《免疫学》（英文版） Chapter 20 Autoimmunity

Autoimmunity chapter 20 ARLY IN THE LAST CENTURY, PAUL EHRLICH realized that the immune system could go awry and, instead of reacting against foreign antigens, could focus its attack on self-antigens. He termed this con- dition"horror autotoxicus "We now understand that while mechanisms of self-tolerance normally protect an individual from potentially self-reactive lymphocytes, there are failures They result in an inappropriate response of the immune system against self-components termed autoimmunity In the 1960s, it was believed that all self-reactive lymphocytes were eliminated during their development in the bone mar row and thymus and that a failure to eliminate these lym- Kidney Biopsy from Goodpasture's Syndrone phocytes led to autoimmune consequences. Since the late 1970s, a broad body of experimental evidence has countered Organ-Specific Autoimmune Diseases that belief, revealing that not all self-reactive lymphocytes are deleted during T-cell and B-cell maturation. Instead, a Systemic Autoimmune Diseases normal healthy individuals have been shown to possess ma- Animal Models for autoimmune diseases ture, recirculating, self-reactive lymphocytes. Since the pres- ence of these self-reactive lymphocytes in the periphery does a Evidence Implicating the CD4+ T Cell, MHC. not inevitably result in autoimmune reactions, their activity and TCR in Autoimmunity must be regulated in normal individuals through clonal a Proposed Mechanisms for Induction of anergy or clonal suppression. a breakdown in this regulation can lead to activation of self-reactive clones of t or b cells Autoimmunity generating humoral or cell-mediated responses against self- a Treatment of Autoimmune Diseases antigens. These reactions can cause serious damage to cells and organs, sometimes with fatal consequences Sometimes the damage to self-cells or organs is caused by antibodies; in other cases, T cells are the culprit For exam ple, a common form of autoimmunity is tissue injury by mechanisms similar to type II hypersensitivity reactions. As mune diseases. These can be divided into two broad cate- Chapter 16 showed, type II hypersensitivity reactions in- volve antibody-mediated destruction of cells. Autoimmune gories: organ-specific and systemic autoimmune disease (Table 20-1). Such diseases affect 5%-7% of the human pop- hemolytic anemia is an excellent example of such an autoim- ulation, often causing chronic debilitating illnesses. Several recognized by auto-antibodies, which results in the destruc experimental animal models used to study autoimmunity and various mechanisms that may contribute to induction tion of the blood cells, which in turn results in anemia. auto- of autoimmune reactions also are described. Finally, current antibodies are also the major offender in Hashimotos thy- and experimental therapies for treating autoimmune dis roiditis, in which antibodies reactive with tissue-specific eases are described ntigens such as thyroid peroxidase and thyroglobulin cause severe tissue destruction Other autoimmune diseases that involve auto-antibodies are listed in table 20-1 Many autoimmune diseases are characterized by tissue Organ-Specific Autoimmune struction mediated directly by T cells. A well-known ex- Diseases ample is rheumatoid arthritis, in which self-reactive T cells attack the tissue in joints, causing an inflammatory response In an organ-specific autoimmune disease, the immune re hat results in swelling and tissue destruction. Other exam- sponse is directed to a target antigen unique to a single organ ples include insulin-dependent diabetes mellitus and multi- or gland, so that the manifestations are largely limited to that ple sclerosis(see Table 20-1) organ. The cells of the target organs may be damaged di-

■ Organ-Specific Autoimmune Diseases ■ Systemic Autoimmune Diseases ■ Animal Models for Autoimmune Diseases ■ Evidence Implicating the CD4+ T Cell, MHC, and TCR in Autoimmunity ■ Proposed Mechanisms for Induction of Autoimmunity ■ Treatment of Autoimmune Diseases Autoimmunity     ,   realized that the immune system could go awry and, instead of reacting against foreign antigens, could focus its attack on self-antigens. He termed this con￾dition “horror autotoxicus.” We now understand that, while mechanisms of self-tolerance normally protect an individual from potentially self-reactive lymphocytes, there are failures. They result in an inappropriate response of the immune system against self-components termed autoimmunity. In the 1960s, it was believed that all self-reactive lymphocytes were eliminated during their development in the bone mar￾row and thymus and that a failure to