreignness, shape, size, and accessibility.

The Role of Macrophages: Antigen Processing and Presentation In most immune reactions, the antigen must be further acted upon and formally presented to lymphocytes by special macrophages or other cells called antigen-processing cells (APCs). One of the most prominent APCs is a large dendritic cell that engulfs the antigen and modifies it so that it will be more immunogenic and recognizable to lymphocytes. After processing is complete, the antigen is moved to the surface of the APC and bound to the MHC receptor so that it will be readily accessible to the lymphocytes during presentation (figure 5). Presentation of Antigen to the Lymphocytes and Its Early Consequences For lymphocytes to respond to the APC-bound antigen, certain conditions must be met. T-cell-dependent antigens, usually protein based, require recognition steps between the macrophage, antigen, and lymphocytes. The first cells on the scene to assist the macrophage in activating B cells and other T cells are a special class of helper T cells (TH). This class of T cell bears a receptor that binds simultaneously with the class II MHC receptor on the macrophage and with one site on the antigen. Once identification has occurred, a cytokine, interleukin-1 (IL-1), produced by the
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macrophage, activates this T helper cell. The TH cell, in turn, produces a different cytokine, interleukin-2 (IL-2) that stimulates a general increase in activity of committed B and T cells.

A few antigens can trigger a response from B lymphocytes without the cooperation of macrophages or T helper cells. These T cell- independent antigens are usually simple molecules such as carbohydrates with many repeating and invariable determinant groups. Examples include lipopolysaccharide from the cell wall of Escherichia coli and polysaccharide from the capsule of Streptococcus pneumoniae. Because so few antigens are of this type, most B-cell reactions require helper T cells.

Figure 5

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ACTIVATION OF B LYMPHOCYTES: CLONAL EXPANSION AND ANTIBODY PRODUCTION

The immunologic activation of most B cells requires a series of events (figure 7): 1. Clonal selection and binding of antigen. In this case, a precommitted B cell of a particular clonal specificity picks up the antigen itself or is presented with the antigen by the macrophage complex so that the antigen is bound to the B-cell receptors. At the same time, the MHC/Ag receptor on the B cell is bound to the TH cell, thereby ensuring self recognition. 2. Instruction by chemical mediators. The B cell receives developmental signals from macrophages and T cells (interleukin-2 and -6) and various other growth factors, such as IL-4 and -5.

3. The combination of these stimuli on the membrane receptors causes a signal to be transmitted internally to the B-cell nucleus (Fig 6). 4. This event triggers B-cell activation. An activated B cell undergoes an increase in DNA synthesis, organelle bulk, and size in preparation for entering the cell cycle and mitosis. 5. Clonal expansion. A stimulated B cell multiplies through successive mitotic divisions and produces a large population of genetically identical daughter cells. Some cells that stop short of becoming fully differentiated are memory cells, which remain for long periods to react with that same antigen at a later time. This reaction also expands the clone size, so that subsequent exposure to that antigen provides more cells with that specificity. This expansion of the clone size accounts for the increased memory response. By far the most numerous progeny are large, specialized, terminally differentiated B cells called plasma cells.
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6. Antibody production and secretion. The primary action of plasma cells is to secrete into the surrounding tissues copious amounts of antibodies with the same specificity as the original receptor (figure 15.13). Although an individual plasma cell can produce around 2,000 antibodies per second, production does not continue indefinitely because of regulation from the Tsuppressor (TS) class of cells. The plasma cells do not survive for long and deteriorate after they have synthesized antibodies.

Figure 6
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ACTIVATION OF T LYMPHOCYTES AND HOW T CELLS RESPOND TO ANTIGEN: CELL-MEDIATED IMMUNITY (CMI) During the time that B cells have been actively responding to antigens, the Tcell limb of the system has been similarly engaged. The responses of T cells, however, are cell-mediated immunities, which require the direct involvement of T lymphocytes throughout the course of the reaction. These reactions are among the most complex and diverse in the immune system and involve several subsets of T cells whose particular actions are dictated by CD receptors. All mature T cells have CD2 (the cause of rosetting), but CD4 and CD8 are found only on certain classes. T cells are restricted; that is, they require some type of MHC (self) recognition before they can be activated, and all produce cytokines with a spectrum of biological effects.

