Diseases Of The Immune System Flashcards

Question

State the mast cell mediators in type 1 hypersensitivity and their actions

Answer 1

Action Mediators Vasodilation, increased vascular permeability :PAF, Histamine Leukotrienes C4, D4, E4 Neutral proteases that activate complement and kinins ,Prostaglandin D2 Smooth muscle spasm: Leukotrienes C4, D4, E4 Histamine Prostaglandins PAF Cellular infiltration :Cytokines (e.g., chemokines, TNF) Leukotriene B4 Eosinophil and neutrophil chemotactic factors (not defined biochemically)

Answer 2

An immediate hypersensitivity reaction may occur as a systemic disorder or as a local reaction. The nature of the reaction is often determined by the route of antigen exposure. Systemic exposure to protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) may result in sys- temic anaphylaxis. Within minutes of the exposure in a sensitized host, itching, urticaria (hives), and skin ery- thema appear, followed in short order by profound respira- tory difficulty caused by pulmonary bronchoconstriction and accentuated by hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gas- trointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with a fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. Local reactions generally occur when the antigen is con- fined to a particular site, such as skin (contact, causing urticaria), gastrointestinal tract (ingestion, causing diar- rhea), or lung (inhalation, causing bronchoconstriction). The common forms of skin and food allergies, hay fever, and certain forms of asthma are examples of localized aller- gic reactions. However, ingestion or inhalation of allergens also can trigger systemic reactions. Susceptibility to localized type I reactions has a strong genetic component, and the term atopy is used to imply familial predisposition to such localized reactions. Patients who suffer from nasobronchial allergy (including hay fever and some forms of asthma) often have a family history of similar conditions. Genes that are implicated in susceptibil- ity to asthma and other atopic disorders include those encoding HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control TH2 responses), a component of the FcεRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways. The reactions of immediate hypersensitivity clearly did not evolve solely to cause human discomfort and disease. The immune response dependent on TH2 cells and IgE—in particular, the late-phase inflammatory reaction—plays an important protective role in combating parasitic infections. IgE antibodies are produced in response to many helmin- thic infections, and their physiologic function is to target helminths for destruction by eosinophils and mast cells. Mast cells also are involved in defense against bacterial infections. And snake aficionados will be relieved to hear that their mast cells may protect them from some snake venoms by releasing granule proteases that degrade the toxins. Why these beneficial responses are inappropriately activated by harmless environmental antigens, giving rise to allergies, remains a puzzle.

Answer 3

Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue components. The antigens may be normal molecules intrinsic to cell membranes or in the extracellular matrix, or they may be adsorbed exoge- nous antigens (e.g., a drug metabolite). Antibody-mediated abnormalities are the underlying cause of many human diseases; examples of these are listed in Table 4–3. In all of these disorders, the tissue damage or functional abnormali- ties result from a limited number of mechanisms. Mechanisms of Antibody-Mediated Diseases Antibodies cause disease by targeting cells for phagocyto- sis, by activating the complement system, and by interfer- ing with normal cellular functions (Fig. 4–10). The antibodies that are responsible typically are high-affinity antibodies capable of activating complement and binding to the Fc receptors of phagocytes. • Opsonization and phagocytosis. When circulating cells, such as erythrocytes or platelets, are coated (opsonized) with autoantibodies, with or without complement pro- teins, the cells become targets for phagocytosis by neutrophils and macrophages (Fig. 4–10, A). These phagocytes express receptors for the Fc tails of IgG anti- bodies and for breakdown products of the C3 comple- ment protein, and use these receptors to bind and ingest opsonized particles. Opsonized cells are usually elimi- nated in the spleen, and this is why splenectomy is of clinical benefit in autoimmune thrombocytopenia and some forms of autoimmune hemolytic anemia. • Inflammation.Antibodiesboundtocellularortissueanti- gens activate the complement system by the “classical” pathway (Fig. 4–10, B). Products of complement activa- tion serve several functions (see Fig. 2–18, Chapter 2), one of which is to recruit neutrophils and monocytes, triggering inflammation in tissues. Leukocytes may also be activated by engagement of Fc receptors, which rec- ognize the bound antibodies. This mechanism of injury is exemplified by Goodpasture syndrome and pemphi- gus vulgaris. • Antibody-mediated cellular dysfunction. In some cases, antibodies directed against cell surface receptors impair or dysregulate cellular function without causing cell injury or inflammation (Fig. 4–10, C). In myasthenia gravis, antibodies against acetylcholine receptors in the motor end plates of skeletal muscles inhibit neuromuscular transmission, with resultant muscle weakness. Antibodies can also stimulate cellular responses excessively. In Graves disease, antibodies against the thyroid-stimulating hormone receptor stim- ulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism. Antibodies against hor- mones and other essential proteins can neutralize and block the actions of these molecules, causing functional derangements.