eliminate these lym￾phocytes led to autoimmune consequences. Since the late 1970s, a broad body of experimental evidence has countered that belief, revealing that not all self-reactive lymphocytes are deleted during T-cell and B-cell maturation. Instead, normal healthy individuals have been shown to possess ma￾ture, recirculating, self-reactive lymphocytes. Since the pres￾ence of these self-reactive lymphocytes in the periphery does not inevitably result in autoimmune reactions, their activity must be regulated in normal individuals through clonal anergy or clonal suppression. A breakdown in this regulation can lead to activation of self-reactive clones of T or B cells, generating humoral or cell-mediated responses against self￾antigens. These reactions can cause serious damage to cells and organs, sometimes with fatal consequences. Sometimes the damage to self-cells or organs is caused by antibodies; in other cases, T cells are the culprit. For exam￾ple, a common form of autoimmunity is tissue injury by mechanisms similar to type II hypersensitivity reactions. As Chapter 16 showed, type II hypersensitivity reactions in￾volve antibody-mediated destruction of cells. Autoimmune hemolytic anemia is an excellent example of such an autoim￾mune disease. In this disease, antigens on red blood cells are recognized by auto-antibodies, which results in the destruc￾tion of the blood cells, which in turn results in anemia. Auto￾antibodies are also the major offender in Hashimoto’s thy￾roiditis, in which antibodies reactive with tissue-specific antigens such as thyroid peroxidase and thyroglobulin cause severe tissue destruction. Other autoimmune diseases that involve auto-antibodies are listed in Table 20-1. Many autoimmune diseases are characterized by tissue destruction mediated directly by T cells. A well-known ex￾ample is rheumatoid arthritis, in which self-reactive T cells attack the tissue in joints, causing an inflammatory response that results in swelling and tissue destruction. Other exam￾ples include insulin-dependent diabetes mellitus and multi￾ple sclerosis (see Table 20-1). This chapter describes some common human autoim￾mune diseases. These can be divided into two broad cate￾gories: organ-specific and systemic autoimmune disease (Table 20-1). Such diseases affect 5%–7% of the human pop￾ulation, often causing chronic debilitating illnesses. Several experimental animal models used to study autoimmunity and various mechanisms that may contribute to induction of autoimmune reactions also are described. Finally, current and experimental therapies for treating autoimmune dis￾eases are described. Organ-Specific Autoimmune Diseases In an organ-specific autoimmune disease, the immune re￾sponse 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 di￾chapter 20 Kidney Biopsy from Goodpasture’s Syndrone E

Autoimmunity CHAPTER 20 TABLE 20-1 Some autoimmune diseases in humans Disease Self-antige Immune response ORGAN-SPECIFIC AUTOIMMUNE DISEASES Adrenal cells Auto-antibodies Autoimmune hemolytic anemia RBC membrane proteins Auto-antibodies Goodpasture's syndrome Renal and lung basement membranes Auto-antibodies Graves'disease Thyroid-stimulating hormone receptor Auto-antibody(stimulating) Hashimoto's thyroiditis Thyroid proteins and cells Idiopathic thrombocyopenia purpura Platelet membrane proteins Auto-antibodies Insulin-dependent diabetes mellitus Pancreatic beta cells Toru cells, auto-antibodies asthenia gravis Acetylcholine receptors Auto-antibody(blocking) Myocardial infarction Heart Auto-antibodies Perni anemla Gastric parietal cells; intrinsic factor Auto-antibody Poststreptococcal glomerulonephritis Kidney Antigen-antibody complexes Spontaneous infertility Sperm Auto-antibodies SYSTEMIC AUTOIMMUNE DISEASES Ankylosing sponkylitis vertebrae Immune complexes Multipl Brain or white matter THI cells and Tc cells, auto-antibodies arthritis Connective tissue, IgG Auto-antibodies, immune complexe Scleroderma Nuclei, heart, lungs, gastrointestinal tract, kidney Auto-antibodies Sjogrens syndrome Salivary gland, liver, kidney, thyroid Auto-antibodies Systemic lupus erythematosus(SLE) DNA, nuclear protein, RBC and platelet membranes Auto-antibodies, immune complexes rectly by humoral or cell-mediated effector mechanisms. and sensitized THl cells specific for thyroid antigens. The Alternatively, the antibodies may overstimulate or block the DTH response is characterized by an intense infiltration of normal function of the target organ. the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers (Figure 20-1). The ensuing inflammatory response causes a Some autoimmune Diseases are goiter, or visible enlargement of the thyroid gland, a