T cells have notable differences in function from B cells. Rather than making antibodies to control foreign antigens, the whole T cell acts directly in contact with the antigen. They also stimulate other T cells, B cells, and phagocytes. The Activation of T Cells and Their Differentiation into Subsets

The mature T cells in lymphoid organs are primed to react with antigens that have been processed and presented to them by macrophages. A T cell is initially sensitized when antigen is bound to its receptor. By mechanisms not yet fully characterized, sensitization leads to the final differentiation of the cell into one of four functionally specialized subsets: helper, suppressor, cytotoxic, or delayed

hypersensitivity T cells (figure 7). As with B cells, activated T cells transform into lymphoblasts in preparation for mitotic divisions, and they divide into one of the subsets of effector cells and memory cells that can interact with the antigen upon subsequent contact. Memory T cells are some of the longest-lived blood cells known (70 years in one well-documented case).

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T Helper (TH) Cells Helper cells play a central role in assisting with immune reactions to antigens, including those of B cells and other T cells. They do this directly by receptor contact and indirectly by releasing cytokines such as interleukin2, which stimulates the primary growth and activation of B and T cells, and interleukins-4, -5, and -6, which stimulate various activities of B cells. T helper cells are the most prevalent type of T cell in the blood and lymphoid organs, making up about 65% of this population. The severe depression of this class of T cells (with CD4 receptors) by HIV is what largely accounts for the immunopathology of AIDS.

Figure 7

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Target Cells That TC Cells Can Destroy Include the Following: Fungi, protozoans, and complex bacteria (mycobacteria). Cancer cells. T cells constantly survey the tissues and immediately attack any abnormal cells they encounter. The importance of this function is clearly demonstrated in the susceptibility of T-cell-deficient people to cancer. Cells from other animals and humans. Cytotoxic CMI is the most important factor in graft rejection. In this instance, the TC cells attack the foreign tissues that have been implanted into a recipients body. Other Types of Killer Cells Natural killer (NK) cells are a type of lymphocyte related to T cells that lack specificity for antigens. They circulate through the spleen, blood, and lungs and are probably the first killer cells to attack cancer cells and virus infected cells. They destroy such cells by similar mechanisms as T cells. Their activities are acutely sensitive to cytokines such as interleukin-12 and alpha and beta interferon. MHC Molecules MHC stands for major histocompatibility complex. This term was coined for a genetic locus on the short arm of chromosome 6 that proved decisive for rejection or acceptance of transplanted tissue. On this multi-gene locus, two main types of transmembrane proteins are encoded: MHC class I and MHC class II. MHC proteins can be understood as IDcards carried by cells to be inspected by T cells in stop and search operations. MHC-I molecules are ID-cards shown to cytotoxic (CD8+) T cells; MHC-II molecules are shown to (CD4+) T-helper cells. MHC I presents an image of all that is being synthesized in the cell. Normally, that will be self-peptides. In the event of a viral infection, peptides from viral proteins will appear on MHC I in addition to normal cellular peptides. MHC II presents extracellular material taken up by antigen-presenting cells (APC). This is intended to activate CD4+ T cells, mainly helper cells. MHC II is
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therefore expressed by a small minority of cells, mainly "professional" APC: dendritic cells, macrophages and B cells. MHC-II molecules, while very similar in overall shape, consist of two equivalent protein chains, and , that are encoded by two separate genes in the MHC. The MHC Encodes Three Major Classes of Molecules The major histocompatibility complex is a collection of genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans and on chromosome 17 in mice. The MHC is referred to as the HLA complex in humans and as the H-2 complex in mice. Although the arrangement of genes is somewhat different, in both cases the MHC genes are organized into regions encoding three classes of molecules (Figure 9). Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of peptide antigens to TC cells. Class II MHC genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, dendritic cells, and B cells), where they present processed antigenic peptides to TH cells. Class III MHC genes encode, in addition to other products, various secreted proteins that have immune functions, including components of the complement system and molecules involved in inflammation.

