《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

Autoimmunity CHAPTER 20 with active MS contains activated T lymphocytes, which infiltrate the brain tissue and cause characteristic inflamma- tory lesions, destroying the myelin. Since myelin functions to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous neurologic dysfunctions Epidemiological studies indicate that Ms is most com mon in the Northern hemisphere and, interestingly, in the United States. Populations who live north of the 37th parallel dence of 11 who live south of the 37th parallel show a prevalence of 57-78 per 100,000 And individuals from south of the 37th parallel who move north assume a new risk if the move occurs before 15 years of age. These provocative data suggest that there is an environmental component of the risk of con- tracting MS. This is not the entire story, however, since genetic influences also are important. While the average per son in the united states has about one chance in 1000 of FIGURE 20-6 Characteristic"butterfly" rash over the cheeks of a developing MS, close relatives of people with MS, such as young girl with systemic lupus erythematosus /From L. Steinman, children or siblings, have 1 chance in 50 to 100 of developing 1993ScAm.2693)80J MS. The identical twin of a person with ms has a 1 in 3 chance of developing the disease. These data point strongly to the genetic component of the disease. And, as is described small blood vessels, a type III hypersensitive reaction devel in the Clinical Focus of this chapter, MS affects women two ops. The complexes activate the complement system and to three times more frequently than men generate membrane-attack complexes and complement split well understood. However, there are some suggestions that in vasculitis and glomerulonephritis l, resulting infection by certain viruses may predispose a person to MS Excessive complement activation in patients with seve Certainly some viruses can cause demyelinating diseases, and SLE produces elevated serum levels of the complement split it is tempting to speculate that virus infection plays a signifi products C3a and C5a, which may be three to four times cant role in MS, but at present there is no definitive data higher than normal. C5a induces increased expression of the Implicating a particular virus type 3 complement receptor(CR3)on neutrophils, facilitat ing neutrophil aggregation and attachment to the vascular Rheumatoid Arthritis Attacks joints endothelium As neutrophils attach to small blood vessels, the Rheumatoid arthritis is a common autoimmune disorder number of circulating neutrophils declines(neutropenia)and most often affecting women from 40 to 60 years old.The various occlusions of the small blood vessels develop(vasculi- major symptom is chronic inflammation of the joints tis). These occlusion can lead to widespread tissue damage although the hematologic, cardiovascular, and respirator Laboratory diagnosis of SLE focuses on the characteristic systems are also frequently affected. Many individuals with antinuclear antibodies, which are directed against double- rheumatoid arthritis produce a group of auto-antibodies stranded or single-stranded DNA, nucleoprotein, histones, called rheumatoid factors that are reactive with determi- and nucleolar RNA. Indirect immunofluorescent staining nants in the Fc region of IgG. The classic rheumatoid factor with serum from SLE patients produces various characteris- is an IgM antibody with that reactivity. Such auto-antibodies tic nucleus-staining patterns bind to normal circulating IgG, forming IgM-lgG complexes that are deposited in the joints. These immune complexe Multiple Sclerosis Attacks the Central activate the complement cascade resulting in a type Ill Nervous system hypersensitive reaction, which leads to chronic inflammation Multiple sclerosis(MS) is the most common cause of neuro. of the joints logic disability associated with disease in Western countries The symptoms may be mild, such as numbness in the limbs, Animal Models for Autoimmune or severe, such as paralysis or loss of vision. Most people wi MS are diagnosed between the ages of 20 and 40 Individuals Diseases with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin Animal models for autoimmune diseases have contributed heath of nerve fibers. The cerebrospinal fluid of patients valuable insights into the mechanism of autoimmunity, to

small blood vessels, a type III hypersensitive reaction devel￾ops. The complexes activate the complement system and generate membrane-attack complexes and complement split products that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis. Excessive complement activation in patients with severe SLE produces elevated serum levels of the complement split products C3a and C5a, which may be three to four times higher than normal. C5a induces increased expression of the type 3 complement receptor (CR3) on neutrophils, facilitat￾ing neutrophil aggregation and attachment to the vascular endothelium. As neutrophils attach to small blood vessels, the number of circulating neutrophils declines (neutropenia) and various occlusions of the small blood vessels develop (vasculi￾tis). These occlusions can lead to widespread tissue damage. Laboratory diagnosis of SLE focuses on the characteristic antinuclear antibodies, which are directed against double￾stranded or single-stranded DNA, nucleoprotein, histones, and nucleolar RNA. Indirect immunofluorescent staining with serum from SLE patients