phs c Mediated by Direct Cellular Damage to a number of thyroid proteins, including thyroglobulin and Autoimmune diseases involving direct cellular damage occur thyroid peroxidase, both of which are involved in the uptake when lymphocytes or antibodies bind to cell-membrane an- of iodine. Binding of the auto-antibodies to these proteins tigens, causing cellular lysis and/or an inflammatory response interferes with iodine uptake and leads to decreased produc in the affected organ. Gradually, the damaged cellular struc- tion of thyroid hormones(hypothyroidism) ture is replaced by connective tissue(scar tissue), and the fund tion of the organ declines. This section briefly describes a few AUTOIMMUNE ANEMIAS examples of this type of autoimmune disease Autoimmune anemias include pernicious anemia, autoim HASHIMOTO'S THYROIDITIS mune hemolytic anemia, and drug-induced hemolytic mia Pernicious anemia is caused by auto-antibodies to intrin- In Hashimoto's thyroiditis, which is most frequently seen in sic factor, a membrane-bound intestinal protein on gastric middle-aged women, an individual produces auto-antibodies parietal cells. Intrinsic factor facilitates uptake of vitamin B12

rectly by humoral or cell-mediated effector mechanisms. Alternatively, the antibodies may overstimulate or block the normal function of the target organ. Some Autoimmune Diseases Are Mediated by Direct Cellular Damage Autoimmune diseases involving direct cellular damage occur when lymphocytes or antibodies bind to cell-membrane an￾tigens, causing cellular lysis and/or an inflammatory response in the affected organ. Gradually, the damaged cellular struc￾ture is replaced by connective tissue (scar tissue), and the func￾tion of the organ declines. This section briefly describes a few examples of this type of autoimmune disease. HASHIMOTO’S THYROIDITIS In Hashimoto’s thyroiditis, which is most frequently seen in middle-aged women, an individual produces auto-antibodies and sensitized TH1 cells specific for thyroid antigens. The DTH response is characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers (Figure 20-1). The ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physio￾logical response to hypothyroidism. 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 produc￾tion of thyroid hormones (hypothyroidism). AUTOIMMUNE ANEMIAS Autoimmune anemias include pernicious anemia, autoim￾mune hemolytic anemia, and drug-induced hemolytic ane￾mia. Pernicious anemia is caused by auto-antibodies to intrin￾sic factor, a membrane-bound intestinal protein on gastric parietal cells. Intrinsic factor facilitates uptake of vitamin B12 Autoimmunity CHAPTER 20 463 TABLE 20-1 Some autoimmune diseases in humans Disease Self-antigen Immune response ORGAN-SPECIFIC AUTOIMMUNE DISEASES Addison’s disease Adrenal cells Auto-antibodies Autoimmune hemolytic anemia RBC membrane proteins Auto-antibodies Goodpasture’s syndrome Renal and lung basement membranes Auto-antibodies Graves’ disease Thyroid-stimulating hormone receptor Auto-antibody (stimulating) Hashimoto’s thyroiditis Thyroid proteins and cells TDTH cells, auto-antibodies Idiopathic thrombocyopenia purpura Platelet membrane proteins Auto-antibodies Insulin-dependent diabetes mellitus Pancreatic beta cells TDTH cells, auto-antibodies Myasthenia gravis Acetylcholine receptors Auto-antibody (blocking) Myocardial infarction Heart Auto-antibodies Pernicious anemia Gastric parietal cells; intrinsic factor Auto-antibody Poststreptococcal glomerulonephritis Kidney Antigen-antibody complexes Spontaneous infertility Sperm Auto-antibodies SYSTEMIC AUTOIMMUNE DISEASES Ankylosing sponkylitis Vertebrae Immune complexes Multiple sclerosis Brain or white matter TH1 cells and TC cells, auto-antibodies Rheumatoid arthritis Connective tissue, IgG Auto-antibodies, immune complexes Scleroderma Nuclei, heart, lungs, gastrointestinal tract, kidney Auto-antibodies Sjogren’s syndrome Salivary gland, liver, kidney, thyroid Auto-antibodies Systemic lupus erythematosus (SLE) DNA, nuclear protein, RBC and platelet membranes Auto-antibodies, immune complexes