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HYPERSENSITIVITY REACTIONS

Hypersensitivity reactions to usually harmless substances are often called allergies or allergic reactions. Antigens that cause allergic reactions are allergens. Hypersensitivities are categorized according to which parts of the immune response are involved and how quickly the response occurs. Most allergic or hypersensitivity reactions fall into one of four major types: Type I: Immediate IgE-mediated Type II: Cytotoxic Type III: Immune complexmediated Type IV: Delayed cell-mediated

IMMEDIATE (TYPE I) HYPERSENSITIVITY Immediate (Type I) hypersensitivity, or anaphylactic hypersensitivity, typically produces an immediate response upon exposure to an allergy-inducing antigen (also known as an allergen). Nonallergic persons do not respond to such antigens. Anaphylaxis (Greek: ana, against, phylaxis, protection) is an immediate, exaggerated allergic reaction to antigens.
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The term anaphylaxis refers to detrimental effects to the host caused by an inappropriate immune response. These effects are the opposite of prophylaxis, the preventive effects generated by an immune response. Anaphylaxis is the harmful result of IgE antibodies made in response to allergens. It can be local or generalized (systemic). Localized anaphylaxis appears as reddening of the skin, watery eyes, hives, asthma, and digestive disturbances. Generalized anaphylaxis appears as a systemic life-threatening reaction such as airway constriction or anaphylactic shock, generalized condition resulting from a sudden extreme drop in blood pressure. ALLERGEN

Immediate hypersensitivity results from two or more exposures to an allergen. An allergen is an ordinarily harmless foreign substance (typically a protein or a chemical bound to a protein) that can cause an exaggerated immunological response. The first exposure to the allergen produces no visible signs or symptoms. Allergens include airborne substances such as pollen, household dust, molds, and dandertiny particles from hair, feathers, or skin. Household dust commonly contains nearly microscopic mites and their fecal pellets. Other allergens include venoms from insect stings, antibiotics, certain foods, sulfites, and foreign substances found in vaccines and in diagnostic or therapeutic materials. Allergens can be introduced into the body by inhalation, ingestion, or injection

CYTOTOXIC (TYPE II) HYPERSENSITIVITY In cytotoxic (Type II) hypersensitivity, specific antibodies react with cell surface antigens interpreted as foreign by the immune system, leading to phagocytosis, killer cell activity, or complement-mediated lysis. The cells to which the antibodies are attached, as well as surrounding tissues, are damaged because of the resulting inflammatory response. Antigens that initiate cytotoxic hypersensitivity typically enter the body in mismatched blood transfusions or during delivery of an Rh-positive infant to an Rh-negative mother.
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IMMUNE COMPLEX (TYPE III) HYPERSENSITIVITY Immune complex (Type III) hypersensitivity results from the formation of antigen-antibody complexes. Under normal circumstances these large immune complexes are engulfed and destroyed by phagocytic cells. Hypersensitivity occurs when antigen-antibody complexes persist or are continuously formed. In type III hypersensitive reaction is mediated by the formation of immune complexes and the ensuing activation of complement. Complement split products serve as immune effector molecules that elicit localized vasodilation and chemotactically attract neutrophils. Deposition of immune complexes near the site of antigen entry can induce an Arthus reaction, in which lytic enzymes released by the accumulated neutrophils and the complement membrane attack complex cause localized tissue damage. CELL-MEDIATED (TYPE IV) HYPERSENSITIVITY Cell-mediated (Type IV) hypersensitivity is also called delayed hypersensitivity because reactions take more than 12 hours to develop. These reactions are mediated by T cellsspecifically, a type of TH1 cell [sometimes called a delayed hypersensitivity T (TDH) cell]not by antibodies. A type IV hypersensitive reaction involves the cell-mediated branch of the immune system. Antigen activation of sensitized TH1 cells induces release of various cytokines that cause macrophages to accumulate and become activated. The net effect of the activation of macrophages is to release lytic enzymes that cause localized tissue damage.

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Disorders of Immune response Humans possess a powerful and intricate system of defense, which by its very nature also carries the potential to cause injury and disease. In most instances, a defect in immune function is expressed in commonplace, but miserable, symptoms such as those of hay fever and dermatitis. But abnormal or undesirable immune functions are also actively involved in debilitating or life threatening diseases such as asthma, anaphylaxis, rheumatoid arthritis, graft rejection, and cancer.

The immune response have centered on its numerous beneficial effects. The precisely coordinated system that seeks out, recognizes, and destroys an unending array of foreign materials is clearly protective, but it also presents another side a side that promotes rather than prevents disease. It is called immunopathology, the study
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of disease states associated with over reactivity or under reactivity of the immune response. In the cases of allergies and autoimmunity, the tissues are innocent bystanders attacked by excessive immunologic functions. In grafts and

transfusions, a recipient reacts to the foreign tissues and cells of another individual. In immunodeficiency diseases, immune function is incompletely developed, suppressed, or destroyed. Cancer falls into a special category, because it is both a cause and an effect of immune dysfunction.

