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