Answer 4

Disease Target Antigen Mechanisms of Disease Clinicopathologic Manifestations Autoimmune hemolytic anemia Red cell membrane proteins (Rh blood group antigens, I antigen) Opsonization and phagocytosis of erythrocytes Hemolysis, anemia Autoimmune thrombocytopenic purpura Platelet membrane proteins (GpIIb/IIIa integrin) Opsonization and phagocytosis of platelets Manifestation:Bleeding Pemphigus vulgaris Proteins in intercellular junctions of epidermal cells (epidermal desmoglein) Antibody-mediated activation of proteases, disruption of intercellular adhesions Skin vesicles (bullae) Vasculitis caused by ANCA : Neutrophil granule proteins, presumably released from activated neutrophils Neutrophil degranulation and inflammation Manifestation:Vasculitis Goodpasture syndrome Noncollagenous protein (NC1) in basement membranes of kidney glomeruli and lung alveoli Complement- and Fc receptor mediated inflammation Nephritis, lung hemorrhage Acute rheumatic fever Streptococcal cell wall antigen; antibody cross-reacts with myocardial antigen Mechanism of disease:Inflammation, macrophage activation Myocarditis Myasthenia gravis Acetylcholine receptor Antibody inhibits acetylcholine binding, downmodulates receptors Muscle weakness, paralysis Graves disease (hyperthyroidism) TSH receptor Antibody-mediated stimulation of TSH receptors Hyperthyroidism Insulin-resistant diabetes Insulin receptor Antibody inhibits binding of insulin Hyperglycemia, ketoacidosis Pernicious anemia Intrinsic factor of gastric parietal Neutralization of intrinsic factor, cells decreased absorption of vitamin B12 Abnormal myelopoiesis, anemia

Answer 5

Immune Complex Diseases (Type III Hypersensitivity) Antigen–antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation. The antigens in these com- plexes may be exogenous antigens, such as microbial pro- teins, or endogenous antigens, such as nucleoproteins. The mere formation of immune complexes does not equate with hypersensitivity disease; small amounts of antigen– antibody complexes may be produced during normal immune responses and are usually phagocytosed and destroyed. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic. Pathogenic immune complexes may form in the circulation and subsequently deposit in blood vessels, or the complexes may form at sites where antigen has been planted (in situ immune complexes). Immune complex–mediated injury is systemic when complexes are formed in the circulation and are deposited in several organs, or it may be localized to particular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site. The mechanism of tissue injury is the same regardless of the pattern of distribution; however, the sequence of events and the conditions leading to the formation of systemic and local immune complexes are different and are considered separately in the following descriptions. Systemic Immune Complex Disease The pathogenesis of systemic immune complex disease can be divided into three phases: (1) formation of antigen– antibody complexes in the circulation and (2) deposition of the immune complexes in various tissues, thereby initiat- ing (3) an inflammatory reaction in various sites through- out the body (Fig. 4–11). Acute serum sickness is the prototype of a systemic immune complex disease. It was first described in humans when large amounts of foreign serum were administered for passive immunization (e.g., in persons receiving horse serum containing antidiphtheria antibody); it is now seen only rarely (e.g., in patients injected with rabbit or horse antithymocyte globulin for treatment of aplastic anemia or graft rejection, or patients with snakebite given anti-venom antibody made in animals). Although serum sickness is no longer common, the study of its pathogenesis sheds light on the mechanisms of human immune complex diseases. Approximately 5 days after the foreign protein is injected, specific antibodies are produced; these react with the antigen still present in the circulation to form antigen– antibody complexes. The complexes deposit in blood vessels in various tissue beds, triggering the subsequent injurious inflammatory reaction. Several variables determine whether immune complex forma- tion leads to tissue deposition and disease. Perhaps foremost among these factors is the size of the complexes. Very large complexes or complexes with many free IgG Fc regions (typically formed in antibody excess) are rapidly removed from the circulation by macrophages in the spleen and liver and are therefore usually harmless. The most pathogenic complexes are formed during antigen excess and are small or intermediate in size and are cleared less effectively by phagocytes and therefore circulate longer. In addition, the charge of the complex, the valency of the antigen, the avidity of the antibody, and the hemodynamics of a given vascular bed all influence the tendency to develop disease. The favored sites of deposition are kidneys, joints, and small blood vessels in many tissues. Localization in the kidney and joints is explained in part by the high hemody- namic pressures associated with the filtration function of the glomerulus and the synovium. For complexes to leave the circulation and deposit within or outside the vessel wall, an increase in vascular permeability also must occur. This is probably triggered when immune complexes bind to leukocytes and mast cells by means of Fc and C3b recep- tors and stimulate release of mediators that increase vas- cular permeability. Once complexes are deposited in the tissue, the third phase, the inflammatory reaction, ensues. During this phase (approximately 10 days after antigen administration), clini- cal features such as fever, urticaria, arthralgias, lymph node enlargement, and proteinuria appear. Wherever immune complexes deposit, characteristic tissue damage occurs. The immune complexes activate the complement system, leading to the release of biologically active frag- ments such as the anaphylatoxins (C3a and C5a), which increase vascular permeability and are chemotactic for neutrophils and monocytes (Chapter 2). The complexes also bind to Fcγ receptors on neutrophils and monocytes, activating these cells. Attempted phagocytosis of immune complexes by the leukocytes results in the secretion of a variety of additional pro-inflammatory substances, includ- ing prostaglandins, vasodilator peptides, and chemotactic substances, as well as lysosomal enzymes capable of digest- ing basement membrane, collagen, elastin, and cartilage, and reactive-oxygen species that damage tissues. Immune complexes can also cause platelet aggregation and activate Hageman factor; both of these reactions augment the inflammatory process and initiate formation of micro- thrombi, which contribute to the tissue injury by producing local ischemia (Fig. 4–11). The resultant pathologic lesion is termed vasculitis if it occurs in blood vessels, glomerulo- nephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on. Predictably, the antibody classes that induce such lesions are complement-fixing antibodies (i.e., IgG and IgM) and antibodies that bind to phagocyte Fc receptors (IgG). During the active phase of the disease, consumption of complement may result in decreased serum complement levels. The role of complement- and Fc receptor–dependent inflammation in the pathogenesis of the tissue injury is supported by the observation that experimental depletion of serum complement levels or knockout of Fc receptors in mice greatly reduces the severity of lesions, as does deple- tion of neutrophils. Local Immune Complex Disease A model of local immune complex diseases is the Arthus reaction, in which an area of tissue necrosis appears as a result of acute immune complex vasculitis. The reaction is produced experimentally by injecting an antigen into the skin of a previously immunized animal (i.e., pre-formed antibodies against the antigen are already present in the circulation). Because of the initial antibody excess, immune complexes are formed as the antigen diffuses into the vas- cular wall; these are precipitated at the site of injection and trigger the same inflammatory reaction and histologic appearance as in systemic immune complex disease. Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection, when the injection site develops visible edema with severe hemorrhage, occasionally fol- lowed by ulceration.