produces various characteris￾tic nucleus-staining patterns. Multiple Sclerosis Attacks the Central Nervous System Multiple sclerosis (MS) is the most common cause of neuro￾logic disability associated with disease in Western countries. The symptoms may be mild, such as 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. Individuals with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers. The cerebrospinal fluid of patients with active MS contains activated T lymphocytes, which infiltrate the brain tissue and cause characteristic inflamma￾tory lesions, destroying the myelin. Since myelin functions to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous neurologic dysfunctions. Epidemiological studies indicate that MS is most com￾mon in the Northern hemisphere and, interestingly, in the United States. Populations who live north of the 37th parallel have a prevalence of 110–140 cases per 100,000, while those who live south of the 37th parallel show a prevalence of 57–78 per 100,000. And individuals from south of the 37th parallel who move north assume a new risk if the move occurs before 15 years of age. These provocative data suggest that there is an environmental component of the risk of con￾tracting MS. This is not the entire story, however, since genetic influences also are important. While the average per￾son in the United States has about one chance in 1000 of developing MS, close relatives of people with MS, such as children or siblings, have 1 chance in 50 to 100 of developing MS. The identical twin of a person with MS has a 1 in 3 chance of developing the disease. These data point strongly to the genetic component of the disease. And, as is described in the Clinical Focus of this chapter, MS affects women two to three times more frequently than men. The cause of MS, like most autoimmune diseases, is not well understood. However, there are some suggestions that infection by certain viruses may predispose a person to MS. Certainly some viruses can cause demyelinating diseases, and it is tempting to speculate that virus infection plays a signifi￾cant role in MS, but at present there is no definitive data implicating a particular virus. 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 determi￾nants 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. Animal Models for Autoimmune Diseases Animal models for autoimmune diseases have contributed valuable insights into the mechanism of autoimmunity, to Autoimmunity CHAPTER 20 467 FIGURE 20-6 Characteristic “butterfly” rash over the cheeks of a young girl with systemic lupus erythematosus. [From L. Steinman, 1993, Sci. Am. 269(3):80.]

468 PART Iv The Immune System in Health and Disease TABLE 20-2 Experimental animal models of autoimmune diseases Diseas Possible human transferred Animal model disease counterpart ducing antigen byt cells SPONTANEOUS AUTOIMMUNE DISEASES nonobese diabetic(NOD) Unknown mellitus(IDDM) (NZB×NZW)F1mou Systemic lupus erythematosus (SLE) Unknown Obese-strain chicken Hashimoto's thyroiditis EXPERIMENTALLY INDUCED AUTOIMMUNE DISEASES# Experimental autoimmune Myasthenia gravis Acetylcholine receptor myasthenia gravis(EAMG) Multiple sclerosis(MS) yelin basic protein( MBP) encephalomyelitis(EAE proteolipid protien(PLP) Autoimmune arthritis (AA) Rheumatoid arthritis M. tuberculosis(proteoglycans) Experimental autoimmune Hashimoto's thyroiditis thyroiditis(EAT) These diseases can be induced by injecting appropriate animals with the indicated antigen in complete Freund's adjuvant. Except for au the antigens used correspond to the self-antigens associated with the human-disease counterpart Rheumatoid arthritis involves reaction to proteoglycans which are self-antigens associated with connective tissue. our understanding of autoimmunity in humans, and to a mouse strain called MRL/lpr/pr. These mice are homozy potential treatments. Autoimmunity develops spontaneously gous for a gene called lpr, which has been identified as a in certain inbred strains of animals and can also be induced defective fas gene. The fas-gene product is a cell-surface pro by certain experimental manipulations(Table 20-2 tein belonging to the TNF family of cysteine-rich membrane receptors(see Figure 12-6d). When the normal Fas protein Autoimmunity Can Develop interacts with its ligand, it transduces a signal that leads to Spontaneously in Animals apoptotic death of the Fas-bearing cells. This mechanism may operate in destruction of target cells by some CTls(see A number of autoimmune diseases that develop sponta- Figure 14-9). Fas is known also to be essential in the death of neously in animals exhibit important clinical and pathologic hyperactivated peripheral CD4* cells. Normally, when ma similarities to certain autoimmune diseases in humans. Cer- ture peripheral T cells become activated, they are induced to tain inbred mouse strains have been particularly valuable express both Fas antigen and Fas ligand, When Fas-bearing models for illuminating the immunologic defects involved in cells come into contact with a neighboring activated cell bear the development of autoimmunity g Fas ligand, the Fas-bearing cell is induced to die. It is alse New Zealand Black(NZB) mice and Fi hybrids of NZb possible that Fas ligand can engage Fas from the same cell, and New Zealand White(NZW)mice spontaneously develop inducing a cellular suicide. In the absence of Fas, mature autoimmune diseases that closely resemble systemic lupus ery- peripheral T cells do not die, and these