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