Answer 6

Disease Antigen Involved Clinicopathologic Manifestations Systemic lupus erythematosus Nuclear antigens Nephritis, skin lesions, arthritis, others Poststreptococcal glomerulonephritis Streptococcal cell wall antigen(s); may be “planted” in glomerular basement membrane Nephritis Polyarteritis nodosa Hepatitis B virus antigens in some cases Systemic vasculitis Reactive arthritis Bacterial antigens (e.g., Yersinia) Acute arthritis ``` Serum sickness Various proteins (e.g., foreign serum protein such as horse antithymocyte globulin) ``` Arthritis, vasculitis, nephritis Arthus reaction (experimental) Various foreign proteins Cutaneous vasculitis

Answer 7

The morphologic appearance of immune complex injury is dominated by acute necrotizing vasculitis, microthrombi, and superimposed ischemic necrosis accompanied by acute inflammation of the affected organs. The necrotic vessel wall takes on a smudgy eosinophilic appearance called fibrinoid necrosis, caused by protein deposition (see Fig. 1–13, Chapter 1). Immune complexes can be visualized in the tissues, usually in the vascular wall (examples of such deposits in the kidney in lupus are shown in Fig. 4–18, E). In due course, the lesions tend to resolve, especially when they were brought about by a single exposure to antigen (e.g., in acute serum sickness or acute poststreptococcal glomerulo- nephritis) (Chapter 13). However, chronic immune complex disease develops when there is persistent antigenemia or repeated exposure to an antigen. This occurs in some human diseases, such as systemic lupus erythematosus (SLE). Most often, even though the morphologic changes and other find- ings strongly implicate immune complex disease, the inciting antigens are unknown.

Answer 8

T Cell–Mediated (Type IV) Hypersensitivity Several autoimmune disorders, as well as pathologic reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells (Table 4–5). The occurrence and significance of T lymphocyte–mediated tissue injury have been increasingly appreciated as the methods for detecting and purifying T cells from patients’ circulation and lesions have improved. This group of diseases is of great clinical interest because many of the new, rationally designed biologic therapies for immune-mediated inflam- matory diseases have been developed to target abnormal T cell reactions. Two types of T cell reactions are capable of causing tissue injury and disease: (1) cytokine-mediated inflammation, in which the cytokines are produced mainly by CD4+ T cells, and (2) direct cell cytotoxicity, mediated by CD8+ T cells (Fig. 4–12). In inflammation, exemplified by the delayed-type hypersensitivity (DTH) reaction, CD4+ T cells of the TH1 and TH17 subsets secrete cytokines, which recruit and activate other cells, especially macrophages, and these are the major effector cells of injury. In cell-mediated cytotoxicity, cytotoxic CD8+ T cells are responsible for tissue damage. ``` Inflammatory Reactions Elicited by CD4+ T Cells The sequence of events in T cell–mediated inflammatory reactions begins with the first exposure to antigen and is essentially the same as the reactions of cell-mediated immunity (Fig. 4–4). Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial proteins in association with class II MHC molecules on the surface of DCs (or macrophages) that have processed the antigens. If the DCs produce IL-12, the naive T cells differentiate into effector cells of the TH1 type. The cytokine IFN-γ, made by NK cells and by the TH1 cells themselves, further promotes TH1 dif- ferentiation, providing a powerful positive feedback loop. If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12, the CD4+ cells develop into TH17 effectors. On subsequent exposure to the antigen, the previously generated effector cells are recruited to the site of antigen exposure and are activated by the antigen presented by local APCs. The TH1 cells secrete IFN-γ, which is the most potent macrophage- activating cytokine known. Activated macrophages have increased phagocytic and microbicidal activity. Activated macrophages also express more class II MHC molecules and costimulators, leading to augmented antigen presenta- tion capacity, and the cells secrete more IL-12, thus stimu- lating more TH1 responses. Upon activation by antigen, TH17 effector cells secrete IL-17 and several other cytokines, which promote the recruitment of neutrophils (and mono- cytes) and thus induce inflammation. Because the cyto- kines produced by the T cells enhance leukocyte recruitment and activation, these inflammatory reactions become chronic unless the offending agent is eliminated or the cycle is interrupted therapeutically. In fact, inflammation occurs as an early response to microbes and dead cells (Chapter 2), but it is greatly increased and prolonged when T cells are involved. Delayed-type hypersensitivity (DTH), described next, is an illustrative model of T cell–mediated inflammation and tissue injury. The same reactions are the underlying basis for several diseases. Contact dermatitis is an example of tissue injury resulting from T cell–mediated inflammation. It is evoked by contact with pentadecylcatechol (also known as urushiol, the active component of poison ivy and poison oak, which probably becomes antigenic by binding to a host protein). On reexposure of a previously exposed person to the plants, sensitized TH1 CD4+ cells accumulate in the dermis and migrate toward the antigen within the epidermis. Here they release cytokines that damage kera- tinocytes, causing separation of these cells and formation of an intraepidermal vesicle, and inflammation manifested as a vesicular dermatitis. It has long been thought that several systemic diseases, such as type 1 diabetes and mul- tiple sclerosis, are caused by TH1 and TH17 reactions against self antigens, and Crohn disease may be caused by uncon- trolled reactions involving the same T cells but directed against intestinal bacteria. T cell–mediated inflammation also plays a role in the rejection of transplants, described later in the chapter ```