activated cells con- thematosus NZB mice spontaneously develop autoimmune tinue to proliferate and produce cytokines that result in hemolytic anemia between 2 and 4 months of age, at which grossly enlarged lymph nodes and spleen. Defects in fas ex- bodies to erythrocytes, nuclear proteins, DNA, and T lym- humans, and these ca d in the /prmouse are observedin ve severe consequences. However phocytes F, hybrid animals develop glomerulonephritis from there is no link between fas expression and SLE in humans, its in the kidney and aturely which suggests that the lpr mouse may not be a true model by 18 months. As in human Sle, the incidence of autoimmu- for SLE. ity in the(nzB x nzw)f, hybrids is greater in females. Another important animal model is the nonobese dia An accelerated and severe form of systemic autoimmune betic(NOD) mouse, which spontaneously develops a form disease resembling systemic lupus erythematosus develops in of diabetes that resembles human insulin-dependent dia-

our understanding of autoimmunity in humans, and to potential treatments. Autoimmunity develops spontaneously in certain inbred strains of animals and can also be induced by certain experimental manipulations (Table 20-2). Autoimmunity Can Develop Spontaneously in Animals A number of autoimmune diseases that develop sponta￾neously in animals exhibit important clinical and pathologic similarities to certain autoimmune diseases in humans. Cer￾tain inbred mouse strains have been particularly valuable models for illuminating the immunologic defects involved in the development of autoimmunity. New Zealand Black (NZB) mice and F1 hybrids of NZB and New Zealand White (NZW) mice spontaneously develop autoimmune diseases that closely resemble systemic lupus ery￾thematosus. NZB mice spontaneously develop autoimmune hemolytic anemia between 2 and 4 months of age, at which time various auto-antibodies can be detected, including anti￾bodies to erythrocytes, nuclear proteins, DNA, and T lym￾phocytes. F1 hybrid animals develop glomerulonephritis from immune-complex deposits in the kidney and die prematurely by 18 months. As in human SLE, the incidence of autoimmu￾nity in the (NZB  NZW)F1 hybrids is greater in females. An accelerated and severe form of systemic autoimmune disease resembling systemic lupus erythematosus develops in a mouse strain called MRL/lpr/lpr. These mice are homozy￾gous for a gene called lpr, which has been identified as a defective fas gene. The fas-gene product is a cell-surface pro￾tein belonging to the TNF family of cysteine-rich membrane receptors (see Figure 12-6d). When the normal Fas protein interacts with its ligand, it transduces a signal that leads to apoptotic death of the Fas-bearing cells. This mechanism may operate in destruction of target cells by some CTLs (see Figure 14-9). Fas is known also to be essential in the death of hyperactivated peripheral CD4+ cells. Normally, when ma￾ture peripheral T cells become activated, they are induced to express both Fas antigen and Fas ligand, When Fas-bearing cells come into contact with a neighboring activated cell bear￾ing Fas ligand, the Fas-bearing cell is induced to die. It is also possible that Fas ligand can engage Fas from the same cell, inducing a cellular suicide. In the absence of Fas, mature peripheral T cells do not die, and these activated cells con￾tinue to proliferate and produce cytokines that result in grossly enlarged lymph nodes and spleen. Defects in fas ex￾pression similar to that found in the lpr mouse are observed in humans, and these can have severe consequences. However there is no link between fas expression and SLE in humans, which suggests that the lpr mouse may not be a true model for SLE. Another important animal model is the nonobese dia￾betic (NOD) mouse, which spontaneously develops a form of diabetes that resembles human insulin-dependent dia- 468 PART IV The Immune System in Health and Disease TABLE 20-2 Experimental animal models of autoimmune diseases Disease Possible human transferred Animal model disease counterpart Inducing antigen by T cells SPONTANEOUS AUTOIMMUNE DISEASES Nonobese diabetic (NOD) Insulin-dependent diabetes Unknown Yes mouse mellitus (IDDM) (NZB  NZW) F1 mouse Systemic lupus erythematosus (SLE) Unknown Yes Obese-strain chicken Hashimoto’s thyroiditis Thyroglobulin Yes EXPERIMENTALLY INDUCED AUTOIMMUNE DISEASES* Experimental autoimmune Myasthenia gravis Acetylcholine receptor Yes myasthenia gravis (EAMG) Experimental autoimmune Multiple sclerosis (MS) Myelin basic protein (MBP); Yes encephalomyelitis (EAE) proteolipid protien (PLP) Autoimmune arthritis (AA) Rheumatoid arthritis M. tuberculosis (proteoglycans) Yes Experimental autoimmune Hashimoto’s thyroiditis Thyroglobulin Yes thyroiditis (EAT) * These diseases can be induced by injecting appropriate animals with the indicated antigen in complete Freund’s adjuvant. Except for autoimmune arthritis, the antigens used correspond to the self-antigens associated with the human-disease counterpart. Rheumatoid arthritis involves reaction to proteoglycans, which are self-antigens associated with connective tissue