464 PART I The Immune System in Health and Disease URE 20-1 Photomicrographs of (a)normal thyroid gland show- Hashimoto's thyroiditis showing intense lymphocyte infiltration / From follicle lined by cuboidal follicular epithelial cells and (b) gland in Web Path, courtesy of E. C Klatt, University of Utah from the small intestine. Binding of the auto-antibody to INSULIN-DEPENDENT DIABETES MELLITUS intrinsic factor blocks the intrinsic factor-mediated absorp- A disease afflicting 0.2% of the population, insulin-dependent tion of vitamin Biz. In the absence of suficient vitamin B12, diabetes mellitus (IDDM) is caused by an autoimmune which is necessary for proper hematopoiesis, the number of attack on the pancreas. The attack is directed against special- functional mature red blood cells decreases below normal. ized insulin-producing cells(beta cells)that are located in Pernicious anemia is treated with injections of vitamin B12, spherical clusters, called the islets of Langerhans, scattered thus circumventing the defect in its absorption An individual with autoimmune hemolytic anemia makes beta cells, resulting in decreased production of insulin and auto-antibody to RBC antigens, triggering complement consequently increased levels of blood glucose. Several factor mediated lysis or antibody-mediated opsonization and phago- are important in the destruction of beta cells. First, activated cytosis of the red blood cells. One form of autoimmune ane- CTLs migrate into an islet and begin to attack the insulin mia is drug-induced: when certain drugs such as penicillin or producing cells. Local cytokine production during this the anti-hypertensive agent methyldopa interact with red blood cells, the cells become antigenic. The immunodiag nostic test for autoimmune hemolytic anemias generally involves a Coombs test, in which the red cells are incubated with an anti-human igg antiserum. If IgG auto-antibodies are present on the red cells, the cells are agglutinated by the antiserum GOODPASTURE'S SYNDROME In Goodpasture's syndrome, auto-antibodies specific for certain basement-membrane antigens bind to the basement membranes of the kidney glomeruli and the alveoli of the lungs. Subsequent complement activation leads to direct cel lular damage and an ensuing inflammatory response medi ated by a buildup of complement split products. Damage to terular 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 Goodpasture's syn- FIGURE 20-2 Fluorescent anti-IgG staining of a kidney biopsy drome stained with fluorescent-labeled anti-IgG and anti- from a patient with Goodpasture's syndrome reveals linear deposits 3b reveal linear deposits of IgG and C3b along the base- of auto-antibody along the basement membrane. / From Web Path, ment membranes(Figure 20-2 courtesy of E. C. Klatt, University of Utah. j

from the small intestine. Binding of the auto-antibody to intrinsic factor blocks the intrinsic factor–mediated absorp￾tion of vitamin B12. In the absence of sufficient vitamin B12, which is necessary for proper hematopoiesis, the number of functional mature red blood cells decreases below normal. Pernicious anemia is treated with injections of vitamin B12, thus circumventing the defect in its absorption. An individual with autoimmune hemolytic anemia makes auto-antibody to RBC antigens, triggering complement￾mediated lysis or antibody-mediated opsonization and phago￾cytosis of the red blood cells. One form of autoimmune ane￾mia is drug-induced: when certain drugs such as penicillin or the anti-hypertensive agent methyldopa interact with red blood cells, the cells become antigenic. The immunodiag￾nostic test for autoimmune hemolytic anemias generally involves a Coombs test, in which the red cells are incubated with an anti–human IgG antiserum. If IgG auto-antibodies are present on the red cells, the cells are agglutinated by the antiserum. GOODPASTURE’S SYNDROME In Goodpasture’s syndrome, auto-antibodies specific for certain basement-membrane antigens bind to the basement membranes of the kidney glomeruli and the alveoli of the lungs. Subsequent complement activation leads to direct cel￾lular damage and an ensuing inflammatory response medi￾ated 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 Goodpasture’s syn￾drome stained with fluorescent-labeled anti-IgG and anti￾C3b reveal linear deposits of IgG and C3b along the base￾ment membranes (Figure 20-2). 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 special￾ized 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. Several factors are important in the destruction of beta cells. First, activated CTLs migrate into an islet and begin to attack the insulin￾producing cells. Local cytokine production during this 464 PART IV The Immune System in Health and Disease (a) (b) FIGURE 20-1 Photomicrographs of (a) normal thyroid gland show￾ing a follicle lined by cuboidal follicular epithelial cells and (b) gland in Hashimoto’s thyroiditis showing intense lymphocyte infiltration. [From Web Path, courtesy of E. C. Klatt, University of Utah.] FIGURE 20-2 Fluorescent anti-IgG staining of a kidney biopsy from a patient with Goodpasture’s syndrome reveals linear deposits of auto-antibody along the basement membrane. [From Web Path, courtesy of E. C. Klatt, University of Utah.]