Answer 9

Delayed-Type Hypersensitivity DTH is a T cell–mediated reaction that develops in response to antigen challenge in a previously sensitized individual. In contrast with immediate hypersensitivity, the DTH reac- tion is delayed for 12 to 48 hours, which is the time it takes for effector T cells to be recruited to the site of antigen chal- lenge and to be activated to secrete cytokines. The classic example of DTH is the tuberculin reaction, elicited by chal- lenge with a protein extract of M. tuberculosis (tuberculin) in a person who has previously been exposed to the tuber- cle bacillus. Between 8 and 12 hours after intracutaneous injection of tuberculin, a local area of erythema and indura- tion appears, reaching a peak (typically 1 to 2 cm in diam- eter) in 24 to 72 hours and thereafter slowly subsiding. On histologic examination, the DTH reaction is characterized by perivascular accumulation (“cuffing”) of CD4+ helper T cells and macrophages (Fig. 4–13). Local secretion of cyto- kines by these cells leads to increased microvascular per- meability, giving rise to dermal edema and fibrin deposition; the latter is the main cause of the tissue induration in these responses. DTH reactions are mediated primarily by TH1 cells; the contribution of TH17 cells is unclear. The tubercu- lin response is used to screen populations for people who have had previous exposure to tuberculosis and therefore have circulating memory T cells specific for mycobacterial proteins. Notably, immunosuppression or loss of CD4+ T cells (e.g., resulting from HIV infection) may lead to a nega- tive tuberculin response even in the presence of a severe infection. Prolonged DTH reactions against persistent microbes or other stimuli may result in a special morphologic pattern of reaction called granulomatous inflammation. The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These accumulated macrophages typically exhibit morphologic evidence of activation; that is, they become large, flat, and eosinophilic, and are called epithelioid cells. The epitheli- oid cells occasionally fuse under the influence of cytokines (e.g., IFN-γ) to form multinucleate giant cells. A micro- scopic aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes, is called a granuloma (Fig. 4–14, A). The process is essentially a chronic form of TH1-mediated inflammation and macrophage activation (Fig. 4–14, B). Older granulomas develop an enclosing rim of fibroblasts and connective tissue. Recognition of a granuloma is of diagnostic importance because of the limited number of conditions that can cause it (Chapter 2). T Cell–Mediated Cytotoxicity In this form of T cell–mediated tissue injury, CD8+ CTLs kill antigen-bearing target cells. As discussed earlier, class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T lymphocytes, stimulat- ing the differentiation of these T cells into effector cells called CTLs. CTLs play a critical role in resistance to virus infections and some tumors. The principal mechanism of killing by CTLs is dependent on the perforin–granzyme system. Perforin and granzymes are stored in the granules of CTLs and are rapidly released when CTLs engage their targets (cells bearing the appropriate class I MHC–bound peptides). Perforin binds to the plasma membrane of the target cells and promotes the entry of granzymes, which are proteases that specifically cleave and thereby activate cellular caspases. These enzymes induce apoptotic death of the target cells (Chapter 1). CTLs play an important role in the rejection of solid-organ transplants and may contribute to many immunologic diseases, such as type 1 diabetes (in which insulin-producing β cells in pancreatic islets are destroyed by an autoimmune T cell reaction). CD8+ T cells may also secrete IFN-γ and contribute to cytokine-mediated inflammation, but less so than CD4+ cells.

Answer 10

Rheumatoid arthritis Collagen?; citrullinated self proteins Inflammation mediated by TH17 (and TH1?)? cytokines; role of antibodies and immune complexes? Chronic arthritis with inflammation, destruction of articular cartilage and bone Multiple sclerosis Protein antigens in myelin (e.g., myelin basic protein) Inflammation mediated by TH1 and TH17 cytokines, myelin destruction by activated macrophages Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions Type 1 diabetes Antigens of pancreatic islet β mellitus cells (insulin, glutamic acid decarboxylase, others) T cell–mediated inflammation, destruction of islet cells by CTLs Insulitis (chronic inflammation in islets), destruction of β cells; diabetes Hashimoto thyroiditis Thyroglobulin, other thyroid proteins Inflammation, CTL-mediated killing of thyroid epithelial cells Hypothyroidism Inflammatory bowel disease Enteric bacteria; self antigens? Inflammation mediated mainly by TH17 cytokines Chronic intestinal inflammation, ulceration, obstruction Autoimmune myocarditis Myosin heavy chain protein CTL-mediated killing of myocardial cells; inflammation mediated by TH1 cytokines Cardiomyopathy Contact sensitivity Various environmental chemicals (e.g., urushiol from poison ivy or poison oak) Inflammation mediated by TH1 (and TH17?) cytokines Epidermal necrosis, dermal inflammation with skin rash and blisters *