Autoimmunity CHAPTER 20 469 betes mellitus (IDDM). Like the human disease, the NOD mBP cFA mouse disease begins with lymphocytic infiltration into the islets of the pancreas. Also, as in IDDM, there is a strong asso- ciation between certain MHC alleles and the development of diabetes in these mice. Experiments have shown that T cells from diabetic mice can transfer diabetes to nondiabetic re- normal rat cipients. For example, when the immune system of normal mice is destroyed by lethal doses of x-rays and then is recon- stituted with an injection of bone-marrow cells from NOD mice, the reconstituted mice develop diabetes. Conversely, when the immune system of still healthy nod mice is de Normal rat MBP-specific stroyed by x-irradiation and then reconstituted with norma bone-marrow cells, the NOd mice do not develop diabet FIGURE 20-7 Experimental autoimmune encephalomyelitis(EAE) Various studies have demonstrated a pivotal role for CD4* can be induced in rats by injecting them win myelin basic protein T cells in the NOD mouse, and recent evidence implicates the THl subset in disease development. (MBP) in complete Freud's adjuvant(CFA). MBP-specific T-cell Several other spontaneous autoimmune diseases have been with MBP. When these T cells are injected io e cells from EAE rats discovered in animals that have served as models for similar human diseases. among these are Obese-strain chickens develop EAE and die, although a few recover. which develop both humoral and cell-mediated reactivity to thyroglobulin resembling that seen in Hashimoto's thyroiditis Autoimmunity Can Be Induced assumed that these clones must have escaped negative selec Experimentally in Animals tion in the thymus. Recent mouse experiments have suggested Autoimmune dysfunctions similar to certain human autoim- peripheral T-cell clones self-tolerant. These studies have paved mals(see Table 20-2). One of the first such animal model was discovered serendipitously in 1973 when rabbits were induced in a number of animals by immunizing with thy- immunized with acetylcholine receptors purified from elec roglobulin in complete Freund's adjuvant Both humoral anti tric eels. The animals soon developed muscular weakness bodies and THl cells directed against the thyroglobulin de- similar to that seen in myasthenia gravis. This experimental velop, resulting in thyroid inflammation. EAT appears to best autoimmune myasthenia gravis(EAMG) was shown to result mimic Hashimoto's thyroiditis In contrast to both EAE and when antibodies to the acetylcholine receptor blocked mus- EAT, which are induced by immunizing with self-antigens, cle stimulation by acetylcholine in the synapse. Within a year autoimmune arthritis(AA) is induced by immunizing rats this animal model had proved its value with the discovery with Mycobacterium tuberculosis in complete Freund's adju- that auto-antibodies to the acetylcholine receptor were the vant. These animals develop an arthritis whose features are cause of myasthenia gravis in humans Experimental autoimmune encephalomyelitis(EAE) is similar to those of rheumatoid arthritis in humans another animal model that has greatly improved under- models of autoimmune disease. EAE is mediated solely by Evidence Implicating the CD4* T Cell T cells and can be induced in a variety of species by immu nization with myelin basic protein (MBP) or prote MHC, and TCR in Autoimmunity protein(PLP)in complete Freund's adjuvant(Figure 20-7). The inappropriate response to self-antigens that character- Within 2-3 weeks the animals develop cellular infiltration of izes all autoimmune diseases can involve either the humoral the myelin sheaths of the central nervous system, resulting or cell-mediated branches of the immune system. Identifying in demyelination and paralysis. Most of the animals die, but the defects underlying human autoimmune diseases has others have milder symptoms, and some animals develop a been difficult; more success has been achieved in characteriz chronic form of the disease that resembles chronic relapsing ing the immune defects in the various animal models. Each and remitting MS in humans. Those that recover are resistant of the animal models has implicated the CD4 T cell as the to the development of disease from a subsequent injection of primary mediator of autoimmune disease For example, the MBP and adjuvant. evidence is quite strong that, in mice, EAE is caused by CD4 The mouse EAE model provides a system for testing THl cells specific for the immunizing antigen. The disease treatments for human MS. For example, because MBP- or can be transferred from one animal into another by t cells PLP-specific T-cell clones are found in the periphery, it is from animals immunized with either MBP or PLP or by

betes mellitus (IDDM). Like the human disease, the NOD mouse disease begins with lymphocytic infiltration into the islets of the pancreas. Also, as in IDDM, there is a strong asso￾ciation between certain MHC alleles and the development of diabetes in these mice. Experiments have shown that T cells from diabetic mice can transfer diabetes to nondiabetic re￾cipients. For example, when the immune system of normal mice is destroyed by lethal doses of x-rays and then is recon￾stituted with an injection of bone-marrow cells from NOD mice, the reconstituted mice develop diabetes. Conversely, when the immune system of still healthy NOD mice is de￾stroyed by x-irradiation and then reconstituted with normal bone-marrow cells, the NOD mice do not develop diabetes. Various studies have demonstrated a pivotal role for CD4+ T cells in the NOD mouse, and recent evidence implicates the TH1 subset in disease development. Several other spontaneous autoimmune diseases have been discovered in animals that have served as models for similar human diseases. Among these are Obese-strain chickens, which develop both