Autoimmunity
Usually, the bodys immune system recognizes its self-antigens and deletes clones of cells that would respond and attack its own tissues. A growing number of diseases are suspected of being caused by an autoimmune process, however, meaning that the immune system of the body is responding to the tissues of the body as if they are foreign. Susceptibility to many of them is influenced by the major histocompatibility makeup of the patient, and so, not surprisingly, they often occur in the same family. Autoimmune diseases may result from reaction to antigens that are similar though not identical to antigens of self. Some bacterial and viral agents try to evade destruction by the immune system by developing amino acid sequences that are similar to self-antigens. As a result, the immune system is unable to discriminate between the agent and self. The immune system may then destroy the substances of self as well as those of the bacteria or virus. It has been found that the likeness of amino acid sequences need not be exact for this self-destruction; even a 50% likeness may lead to an autoimmune response. Autoimmune responses may also occur after tissue injury in which self-antigens are released from the injured organ, as in the case of a heart attack. The auto antibodies formed react with heart tissue and evidence suggests that they can cause further damage.

The human autoimmune diseases can be divided into two broad categories: organ-specific and systemic autoimmune disease. Such diseases affect 5%7% of
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the human population. In an organ-specific autoimmune disease, the immune response is directed to a target antigen unique to a single organ or gland, so that the manifestations are largely limited to that organ. The cells of the target organs may be damaged directly by humoral or cell-mediated mechanisms.

HASHIMOTOS THYROIDITIS In Hashimotos thyroiditis, which is most frequently seen in middle-aged women, an individual produces auto-antibodies and sensitized TH1 cells specific for thyroid antigens. Antibodies are formed to a number of thyroid proteins, including thyroglobulin and thyroid peroxidase, both of which are involved in the uptake of iodine. Binding of the auto-antibodies to these proteins interferes with iodine uptake and leads to decreased production of thyroid hormones (hypothyroidism). GOODPASTURES SYNDROME In Goodpastures syndrome, auto-antibodies specific for certain basementmembrane antigens bind to the basement membranes of the kidney glomeruli and the alveoli of the lungs. Subsequent complement activation leads to direct cellular
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damage and an ensuing inflammatory response mediated by a buildup of complement split products. Damage to the glomerular and alveolar basement membranes leads to progressive kidney damage and pulmonary hemorrhage. Death may ensue within several months of the onset of symptoms. Biopsies from patients with Goodpastures syndrome stained with fluorescent-labeled anti-IgG and antiC3b reveal linear deposits of IgG and C3b along the basement membranes.

INSULIN-DEPENDENT DIABETES MELLITUS A disease afflicting 0.2% of the population, insulin-dependent diabetes mellitus (IDDM) is caused by an autoimmune attack on the pancreas. The attack is directed against specialized insulin-producing cells (beta cells) that are located in spherical clusters, called the islets of Langerhans, scattered throughout the pancreas. The autoimmune attack destroys beta cells, resulting in decreased production of insulin and consequently increased levels of blood glucose. Systemic Autoimmune Diseases In systemic autoimmune diseases, the response is directed toward a broad range of target antigens and involves a number of organs and tissues. These diseases reflect a general defect in immune regulation that results in hyperactive T cells and B cells. Tissue damage is widespread, both from cell mediated immune responses and from direct cellular damage caused by auto-antibodies or by accumulation of immune complexes. Systemic Lupus Erythematosus Attacks One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus (SLE), which typically appears in women between 20 and 40 years of age; the ratio of female to male patients is 10:1. SLE is characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction. Multiple sclerosis (MS) is the most common cause of neurologic disability associated with disease in Western countries. The symptoms may be mild, such as
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numbness in the limbs, or severe, such as paralysis or loss of vision. Most people with MS are diagnosed between the ages of 20 and 40.

