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