Autoimmunity CHAPTER 20 465 (a) FIGURE 20-3 Photomicrographs of an islet of Langerhans(a)in the lymphocyte infiltration into the islet(insulitis)in(b).[From MA pancreas from a normal mouse and (b)one in pancreas from a mouse Atkinson and N K Maclaren, 1990, Sci. Am. 263(1): 62/ with a disease resembling insulin-dependent diabetes mellitus. Note response includes IFN-Y, TNF-a, and IL-1. Auto-antibody and stimulating inappropriate activity. This usually leads to production can also be a contributing factor in IDDM. The an overproduction of mediators or an increase in cell growth. first CTL infiltration and activation of macrophages, fre- Conversely, auto-antibodies may act as antagonists, binding quently referred to as insulitis(Figure 20-3), is followed by hormone receptors but blocking receptor function. This gen- leads to a cell-mediated DTH response. The subsequent atrophy of the affected oral h of mediators and gradual cytokine release and the presence of auto-antibodies, which erally causes impaired secretio beta-cell destruction is thought to be mediated by cytokines leased during the dth response and by lytic enzymes GRAVES DISEASE released from the activated macrophages. Auto-antibodies to The production of thyroid hormones is carefully regulated by beta cells may contribute to cell destruction by facilitatin thyroid-stimulating hormone (TSH), which is produced by either antibody-plus-complement lysis or antibody-dependent the pituitary gland. Binding of tsH to a receptor on thyroid cell-mediated cytotoxicity (ADCC) cells activates adenylate cyclase and stimulates the synthesis of The abnormalities in glucose metabolism that are caused two thyroid hormones, thyroxine and triodothyronine. a by the destruction of islet beta cells result in serious meta- patient with Graves'disease produces auto-antibodies that bolic problems that include ketoacidosis and increased urine bind the receptor for tSh and mimic the normal action of production. The late stages of the disease are often character- TSH, activating adenylate cyclase and resulting in produc- ized by atherosclerotic vascular lesions-which in turn cause tion of the thyroid hormones. Unlike TSH, however, the auto gangrene of the extremities due to impeded vascular flow- antibodies are not regulated, and consequently they over- renal failure, and blindness. If untreated, death can result. stimulate the thyroid. For this reason these auto-antibodies The most common therapy for diabetes is daily administra- are called long-acting thyroid-stimulating(LATSantibod- tion of insulin. This is quite helpful in managing the disease, ies(Figure 20-4) but, because sporadic doses are not the same as metabolically regulated continuous and controlled release of the hormone, MYASTHENIA GRAVIS periodically injected doses of insulin do not totally alleviate Myasthenia gravis is the prototype autoimmune disease the problems caused by the disease. Another complicating mediated by blocking antibodies. a patient with this disease feature of diabetes is that the disorder can go undetected for produces auto-antibodies that bind the acetylcholine recep several years, allowing irreparable loss of pancreatic tissue to tors on the motor end-plates of muscles, blocking the normal occur before treatment begins binding of acetylcholine and also inducing complement mediated lysis of the cells. The result is a progressive weaken- Some autoimmune diseases are mediated ing of the skeletal muscles( Figure 20-5). Ultimately, the anti- by Stimulating or Blocking Auto-Antibodies bodies destroy the cells bearing the receptors. The early signs of this disease include drooping eyelids and inability to In some autoimmune diseases, antibodies act as agonists, retract the corners of the mouth, which gives the appearance binding to hormone receptors in lieu of the normal ligand of snarling. Without treatment, progressive weakening of the

