《免疫学》（英文版） Chapter 20 Autoimmunity

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