Answer 11

Immune reactions to self antigens (i.e., autoimmunity) are the underlying cause of numerous human diseases. Auto- immune diseases currently are estimated to affect 2% to 5% of the population in developed countries, and appear to be increasing in incidence. The evidence that these diseases are indeed the result of autoimmune reactions is more per- suasive for some than for others. For instance, in many of these disorders, multiple high-affinity autoantibodies have been identified, and in some cases these antibodies are known to cause pathologic abnormalities (Table 4–6). Simi- larly, with improving technology, there is growing evi- dence for the activation of pathogenic self-reactive T cells in some of these diseases. In addition, experimental models have proved very informative, providing circumstantial evidence supporting an autoimmune etiology. Neverthe- less, it is fair to say that for many disorders traditionally classified as autoimmune, this etiologic origin is suspected but not proved. Presumed autoimmune diseases range from those in which specific immune responses are directed against one particular organ or cell type and result in localized tissue damage, to multisystem diseases characterized by lesions in many organs and associated with multiple autoantibod- ies or T cell–mediated reactions against numerous self anti- gens. In many of the systemic diseases that are caused by immune complexes and autoantibodies, the lesions affect principally the connective tissue and blood vessels of the various organs involved. Therefore, these diseases are often referred to as “collagen vascular” or “connective tissue” disorders, even though the immunologic reactions are not specifically directed against constituents of connec- tive tissue or blood vessels. Normal persons are unresponsive (tolerant) to their own (self) antigens, and autoimmunity results from a failure of self-tolerance. Therefore, understanding the pathogenesis of autoimmunity requires familiarity with the mechanisms of normal immunologic tolerance. Immunologic Tolerance Immunologic tolerance is unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that antigen. Self- tolerance refers to a lack of immune responsiveness to one’s own tissue antigens. Billions of different antigen receptors are randomly generated in developing T and B lymphocytes, and it is not surprising that during this process, receptors are produced that can recognize self antigens. Since these antigens cannot all be concealed from the immune system, there must be means of eliminating or controlling self-reactive lymphocytes. Several mechanisms work in concert to select against self-reactivity and to thus prevent immune reactions against the body’s own antigens. These mechanisms are broadly divided into two groups: central tolerance and peripheral tolerance (Fig. 4–15). Central tolerance. The principal mechanism of central tol- erance is the antigen-induced deletion (death) of self- reactive T and B lymphocytes during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). In the thymus, many autologous (self) protein antigens are pro- cessed and presented by thymic APCs in association with self MHC. Any immature T cell that encounters such a self antigen undergoes apoptosis (a process called deletion, or negative selection), and the T cells that complete their maturation are thereby depleted of self-reactive cells (Fig. 4–15). An exciting advance has been the identifica- tion of putative transcription factors that induce the expres- sion of peripheral tissue antigens in the thymus, thus making the thymus an immunologic mirror of self. One such factor is called the autoimmune regulator (AIRE); mutations in the AIRE gene are responsible for an autoim- mune polyendocrine syndrome in which T cells specific for multiple self antigens escape deletion (presumably because these self antigens are not expressed in the thymus), and attack tissues expressing the self antigens. Some T cells that encounter self antigens in the thymus are not killed but differentiate into regulatory T cells, as described later. Immature B cells that recognize self antigens with high affinity in the bone marrow also may die by apoptosis. Some self-reactive B cells may not be deleted but may undergo a second round of rearrangement of antigen receptor genes and then express new receptors that are no longer self-reactive (a process called “receptor editing”). Unfortunately, the process of deletion of self-reactive lymphocytes is not perfect. Many self antigens may not be present in the thymus, so T cells bearing receptors for such autoantigens can escape into the periphery. There is similar “slippage” in the B cell system as well, and B cells that bear receptors for a variety of self antigens, including thyro- globulin, collagen, and DNA, can be found in healthy persons. Peripheral tolerance. Self-reactive T cells that escape negative selection in the thymus can potentially wreak havoc unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified (Fig. 4–15): • Anergy:Thistermreferstofunctionalinactivation(rather than death) of lymphocytes induced by encounter with antigens under certain conditions. As described previ- ously, activation of T cells requires two signals: recogni- tion of peptide antigen in association with self MHC molecules on APCs, and a set of second costimulatory signals (e.g., through B7 molecules) provided by the APCs. If the second costimulatory signals are not deliv- ered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self antigen, the T cell becomes anergic and cannot respond to the antigen (Fig. 4–15). Because costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreac- tive T cells and self antigens in tissues may result in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells. • Suppression by regulatory T cells: The responses of T lym- phocytes to self antigens may be actively suppressed by regulatory T cells. The best-defined populations of regu- latory T cells express CD25, one of the chains of the receptor for IL-2, and require IL-2 for their generation and survival. These cells also express a unique transcrip- tion factor called FoxP3. This protein is necessary for the development of regulatory cells, and mutations in the FOXP3 gene are responsible for a systemic autoimmune disease called IPEX (immune dysregulation, polyendo- crinopathy, enteropathy, X-linked syndrome), which is associated with deficiency of regulatory T cells. Several mechanisms have been proposed to explain how regula- tory T cells control immune responses, including secre- tion of immunosuppressive cytokines (e.g., IL-10, transforming growth factor-β [TGF-β]), which can dampen a variety of T cell responses, and competitive blocking of B7 molecules on APCs. • Activation-induced cell death: Another mechanism of peripheral tolerance involves apoptosis of mature lym- phocytes as a result of self-antigen recognition. One mechanism of apoptosis involves the death receptor Fas (a member of the TNF receptor family), which can be engaged by its ligand coexpressed on the same or neigh- boring cells. The same pathway is important for the deletion of self-reactive B cells by Fas ligand expressed on T cells. The importance of this pathway of self- tolerance is illustrated by the discovery that mutations in the FAS gene are responsible for an autoimmune disease called the autoimmune lymphoproliferative syn- drome (ALPS), characterized by lymphadenopathy and multiple autoantibodies including anti-DNA. Defects in Fas and Fas ligand are also the cause of similar autoim- mune diseases in mice. The mitochondrial pathway of apoptosis, which does not depend on death receptors, may also be involved in the elimination of self-reactive lymphocytes.