humoral and cell-mediated reactivity to thyroglobulin resembling that seen in Hashimoto’s thyroiditis. Autoimmunity Can Be Induced Experimentally in Animals Autoimmune dysfunctions similar to certain human autoim￾mune diseases can be induced experimentally in some ani￾mals (see Table 20-2). One of the first such animal models was discovered serendipitously in 1973 when rabbits were immunized with acetylcholine receptors purified from elec￾tric eels. The animals soon developed muscular weakness similar to that seen in myasthenia gravis. This experimental autoimmune myasthenia gravis (EAMG) was shown to result when antibodies to the acetylcholine receptor blocked mus￾cle stimulation by acetylcholine in the synapse. Within a year, this animal model had proved its value with the discovery that auto-antibodies to the acetylcholine receptor were the cause of myasthenia gravis in humans. Experimental autoimmune encephalomyelitis (EAE) is another animal model that has greatly improved under￾standing of autoimmunity. This is one of the best-studied models of autoimmune disease. EAE is mediated solely by T cells and can be induced in a variety of species by immu￾nization with myelin basic protein (MBP) or proteolipid protein (PLP) in complete Freund’s adjuvant (Figure 20-7). Within 2–3 weeks the animals develop cellular infiltration of the myelin sheaths of the central nervous system, resulting in demyelination and paralysis. Most of the animals die, but others have milder symptoms, and some animals develop a chronic form of the disease that resembles chronic relapsing and remitting MS in humans. Those that recover are resistant to the development of disease from a subsequent injection of MBP and adjuvant. The mouse EAE model provides a system for testing treatments for human MS. For example, because MBP- or PLP-specific T-cell clones are found in the periphery, it is assumed that these clones must have escaped negative selec￾tion in the thymus. Recent mouse experiments have suggested that orally administered MBP may make these antigen-specific peripheral T-cell clones self-tolerant. These studies have paved the way for clinical trials in MS patients. Experimental autoimmune thyroiditis (EAT) can be induced in a number of animals by immunizing with thy￾roglobulin in complete Freund’s adjuvant. Both humoral anti￾bodies and TH1 cells directed against the thyroglobulin de￾velop, resulting in thyroid inflammation. EAT appears to best mimic Hashimoto’s thyroiditis. In contrast to both EAE and EAT, which are induced by immunizing with self-antigens, autoimmune arthritis (AA) is induced by immunizing rats with Mycobacterium tuberculosis in complete Freund’s adju￾vant. These animals develop an arthritis whose features are similar to those of rheumatoid arthritis in humans. Evidence Implicating the CD4+ T Cell, MHC, and TCR in Autoimmunity The inappropriate response to self-antigens that character￾izes all autoimmune diseases can involve either the humoral or cell-mediated branches of the immune system. Identifying the defects underlying human autoimmune diseases has been difficult; more success has been achieved in characteriz￾ing the immune defects in the various animal models. Each of the animal models has implicated the CD4+ T cell as the primary mediator of autoimmune disease. For example, the evidence is quite strong that, in mice, EAE is caused by CD4+ TH1 cells specific for the immunizing antigen. The disease can be transferred from one animal into another by T cells from animals immunized with either MBP or PLP or by Autoimmunity CHAPTER 20 469 Normal rat MBP + CFA Lymph-node cells + MBP EAE rat (paralysis) EAE rat Normal rat (most die; some recover) MBP-specific T-cell clones FIGURE 20-7 Experimental autoimmune encephalomyelitis (EAE) can be induced in rats by injecting them with myelin basic protein (MBP) in complete Freud’s adjuvant (CFA). MBP-specific T-cell clones can be generated by culturing lymph-node cells from EAE rats with MBP. When these T cells are injected into normal animals, most develop EAE and die, although a few recover

PART IV The Immune System in Health and Disease clonedT-cell lines from such animals. It also has been shown further evidence for the different roles of THl and TH2 cells in that disease can be prevented by treating animals with anti- autoimmunity. When mice were injected with IL-4 at the time CD4 antibodies. These data are compelling evidence for the of immunization with MBP plus adjuvant, the development of involvement of cd4 in the establishment of eae EAE was inhibited whereas administration of il-12 had the T-cell recognition of antigen, of course, involves a trimol- opposite effect, promoting the development of EAE. As noted ecular complex of the T-cell receptor, an MHC molecule, and in Chapter 12, IL-4 promotes development of TH2 cells and antigenic peptide(see Figure 9-16). Thus, an individual sus- IFN-Y, in addition to other cytokines such as IL-12, promotes ceptible to autoimmunity must possess MHC molecules and development of THl cells(see Figure 12-12). Thus, the ob- T-cell receptors ca of binding self-antigens. served effects of IL-4 and IL-12 on EAE development are con sistent with a role for THl cells in the genesis of autoimmunity CD4+ T Cells and Tul/Tu2 Balance Plays an Important Role in Autoimmunity Autoimmunity Can Be Associated with in Some animal models the MHC or with Particular T-Cell Receptors Autoimmune T-cell clones have been obtained from all of the Several