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.]