Answer 12

Mechanisms of Autoimmunity Proceeding from the foregoing summary of the principal mechanisms of self-tolerance, we can ask how these mecha- nisms might break down to give rise to pathologic autoim- munity. Unfortunately, there are no simple answers to this question, and the underlying causes of most human auto- immune diseases remain to be determined. As mentioned earlier, certain mutations can compromise one or another pathway of self-tolerance and cause pathologic autoim- munity. Study of these single-gene mutations is extremely informative, and such research helps to establish the bio- logic significance of the various pathways of self-tolerance. The diseases caused by such mutations are rare, however, and most autoimmune diseases cannot be explained by defects in single genes. It is believed that the breakdown of self-tolerance and devel- opment of autoimmunity result from a combination of inherited susceptibility genes, which influence lymphocyte tolerance, and environmental factors, such as infections or tissue injury, that alter the display of self antigens (Fig. 4–16). Genetic Factors in Autoimmunity There is abundant evidence that susceptibility genes play an important role in the development of autoimmune diseases. • Autoimmune diseases have a tendency to run in fami- lies, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins. • Several autoimmune diseases are linked with the HLA locus, especially class II alleles (HLA-DR, -DQ). The fre- quency of a disease in a person with a particular HLA allele, compared with that in people who do not inherit that allele, is called the odds ratio or relative risk (Table 4–7). The relative risk ranges from 3 or 4 for rheumatoid arthritis (RA) and HLA-DR4 to 100 or more for ankylos- ing spondylitis and HLA-B27. However, how MHC genes influence the development of autoimmunity is still not clear, especially because MHC molecules do not distinguish between self and foreign peptide antigens. It is also worthy of note that most people with a susceptibility-related MHC allele never develop any disease, and, conversely, people without the relevant MHC gene can develop the disease. Expression of a particular MHC gene is therefore but one variable that can contribute to autoimmunity. • Genome-wideassociationstudiesandlinkagestudiesin families are revealing many genetic polymorphisms that are associated with different autoimmune diseases (Table 4–8). Some of these polymorphisms seem to be associated with several diseases, suggesting that the genes involved influence general mechanisms of self- tolerance and immune regulation. Others are disease- specific and may influence end-organ sensitivity or display of particular self antigens. There is great interest in elucidating how these genes contribute to autoim- munity, and many plausible hypotheses have been pro- posed (Table 4–8), but the actual role of these genes in the development of particular autoimmune diseases is not established.

Answer 13

Role of Infections and Tissue Injury A variety of microbes, including bacteria, mycoplasmas, and viruses, have been implicated as triggers for autoim- munity. Microbes may induce autoimmune reactions by several mechanisms Viruses and other microbes may share cross-reacting epitopes with self antigens, such that responses may be induced by the microbe but may attack self tissues. This phenome- non is called molecular mimicry. It is the probable cause of a few diseases, the best example being rheumatic heart disease, in which an immune response against streptococci cross-reacts with cardiac antigens. It is not known if more subtle mimicry plays a role in other auto- immune diseases. • Microbialinfectionswithresultanttissuenecrosisandinflam- mation can cause upregulation of costimulatory molecules on APCs in the tissue, thus favoring a breakdown of T cell anergy and subsequent T cell activation. There is no lack of possible mechanisms to explain how infectious agents might participate in the pathogenesis of autoimmunity. At present, however, no evidence is avail- able that clearly implicates any microbe in the causation of human autoimmune diseases. Adding to the complexity are recent suggestions (based largely on epidemiologic data) that infections may paradoxically protect affected persons from some autoimmune diseases, notably type 1 diabetes and multiple sclerosis. The possible mechanisms underlying this effect are not understood. The display of tissue antigens may be altered by a variety of environmental insults, not only infections. As discussed later, ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens, which elicit patho- logic immune responses in lupus; this mechanism is the proposed explanation for the association of lupus flares with exposure to sunlight. Smoking is a risk factor for RA, perhaps because it leads to chemical modification of self antigens. Local tissue injury for any reason may lead to the release of self antigens and autoimmune responses. Finally, there is a strong gender bias of autoimmunity, with many of these diseases being more common in women than in men. The underlying mechanisms are still not well understood, and may include the effects of hormones and other factors. An autoimmune response may itself promote further autoimmune attack. Tissue injury caused by an autoim- mune response or any other cause may lead to exposure of self antigen epitopes that were previously concealed but are now presented to T cells in an immunogenic form. The activation of such autoreactive T cells is called “epitope spreading,” because the immune response “spreads” to epitopes that were not recognized initially. This is one of the mechanisms that may contribute to the chronicity of autoimmune diseases.