types of studies have supported an association be animal models listed in Table 20-2 by culturing lymphocytes tween expression of a particular MHC allele and susceptibil- from the autoimmune animals in the presence of various ity to autoimmunity, an issue covered in detail in Chapter 7. T-cell growth factors and by inducing proliferation of spe- The strongest association between an HLA allele and an cific autoimmune clones with the various autoantigens For autoimmune disease is seen in ankylosing spondylitis, an example, when lymph-node cells from EAE rats are cultured inflammatory disease of vertebral joints. Individuals who in vitro with myelin basic protein(MBP), clones of activated have HLA-B27 have a 90 times greater likelihood of develop- T cells emerge. When sufficient numbers of these MBP- ing ankylosing spondylitis than individuals with a different specific T-cell clones are injected intravenously into normal HLA-B allele. However, the existence of such an association syngeneic animals, the cells cross the blood-brain barrier and should not be interpreted to imply that the expression of a induce demyelination; EAE develops very quickly, within particular MHC allele has caused the disease, because the 5 days(see Figure 20-7) relationship between MHC alleles and development of auto- A similar experimental protocol has been used to isolate immune disease is complex. It is interesting to note that, T-cell clones specific for thyroglobulin and for M tuberculosis unlike many other autoimmune diseases, 90% of the cases of from EAT and AA animals, respectively. In each case, the T-cell ankylosing spondylitis are male clone induces the experimental autoimmune disease in nor- The presence of T-cell receptors containing particular va mal animals. Examination of these t cells has revealed that and VB domains also has been linked to a number of auto- they bear the CD4 membrane marker In a number of animal immune diseases, including experimental EAE and its human models for autoimmune diseases it has been possible to reverse counterpart, multiple sclerosis. In one approach, T cells spe- the autoimmunity by depleting the T-cell population with cific for various encephalitogenic peptides of MBP were antibody directed against CD4. For example, weekly injections cloned and their T-cell receptors analyzed. For example, of anti-CD4 monoclonal antibody abolished the autoimmune T-cell clones were obtained from PL/J mice by culturing their symptoms in(NZB X NZW) Fi mice and in mice with EAE. T cells with the acetylated amino-terminal nonapeptide of Most cases of organ-specific autoimmune disease develop MBP presented in association with a class I IA MHC mole- as a consequence of self-reactive CD4* Tcells. Analysis of these cule. Analysis of the T-cell receptors on these clones revealed a cells has revealed that the THl/TH2 balance can affect whether restricted repertoire of Va and VB domains: 100% of the autoimmunity develops. THl cells have been implicated in the T-cell clones expressed va 4.3, and 80%of the T-cell clones development of autoimmunity, whereas, in a number of cases, expressed VB 8.2. In human autoimmune diseases, evidence TH2 cells not only protect against the induction of disease but for restricted TCR expression has been obtained for both mul also against progression of established disease. In EAE, for tiple sclerosis and myasthenia gravis. The preferential expres- example immunohistologic studies revealed the presence of sion of TCR variable-region genes in these autoimmune T-cell TH1 cytokines(IL-2, TNF-a, and IFN-y) in the central ner- clones suggests that a single epitope might induce the clonal vous system tissues at the height of the disease. In addition, the expansion of a small number of pathogenic cells. MBP-specific CD4* T-cell clones generated from animals w EAE, as shown in Figure 20-7, can be separated into THl and TH2 clones iments have shown that only the THl clones transfer EAE to normal healthy mice, whereas the TH2 clones Proposed Mechanisms for Induction not only do not transfer EAE to normal healthy mice but also of Autoimmunity protect the mice against induction of eae by subsequent immunization with MBP plus adjuvant. A variety of mechanisms have been proposed to account for Experiments that assessed the role of various cytokines or the T-cell-mediated generation of autoimmune diseases cytokine inhibitors on the development of EAE have provided(Figure 20-8). Evidence exists for each of these mechanisms

cloned T-cell lines from such animals. It also has been shown that disease can be prevented by treating animals with anti￾CD4 antibodies. These data are compelling evidence for the involvement of CD4 in the establishment of EAE. T-cell recognition of antigen, of course, involves a trimol￾ecular complex of the T-cell receptor, an MHC molecule, and antigenic peptide (see Figure 9-16). Thus, an individual sus￾ceptible to autoimmunity must possess MHC molecules and T-cell receptors capable of binding self-antigens. CD4+ T Cells and TH1/TH2 Balance Plays an Important Role in Autoimmunity in Some Animal Models Autoimmune T-cell clones have been obtained from all of the animal models listed in Table 20-2 by culturing lymphocytes from the autoimmune animals in the presence of various T-cell growth factors and by inducing proliferation of spe￾cific autoimmune clones with the various autoantigens. For example, when lymph-node cells from EAE rats are cultured in vitro with myelin basic protein (MBP), clones of activated T cells emerge. When sufficient numbers of these MBP￾specific T-cell clones are injected intravenously into normal syngeneic animals, the cells cross the blood-brain barrier and induce demyelination; EAE develops very quickly, within 5 days (see Figure 20-7). A similar experimental protocol has been used to isolate T-cell clones specific for thyroglobulin and for M. tuberculosis from EAT and AA animals, respectively. In each case, the T-cell clone induces the experimental autoimmune disease in nor￾mal animals. Examination of these T cells has revealed that they bear the CD4 membrane marker. In a number of animal models for autoimmune diseases it has been possible to reverse the autoimmunity by depleting the T-cell population with antibody directed against CD4. For example, weekly injections of anti-CD4 monoclonal antibody abolished the autoimmune symptoms in (NZB  NZW) F1 mice and in mice with EAE. Most cases of organ-specific autoimmune disease develop as a consequence of self-reactive CD4+ T cells.Analysis of these cells has revealed that the TH1/TH2 balance can affect whether autoimmunity develops. TH1 cells have been implicated in the development of autoimmunity, whereas, in a number of cases, TH2 cells not only protect against the induction of disease but also against progression of established disease. In EAE, for example, immunohistologic studies revealed the presence of TH1 cytokines (IL-2, TNF-, and IFN-) in the central ner￾vous system tissues at the height of the disease. In addition, the MBP-specific CD4+ T-cell clones generated from animals with EAE, as shown in Figure 20-7, can be separated into TH1 and TH2 clones. Experiments have shown that only the TH1 clones transfer EAE to normal healthy mice, whereas the TH2 clones not only do not transfer EAE to normal healthy mice but also protect the mice against induction of EAE by subsequent immunization with MBP plus adjuvant. Experiments that assessed the role of various cytokines or cytokine inhibitors on the development of EAE have provided further evidence for the different roles of TH1 and TH2 cells in autoimmunity. When mice were injected with IL-4 at the time of immunization with MBP plus adjuvant, the development of EAE was inhibited, whereas administration of IL-12 had the opposite effect, promoting the development of EAE. As noted in Chapter 12, IL-4 promotes development of TH2 cells and IFN-, in addition to other cytokines such as IL-12, promotes development of TH1 cells (see Figure 12-12). Thus, the ob￾served effects of IL-4 and IL-12 on EAE development are con￾sistent with a role for TH1 cells in the genesis of autoimmunity. Autoimmunity Can Be Associated with the MHC or with Particular T-Cell Receptors Several types of studies have supported an association be￾tween expression of a particular MHC allele and susceptibil￾ity to autoimmunity, an issue covered in detail in Chapter 7. The strongest association between an HLA allele and an autoimmune disease is seen in ankylosing spondylitis, an inflammatory disease of vertebral joints. Individuals who have HLA-B27 have a 90 times greater likelihood of develop￾ing ankylosing spondylitis than individuals with a different HLA-B allele. However, the existence of such an association should not be interpreted to imply that the expression of a particular MHC allele has caused the disease, because the relationship between MHC alleles and development of auto￾immune disease is complex. It is interesting to note that, unlike many other autoimmune diseases, 90% of the cases of ankylosing spondylitis are male. The presence of T-cell receptors containing particular V and V domains also has been linked to a number of auto￾immune diseases, including experimental EAE and its human counterpart, multiple sclerosis. In one approach, T cells spe￾cific for various encephalitogenic peptides of MBP were cloned and their T-cell receptors analyzed. For example, T-cell clones were obtained from PL/J mice by culturing their T cells with the acetylated amino-terminal nonapeptide of MBP presented in association with a class II IAu MHC mole￾cule. Analysis of the T-cell receptors on these clones revealed a restricted repertoire of V and V domains: 100% of the T-cell clones expressed V 4.3, and 80% of the T-cell clones expressed V 8.2. In human autoimmune diseases, evidence for restricted TCR expression has been obtained for both mul￾tiple sclerosis and myasthenia gravis. The preferential expres￾sion of TCR variable-region genes in these autoimmune T-cell clones suggests that a single epitope might induce the clonal expansion of a small number of pathogenic T cells. Proposed Mechanisms for Induction of Autoimmunity A variety of mechanisms have been proposed to account for the T-cell–mediated generation of autoimmune diseases (Figure 20-8). Evidence exists for each of these mechanisms, 470 PART IV The Immune System in Health and Disease