response includes IFN-, TNF-, and IL-1. Auto-antibody production can also be a contributing factor in IDDM. The first CTL infiltration and activation of macrophages, fre￾quently referred to as insulitis (Figure 20-3), is followed by cytokine release and the presence of auto-antibodies, which leads to a cell-mediated DTH response. The subsequent beta-cell destruction is thought to be mediated by cytokines released during the DTH response and by lytic enzymes released from the activated macrophages. Auto-antibodies to beta cells may contribute to cell destruction by facilitating either antibody-plus-complement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC). The abnormalities in glucose metabolism that are caused by the destruction of islet beta cells result in serious meta￾bolic problems that include ketoacidosis and increased urine production. The late stages of the disease are often character￾ized by atherosclerotic vascular lesions—which in turn cause gangrene of the extremities due to impeded vascular flow— renal failure, and blindness. If untreated, death can result. The most common therapy for diabetes is daily administra￾tion of insulin. This is quite helpful in managing the disease, but, because sporadic doses are not the same as metabolically regulated continuous and controlled release of the hormone, periodically injected doses of insulin do not totally alleviate the problems caused by the disease. Another complicating feature of diabetes is that the disorder can go undetected for several years, allowing irreparable loss of pancreatic tissue to occur before treatment begins. Some Autoimmune Diseases Are Mediated by Stimulating or Blocking Auto-Antibodies In some autoimmune diseases, antibodies act as agonists, binding to hormone receptors in lieu of the normal ligand and stimulating inappropriate activity. This usually leads to an overproduction of mediators or an increase in cell growth. Conversely, auto-antibodies may act as antagonists, binding hormone receptors but blocking receptor function. This gen￾erally causes impaired secretion of mediators and gradual atrophy of the affected organ. GRAVES’ DISEASE The production of thyroid hormones is carefully regulated by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones, thyroxine and triiodothyronine. A patient with Graves’ disease produces auto-antibodies that bind the receptor for TSH and mimic the normal action of TSH, activating adenylate cyclase and resulting in produc￾tion of the thyroid hormones. Unlike TSH, however, the auto￾antibodies are not regulated, and consequently they over￾stimulate the thyroid. For this reason these auto-antibodies are called long-acting thyroid-stimulating (LATS) antibod￾ies (Figure 20-4). MYASTHENIA GRAVIS Myasthenia gravis is the prototype autoimmune disease mediated by blocking antibodies. A patient with this disease produces auto-antibodies that bind the acetylcholine recep￾tors on the motor end-plates of muscles, blocking the normal binding of acetylcholine and also inducing complement￾mediated lysis of the cells. The result is a progressive weaken￾ing of the skeletal muscles (Figure 20-5). Ultimately, the anti￾bodies destroy the cells bearing the receptors. The early signs of this disease include drooping eyelids and inability to retract the corners of the mouth, which gives the appearance of snarling. Without treatment, progressive weakening of the Autoimmunity CHAPTER 20 465 (a) (b) FIGURE 20-3 Photomicrographs of an islet of Langerhans (a) in pancreas from a normal mouse and (b) one in pancreas from a mouse with a disease resembling insulin-dependent diabetes mellitus. Note the lymphocyte infiltration into the islet (insulitis) in (b). [From M. A. Atkinson and N. K. Maclaren, 1990, Sci. Am. 263(1):62.]