Answer 14

``` Organ-Specific Systemic Diseases Mediated by Antibodies Autoimmune hemolytic anemia Autoimmune thrombocytopenia Autoimmune atrophic gastritis of pernicious anemia Myasthenia gravis Graves disease Goodpasture syndrome ``` Systemic: Systemic lupus erythematosus Diseases Mediated by T Cells* Type 1 diabetes mellitus Multiple sclerosis Hashimoto thyroiditis Crohn disease Systemic: Rheumatoid arthritis, Systemic sclerosis (scleroderma) Sjögren syndrome(systemic for the last two diseases) Diseases Postulated to Be of Autoimmune Origin† Primary biliary cirrhosis -systemic:Polyarteritis nodosa Autoimmune (chronic active) hepatitis - Systemic:Inflammatory myopathies

Answer 15

REJECTION OF TRANSPLANTS The major barrier to transplantation of organs from one individual to another of the same species (called allografts) is immunologic rejection of the transplanted tissue. Rejec- tion is a complex phenomenon involving both cell- and antibody-mediated reactions that destroy the graft. The key to successful transplantation has been the development of therapies that prevent or minimize rejection. Discussed next is how grafts are recognized as foreign and how they are rejected. Immune Recognition of Allografts Rejection of allografts is a response mainly to MHC molecules, which are so polymorphic that most individuals in an outbred population differ in at least some of the MHC molecules they express (except, of course, for identical twins). There are two main mechanisms by which the host immune system recognizes and responds to the MHC mol- ecules on the graft (Fig. 4–23): • Directrecognition.HostTcellsdirectlyrecognizetheallo- geneic (foreign) MHC molecules that are expressed on graft cells. Direct recognition of foreign MHC seems to violate the rule of MHC restriction, which states that in every individual, all of the T cells are educated to recog- nize foreign antigens displayed by only that individual’s MHC molecules. It is postulated that allogeneic MHC molecules (with any bound peptides) structurally mimic self MHC and foreign peptide, and so direct recognition of the allogeneic MHC is essentially an immunologic cross-reaction. Because DCs in the graft express high levels of MHC as well as costimulatory molecules, they are believed to be the major culprits contributing to direct recognition. The most important consequence of direct recognition is the activation of host CD8+ T cells that recognize class I MHC (HLA-A, -B) molecules in the graft. These T cells differentiate into CTLs, which kill the cells in the graft. Host CD4+ helper T cells may be trig- gered into proliferation and cytokine production by rec- ognition of donor class II MHC (HLA-D) molecules and drive an inflammatory response. • Indirect recognition. In this pathway, host CD4+ T cells recognize donor MHC molecules after these molecules are picked up, processed, and presented by the host’s own APCs. This sequence is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens. The activated CD4+ T cells then recognize APCs displaying graft antigens and secrete cytokines that induce inflammation and damage the graft. The indirect pathway is also involved in the pro- duction of antibodies against graft alloantigens; if these antigens are proteins, they are picked up by host B cells, and peptides are presented to helper T cells, which then stimulate antibody responses.

Answer 16

Effector Mechanisms of Graft Rejection Both T cells and antibodies reactive with the graft are involved in the rejection of most solid-organ allografts (Fig. 4–23). T Cell–Mediated Rejection CTLs kill cells in the grafted tissue, causing parenchymal and endothelial cell death (the latter resulting in thrombo- sis and graft ischemia). Cytokine-secreting CD4+ T cells trigger inflammatory reactions resembling DTH in the tissues and blood vessels, with local accumulation of mononuclear cells (lymphocytes and macrophages). Acti- vated microphages can injure graft cells and vasculature. The microvascular injury also results in tissue ischemia, which contributes to graft destruction. Antibody-Mediated Rejection Although T cells are of paramount importance in allograft rejection, antibodies also mediate some forms of rejection. Alloantibodies directed against graft MHC molecules and other alloantigens bind to the graft endothelium and cause vascular injury through complement activation and recruit- ment of leukocytes. Superimposed on the resulting endo- thelial damage and dysfunction is thrombosis, adding further ischemic insult to the injury. Hyperacute rejection is a special form of rejection occur- ring if pre-formed anti-donor antibodies are present in the circulation of the host before transplantation. This may happen in multiparous women who have anti-HLA anti- bodies against paternal antigens encountered during preg- nancy, or in individuals exposed to foreign HLA (on platelets or leukocytes) from previous blood transfusions. Obviously, such antibodies also may be present in a patient who has previously rejected an organ transplant. Subse- quent transplantation in such patients will result in imme- diate rejection (within minutes to hours) because the circulating antibodies rapidly bind to the endothelium of the grafted organ, with resultant complement activation and vascular thrombosis. With the current practice of screening potential recipients for pre-formed anti-HLA antibodies and cross-matching (testing recipients for the presence of antibodies directed against the donor’s lym- phocytes), hyperacute rejection occurs in less than 0.4% of transplant recipients.

Answer 17

On the basis of the time course and morphology of rejection reactions, they have been classified as hyperacute, acute, and chronic (Fig. 4–24). This classification is helpful for under- standing the mechanism of rejection, because each pattern is caused by a different type of dominant immunologic reaction. The morphology of these patterns is described in the context of renal transplants; however, similar changes are encoun- tered in other vascularized organ transplants. Hyperacute Rejection Hyperacute rejection occurs within minutes to a few hours after transplantation in a presensitized host and typically is recognized by the surgeon just after the vascular anastomosis is completed. In contrast with a nonrejecting kidney graft, which regains a normal pink color and tissue turgor and promptly excretes urine, a hyperacutely rejecting kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete only a few drops of bloody fluid. The histologic picture is characterized by widespread acute arteritis and arteriolitis, vessel thrombosis, and ischemic necrosis, all resulting from the binding of preformed antibodies to graft endothelium. Virtually all arterioles and arteries exhibit char- acteristic acute fibrinoid necrosis of their walls, with narrow- ing or complete occlusion of the lumens by precipitated fibrin