Autoimmunity CHAPTER 20 VISUALIZING CONCEPTS Activated nflammation and local dth sequestered antigen epithelium MHC exp Class I mhc TH cell Tu cell APC with Tu cell THell Ag(molecular Ab to self-an TH cell Polyclonal activation FIGURE 20-8 Proposed mechanisms for inducing autoim- B cells, is thought to induce an autoimmune response, in this mune responses. Normal thymic selection appears to generate case resulting in tissue damage. In all likelihood, several mecha- some self-reactive TH cells; abnormalities in this process may nisms are involved in each autoimmune disease. /Adapted from generate even more self-reactive TH cells. Activation of these self- V Kumar et al., 1989, Annu. Rev. Immunol. 7: 657] reactive T cells in various ways, as well as polyclonal activation of and it is likely that autoimmunity does not develop from a T cells in the thymus, will not induce self-tolerance. Exposure single event but rather from a number of different events. of mature T cells to such normally sequestered antigens at a In addition, susceptibility to many autoimmune diseases later time might result in their activation differs between the two sexes. as noted earlier. hashimotos Myelin basic protein(MBP) is an example of an antigen thyroiditis, systemic lupus erythematosus, multiple sclerosis, orally sequestered from the immune system, in this case by rheumatoid arthritis, and scleroderma preferentially affect the blood-brain barrier. In the EAE model, animals women. Factors that have been proposed to account for this jected directly with MBP, together with adjuvant, under con- preferential susceptibility, such as hormonal differences be- ditions that maximize immune exposure. In this type of ani tween the sexes and the potential effects of fetal cells in the mal model, the immune system is exposed to sequestered self- maternal circulation during pregnancy, are discussed in the antigens under nonphysiologic conditions; however, trauma Clinical focus to tissues following either an accident or a viral or bacterial infection might also release sequestered antigens into the cir Release of Sequestered Antigens Can Induce culation. A few tissue antigens are known to fall into this cate- Autoimmune disease gory. For example, sperm arise late in development and are sequestered from the circulation. However, after a vasectomy, As discussed in Chapter 10, the induction of self-tolerance in some sperm antigens are released into the circulation and ca T cells results from exposure of immature thymocytes to self- induce auto-antibody formation in some men. Similarly, the antigens and the subsequent clonal deletion of those that are release of lens protein after eye damage or of heart-muscle self-reactive. Any tissue antigens that are sequestered from antigens after myocardial infarction has been shown to lead on the circulation, and are therefore not seen by the developing occasion to the formation of auto-antibodies

and it is likely that autoimmunity does not develop from a single event but rather from a number of different events. In addition, susceptibility to many autoimmune diseases differs between the two sexes. As noted earlier, Hashimoto’s thyroiditis, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and scleroderma preferentially affect women. Factors that have been proposed to account for this preferential susceptibility, such as hormonal differences be￾tween the sexes and the potential effects of fetal cells in the maternal circulation during pregnancy, are discussed in the Clinical Focus. Release of Sequestered Antigens Can Induce Autoimmune Disease As discussed in Chapter 10, the induction of self-tolerance in T cells results from exposure of immature thymocytes to self￾antigens and the subsequent clonal deletion of those that are self-reactive. Any tissue antigens that are sequestered from the circulation, and are therefore not seen by the developing T cells in the thymus, will not induce self-tolerance. Exposure of mature T cells to such normally sequestered antigens at a later time might result in their activation. Myelin basic protein (MBP) is an example of an antigen normally sequestered from the immune system, in this case by the blood-brain barrier. In the EAE model, animals are in￾jected directly with MBP, together with adjuvant, under con￾ditions that maximize immune exposure. In this type of ani￾mal model, the immune system is exposed to sequestered self￾antigens under nonphysiologic conditions; however, trauma to tissues following either an accident or a viral or bacterial infection might also release sequestered antigens into the cir￾culation. A few tissue antigens are known to fall into this cate￾gory. For example, sperm arise late in development and are sequestered from the circulation. However, after a vasectomy, some sperm antigens are released into the circulation and can induce auto-antibody formation in some men. Similarly, the release of lens protein after eye damage or of heart-muscle antigens after myocardial infarction has been shown to lead on occasion to the formation of auto-antibodies. Autoimmunity CHAPTER 20 471 VISUALIZING CONCEPTS TH cell Tissue damage Inflammation and local DTH Ab to self-antigens Activated macrophage Target tissue epithelium IFN-γ TH cell Activated TH cell TH cell CTL TH cell Help Plasma cell B cell TC cell Polyclonal activation TH cell B cell TH cell IL-2 Class II MHC Release of sequestered antigen Inappropriate MHC expression on non-APCs APC with cross-reacting Ag (molecular mimicry) FIGURE 20-8 Proposed mechanisms for inducing autoim￾mune responses. Normal thymic selection appears to generate some self-reactive TH cells; abnormalities in this process may generate even more self-reactive TH cells. Activation of these self￾reactive T cells in various ways, as well as polyclonal activation of B cells, is thought to induce an autoimmune response, in this case resulting in tissue damage. In all likelihood, several mecha￾nisms are involved in each autoimmune disease. [Adapted from V. Kumar et al., 1989, Annu. Rev. Immunol. 7:657.]