PART IV The Immune System in Health and Disease STIMULATING AUTO-ANTIBODIES (Graves'disease) Systemic Autoimmune Diseases In systemic autoimmune diseases, the response is directed Pituitary gland Auto-antibody toward a broad range of target antigens and involves a num- ber of organs and tissues. These diseases reflect a general de- fect in immune regulation that results in hyperactive T cells TSH receptor and B cells. Tissue damage is widespread, both from cell mediated immune responses and from direct cellular dam age caused by auto-antibodies or by accumulation of im Stimulate mune complexes Systemic Lupus Erythematosus Attacks Many Tiss One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus(SLE), which typically appears Regulated production of Unregulated overproduction in women between 20 and 40 years of age: the ratio of female of thyroid hormones to male patients is 10: 1. SLE is characterized by fever, weak ness, arthritis, skin rashes, pleurisy, and kidney dysfunction FIGURE 20-4 In Graves'disease, binding of auto-antibodies to the (Figure 20-6). Lupus is more frequent in African-American eceptor for thyroid-stimulating hormone(TSH)induces unregu- and Hispanic women than in Caucasians, although it is not lated activation of the thyroid, leading to overproduction of the thy- known why this is so. Affected individuals may produce auto- roid hormones(purple dots) antibodies to a vast array of tissue antigens, such as DNA, his tones, RBCs, platelets, leukocytes, and clotting factors; inter- action of these auto-antibodies with their specific antigens produces various symptoms. Auto-antibody specific for RBCs muscles can lead to severe impairment of eating as well as and platelets, for example, can lead to complement-mediated problems with movement. However, with appropriate treat- lysis, resulting in hemolytic anemia and thrombocytopenia, ment, this disease can be managed quite well and afflicted respectively. When immune complexes of auto-antibodies individuals can lead a normal life with various nuclear antigens are deposited along the walls of BLOCKING AUTO-ANTIBODIES (Myasthenia gravis) Nerve Acetylcholine 2 AChR Muscle activation Muscle activation inhibited GURE 20-5 In myasthenia gravis, binding of auto-antibodies to addition, the anti-AChR auto-antibody activates complement, which the acetylcholine receptor (right) blocks the normal binding of acetyl- damages the muscle end-plate the number of acetylcholine receptors choline(burgandy dots)and subsequent muscle activation (left). In declines as the disease progresses. AChR= acetylcholine receptor

muscles can lead to severe impairment of eating as well as problems with movement. However, with appropriate treat￾ment, this disease can be managed quite well and afflicted individuals can lead a normal life. Systemic Autoimmune Diseases In systemic autoimmune diseases, the response is directed toward a broad range of target antigens and involves a num￾ber of organs and tissues. These diseases reflect a general de￾fect 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 dam￾age caused by auto-antibodies or by accumulation of im￾mune complexes. Systemic Lupus Erythematosus Attacks Many Tissues 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, weak￾ness, arthritis, skin rashes, pleurisy, and kidney dysfunction (Figure 20-6). Lupus is more frequent in African-American and Hispanic women than in Caucasians, although it is not known why this is so. Affected individuals may produce auto￾antibodies to a vast array of tissue antigens, such as DNA, his￾tones, RBCs, platelets, leukocytes, and clotting factors; inter￾action of these auto-antibodies with their specific antigens produces various symptoms. Auto-antibody specific for RBCs and platelets, for example, can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively. When immune complexes of auto-antibodies with various nuclear antigens are deposited along the walls of 466 PART IV The Immune System in Health and Disease STIMULATING AUTO-ANTIBODIES (Graves’ disease) Pituitary gland TSH TSH receptor Thyroid cell Stimulates hormone synthesis Auto-antibody to receptor Regulated production of thyroid hormones Unregulated overproduction of thyroid hormones Negative feedback control Stimulates hormone synthesis BLOCKING AUTO-ANTIBODIES (Myasthenia gravis) Nerve Nerve Acetylcholine Muscle cell AChR Auto-antibody to AChR Muscle activation Muscle activation inhibited FIGURE 20-4 In Graves’ disease, binding of auto-antibodies to the receptor for thyroid-stimulating hormone (TSH) induces unregu￾lated activation of the thyroid, leading to overproduction of the thy￾roid hormones (purple dots). FIGURE 20-5 In myasthenia gravis, binding of auto-antibodies to the acetylcholine receptor (right) blocks the normal binding of acetyl￾choline (burgandy dots) and subsequent muscle activation (left). In addition, the anti-AChR auto-antibody activates complement, which damages the muscle end-plate; the number of acetylcholine receptors declines as the disease progresses. AChR = acetylcholine receptor