and cellular debris Acute Rejection Acute rejection may occur within days to weeks of transplan- tation in a nonimmunosuppressed host or may appear months or even years later, even in the presence of adequate immunosuppression. Acute rejection is caused by both cel- lular and humoral immune mechanisms, and in any one patient, one or the other may predominate, or both may be present. On histologic examination, cellular rejection is marked by an interstitial mononuclear cell infiltrate with asso- ciated edema and parenchymal injury, whereas humoral rejection is associated with vasculitis. Acute cellular rejection most commonly is seen within the first months after transplantation and typically is accom- panied by clinical signs of renal failure. Histologic examination usually shows extensive interstitial CD4+ and CD8+ T cell infiltration with edema and mild interstitial hemorrhage (Fig. 4–24, B). Glomerular and peritubular capillaries contain large numbers of mononuclear cells, which also may invade the tubules, leading to focal tubular necrosis. In addition to tubular injury, CD8+ T cells also may injure the endothelium, causing an endothelitis. Cyclosporine (a widely used immu- nosuppressive agent) is also nephrotoxic and induces so- called arteriolar hyaline deposits. Renal biopsy is used to distinguish rejection from drug toxicity. Accurate recogni- tion of cellular rejection is important, because patients typi- cally respond promptly to increased immunosuppressive therapy. Acute humoral rejection (rejection vasculitis) caused by antidonor antibodies also may participate in acute graft rejection. The histologic lesions may take the form of necro- tizing vasculitis with endothelial cell necrosis; neutrophilic infiltration; deposition of antibody, complement, and fibrin; and thrombosis. Such lesions may be associated with isch- emic necrosis of the renal parenchyma. Somewhat older subacute lesions are characterized by marked thickening of the intima by proliferating fibroblasts, myocytes, and foamy macrophages (Fig. 4–24, C). The resultant narrowing of the arterioles may cause infarction or renal cortical atrophy. The proliferative vascular lesions mimic arteriosclerotic thickening and are believed to be caused by cytokines that stimulate proliferation of vascular smooth muscle cells. Local deposi- tion of complement breakdown products (specifically C4d) is used to detect antibody-mediated rejection of kidney allografts. Chronic Rejection Patients present with chronic rejection late after transplanta- tion (months to years) with a progressive rise in serum cre- atinine levels (an index of renal function) over a period of 4 to 6 months. Chronic rejection is dominated by vascular changes, interstitial fibrosis, and loss of renal parenchyma; there are typically only mild or no ongoing cellular parenchy- mal infiltrates. The vascular changes occur predominantly in the arteries and arterioles, which exhibit intimal smooth muscle cell proliferation and extracellular matrix synthesis (Fig. 4–24, D). These lesions ultimately compromise vascular perfusion and result in renal ischemia manifested by loss or hyalinization of glomeruli, interstitial fibrosis, and tubular atrophy. The vascular lesion may be caused by cytokines released by activated T cells that act on the cells of the vas- cular wall, and it may be the end stage of the proliferative arteritis described earlier.

Answer 18

Immune deficiency diseases may be caused by inherited defects affecting immune system development, or they may result from secondary effects of other diseases (e.g., infection, malnutrition, aging, immunosuppression, autoimmunity, or chemotherapy). Clinically, patients with immune deficiency present with increased susceptibility to infec- tions as well as to certain forms of cancer. The type of infec- tions in a given patient depends largely on the component of the immune system that is affected. Patients with defects in immunoglobulin, complement, or phagocytic cells typi- cally suffer from recurrent infections with pyogenic bacte- ria, whereas those with defects in cell-mediated immunity are prone to infections caused by viruses, fungi, and intra- cellular bacteria. Discussed next are some of the more important primary (congenital) immune deficiencies, fol- lowed by a detailed description of the acquired immuno- deficiency syndrome (AIDS), the most devastating example of secondary (acquired) immune deficiency. Primary (Congenital) Immune Deficiencies Primary immune deficiency states are fortunately rare, but their study has nevertheless contributed greatly to the current understanding of the development and function of the immune system. Most primary immune deficiency diseases are genetically determined and affect either adap- tive immunity (i.e., humoral or cellular) or innate host defense mechanisms, including complement proteins and cells such as phagocytes and NK cells. Defects in adaptive immunity are often subclassified on the basis of the primary component involved (i.e., B cells or T cells, or both); however, because of the interactions between T and B lym- phocytes, these distinctions are not clear-cut. For instance, T cell defects frequently lead to impaired antibody synthe- sis, and hence isolated deficiencies of T cells may be indis- tinguishable from combined deficiencies of T and B cells. Most primary immune deficiencies come to attention early in life (between the ages of 6 months and 2 years), usually because the affected infants are susceptible to recurrent infections. One of the most impressive accomplishments of modern molecular biology has been the identification of the genetic basis for many primary immune deficiencies (Fig. 4–25), laying the foundation for future gene replace- ment therapy.

Answer 19

Amyloidosis is a disorder characterized by the extracel- lular deposits of misfolded proteins that aggregate to form insoluble fibrils. • The deposition of these proteins may result from exces- sive production of proteins that are prone to misfolding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; or defective or incomplete proteolytic degradation of extracellular proteins. • Amyloidosis may be localized or systemic. It is seen in association with a variety of primary disorders, including monoclonal plasma cell proliferations (in which the amyloid deposits consist of immunoglobulin light chains); chronic inflammatory diseases such as RA (deposits of amyloid A protein, derived from an acute-phase protein produced in inflammation); Alzheimer disease (amyloid B protein); familial conditions in which the amyloid deposits consist of mutants of normal proteins (e.g., transthyretin in familial amyloid polyneuropathies); amyloidosis associ- ated with dialysis (deposits of β2-microglobulin, whose clearance is defective). • Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues.They do not evoke an inflammatory response.