Rheumatoid Arthritis Attacks Joints Rheumatoid arthritis is a common autoimmune disorder, most often affecting women from 40 to 60 years old. The major symptom is chronic inflammation of the joints, although the hematologic, cardiovascular, and respiratory systems are also frequently affected. Many individuals with rheumatoid arthritis produce a group of auto-antibodies called rheumatoid factors that are reactive with determinants in the Fc region of IgG. The classic rheumatoid factor is an IgM antibody with that reactivity. Such auto-antibodies bind to normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints. These immune complexes can activate the complement cascade, resulting in a type III hypersensitive reaction, which leads to chronic inflammation of the joints.

Immunodeficiency Diseases

Components of the immune response system are absent. Deficiencies involve B and T cells, phagocytes, and complement. A. Primary immunodeficiency is genetically based, congenital; defect in inheritance leads to lack of B-cell activity, T-cell activity, or both. B. B-cell defect is called agammaglobulinemia; patient lacks antibodies; serious recurrent bacterial infections result. In Ig deficiency, one of the classes of antibodies is missing or deficient. C. In T-cell defects, the thymus is missing or abnormal. In DiGeorge syndrome, the thymus fails to develop; afflicted children experience recurrent infections with eukaryotic pathogens and viruses; immune response is generally underdeveloped.

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D. In severe combined immunodeficiency (SCID), both limbs of the lymphocyte system are missing or defective; no adaptive immune response exists; fatal without replacement of bone marrow or other therapies. E. Secondary (acquired) immunodeficiency is due to damage after birth (infections, drugs, radiation). AIDS is the most common of these; T helper cells are main target; deficiency manifests in numerous opportunistic infections and cancers.

Transplantation Immunology Transplantation immunology refers to the act of transferring cells, tissues, or organs from one site to another. The desire to accomplish transplants stems from the realization that many diseases can be cured by implantation of a healthy organ, tissue, or cells (a graft) from one individual (the donor) to another in need of the transplant (the recipient or host). The development of surgical techniques that allow the facile reimplantation of organs has removed one barrier to successful transplantation, but others remain. Immunologic Basis of Graft Rejection The degree of immune response to a graft varies with the type of graft. The following terms are used to denote different types of transplants: Autograft is self-tissue transferred from one body site to another in the same individual. Transferring healthy skin to a burned area in burn patients and use of healthy blood vessels to replace blocked coronary arteries are examples of frequently used autografts. Isograft is tissue transferred between genetically identical individuals. In inbred strains of mice, an isograft can be performed from one mouse to another syngeneic mouse. In humans, an isograft can be performed between genetically identical (monozygotic) twins.

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Allograft is tissue transferred between genetically different members of the same species. In mice, an allograft is performed by transferring tissue or an organ from one strain to another. In humans, organ grafts from one individual to another are allografts unless the donor and recipient are identical twins. Xenograft is tissue transferred between different species (e.g., the graft of a baboon heart into a human). Because of significant shortages in donated organs, raising animals for the specific purpose of serving as organ donors for humans is under serious consideration. Basics of graft rejection First and second set reactions When a graft is undergoing rejection for the first time, there is very rapid invasion by polymorphs and lymphoid cells, including plasma cells. Thrombosis and acute cell destruction can be seen in three to four days. This first time reaction to a foreign graft is known as the First set reaction. Second set rejection occurs during subsequent grafting, taken from the original donor or a related subject. It does not occur if the allograft has been donated by an entirely unrelated subject with a completely different set of tissue antigens. (Such grafts are rejected as first set of reactions). The recipient of a second graft from a donor who has already been rejected, will mount an accelerated rejection of the second graft. Since T cells are implicated in graft rejection, it demonstrated that they are primed and retain memory of the first contact with graft antigens. During rejection humoral antibodies, with specificity for the graft antigens are produced. Such antibodies are produced in a T cell dependant manner i.e., with T cell help. Immune Mechanisms in Graft Rejection Immune mechanisms in graft rejection are best illustrated using rejection of the grafted kidney as a model. A. Acute rejection

