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Autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are relatively common disorders.1 Although the underlying etiologies of these illnesses are still elusive, they arise in the context of a break in the immune tolerance to self.2,3 The mechanisms for abrogation of immune self-tolerance appear to be multifactorial, including genetic and environmental, that work in concert to initiate the eventual hallmarks of disease: unregulated immune activation against self-antigens and subsequent tissue destruction. Immune activation against self-antigens is clinically manifest by the presence of autoantibodies and autoreactive T cells.1,2 Based upon their autoantigenic targets, autoimmune diseases can be classified into organ-specific and systemic autoimmune processes. For example, Grave's disease, with its autoantibodies against the thyroid-stimulating hormone (TSH) receptor, is a typical example of organ-specific autoimmune disease, as is type I diabetes mellitus (DM) with its autoantibodies and autoreactive T cells directed against components of pancreatic β cells, whereas SLE with its characteristic autoantibodies against ubiquitous nuclear antigens is a good example of a systemic autoimmune disease. Although adaptive immune cells such as B cells and T cells recognize self-antigens and hence dominate the phenotype of the patient with autoimmunity, other immune components including antigen-presenting cells (APC) and complement are involved in various steps from initiation of the autoimmune response to tissue destruction.4–6 In this chapter, the contributions of these components to the development of autoimmune diseases will be discussed, focusing on the latest discoveries.
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Autoimmune Diseases Are Polygenic
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Autoimmune diseases are polygenic, involving both major histocompatibility complex (MHC) and non-MHC genes.7,8 Yet, the concordance rate of autoimmune diseases in monozygotic twins is not 100%, ranging from 10% to 50%, including in RA and SLE,7,9 indicating a significant role for nongenetic factors in the development of these disorders. Nevertheless, genetic influences are strong. For instance, the contribution of alleles of MHC to the development of autoimmunity has been known for more than 30 years. An increased frequency of HLA (human leukocyte antigen)-DR4 has been observed in some patients with RA.8 Using more sophisticated molecular techniques, the sequence of genetic alleles encoding HLA loci have been typed, ...