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Antigen presenting cells (APC) in the grafted tissue provide the primary stimulus. These MHC Class II-positive cells are mainly dendritic cells and to a lesser extent - monocytes. These cells are necessary to present antigen in a form that recipient lymphocytes can recognize. These cells are sometimes called passenger cells since they come along with the graft. B. Hyperacute rejection Hyperacute rejection occurs within minutes of transplantation and is characterized by sludging of red cells and microthrombi in the glomerulus. This type of rejection occurs in individuals with pre existing antibodies to blood group antigens or in those that are pre sensitized to MHC Class I antigens of the donor, through blood transfusions. Antigen antibody complexes formed during rejection, fix complement and complement activation ensues, followed by activation of the clotting pathway. C. Chronic rejection Chronic rejection occurs months to years after transplantation. It is characterized by a narrowing of the vascular arterial lumen, owing to growth of endothelial cells that line the vascular bed. Tissue typing clinical transplantation A tissue type test is a blood test that measures substances called antigens on the surface of body cells and tissues. Checking the antigens can tell if donor tissue is safe (compatible) for transplant to another person. This test may also be called HLA typing. Antigens can tell the difference between normal body tissue or foreign tissue (for example, tissue from another person's body). Tissue type helps find the best match for tissues or blood cells (such as platelets). Sometimes tissue type test is done to check the autoimmune diseases. A special pattern of antigens (called tissue type) is present on each person's cells and tissues. Half of each person's antigens come from (inherited) the mother and half from the father. Identical twins have the same pattern, but everyone else has his or her own special pattern. Brothers and sisters have a 1in4 chance of having an
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identical match. Each person's antigen pattern can be "fingerprinted" through a tissue type test. The closer the match of antigens, the more likely that transplanted tissues or organs will not be rejected. The more similar the antigen patterns are from two people, the more likely it is that they are related. Two main antigen groups are used for a tissue type test. Class I has three classes of antigens (HLAA, HLAB, HLAC) that are found on some kinds of blood cells. Class II has one class of antigens (HLAD) that are found only on certain cells in the body. There are many different types of antigens in each category. CANCER IMMUNOLOGY Cancer: Origin and Terminology In most organs and tissues of a mature animal, a balance is usually maintained between cell renewal and cell death. The various types of mature cells in the body have a given life span; as these cells die, new cells are generated by the proliferation and differentiation of various types of stem cells. Under normal circumstances, the production of new cells is regulated so that the number of any particular type of cell remains constant. Occasionally, though, cells arise that no longer respond to normal growth-control mechanisms. These cells give rise to clones of cells that can expand to a considerable size, producing a tumor, or neoplasm. A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is benign. A tumor that continues to grow and becomes progressively invasive is malignant; the term cancer refers specifically to a malignant tumor. In addition to uncontrolled growth, malignant tumors exhibit metastasis; in this process, small clusters of cancerous cells dislodge from a tumor, invade the blood or lymphatic vessels, and are carried to other tissues, where they continue to proliferate. In this way a primary tumor at one site can give rise to a secondary tumor at another site (Figure 1).

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Malignant tumors or cancers are classified according to the embryonic origin of the tissue from which the tumor is derived. Most (>80%) are carcinomas, tumors that arise from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. The majority of cancers of the colon, breast, prostate, and lung are carcinomas. The leukemias and lymphomas are malignant tumors of hematopoietic cells of the bone marrow and account for about 9% of cancer incidence in the United States. Leukemias proliferate as single cells, whereas lymphomas tend to grow as tumor masses. Sarcomas, which arise less frequently (around 1% of the incidence in the United States) are derived from mesodermal connective tissues such as bone, fat, and cartilage.

Tumor antigen The subdiscipline of tumor immunology involves the study of antigens on tumor cells and the immune response to these antigens. Two types of tumor antigens
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Immunology Dr.M.Kannan

2012-13

have been identified on tumor cells: tumor-specific transplantation antigens (TSTAs) and tumor-associated transplantation antigens (TATAs). Tumor-specific antigens are unique to tumor cells and do not occur on normal cells in the body. They may result from mutations in tumor cells that generate altered cellular proteins. Tumor-associated antigens may also be proteins that are normally expressed at extremely low levels on normal cells but are expressed at much higher levels on tumor cells.

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Immunology Dr.M.Kannan

2012-13

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Immunology Dr.M.Kannan

2012-13

IMMUNERESPONSE TO TUMOR THE FUNCTION OF THE IMMUNE SYSTEM IN CANCER A concept that readily explains the detection and elimination of cancer cells is immune surveillance. Many experts postulate that cells with cancer-causing potential arise constantly in the body but that the immune system ordinarily discovers and destroys these cells, thus keeping cancer in check. In some cases, the cancer may not be immunogenic enough; it may retain self markers and not be targeted by the surveillance system. It may turn out that most cancers are associated with some sort of immunodeficiency, even a slight or transient one.

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