Autoimmune diseases result from the failure of immune tolerance, the process by which the immune system recognises and accepts self-tissue. Central immune tolerance occurs during lymphocyte development, when T and B lymphocytes that recognise self-antigens are eliminated before they develop into fuly immunocompetent cels. This process is most active in fetal life but continues throughout life as immature lymphocytes are generated. Some autoreactive cels inevitably evade deletion and escape into the circulation, however, and are controlled through peripheral tolerance mechanisms. Peripheral immune tolerance mechanisms include the sup pression of autoreactive cels by regulatory T cels; the generation of functional hyporesponsiveness (anergy) in lymphocytes that encounter antigen in the absence of the co-stimulatory signals that accompany inflammation ; and cel death by apoptosis. Autoimmune diseases develop when self-re active lymphocytes escape from these tolerance mechanisms. Multiple genetic and environmental factors contribute to the development  of autoimmune disease. Autoimmune diseases are much more common in women than in men, for reasons that remain unclear. Many are associated with genetic variations in the HLA loci, reflecting the importance of HLA genes in shaping lymphocyte responses. Other important susceptibility genes include those determining cytokine activity, co-stimulation  (the expression of second signals required for full T-cel activation; see Figs. 4.7 and 4.8) and cel death. Many of the same gene variants under lie multiple autoimmune disorders, reflecting  their common pathogenesis (Box 4.14).

Even though some of these associations are the strongest that have been identified  in complex genetic diseases, they have very limited predictive value and are generally not useful in determining management of individual patients. Several environmental factors may be associated with autoimmunity in genetically predisposed individuals, including infection, cigarette smoking and hormone levels. The most widely studied of these is infection, as occurs in acute rheumatic fever following streptococcal infection or reactive arthritis following bacterial infection. Several mechanisms have been invoked to explain the autoimmunity that occurs after an infectious  trigger. These include cross-reactivity between proteins expressed by the pathogen and the host (molecular mimicry), such as Guilain–Barré syndrome and Campylobacter infection; release of sequestered antigens from tissues that are damaged during infections that are not usually visible  to the immune system; and production of inflammatory cytokines that overwhelm the normal control mechanisms that prevent bystander dam age. Occasionally, autoimmune disease may be an adverse effect of drug treatment. For example, metabolic products of the anaesthetic agent halothane can bind to liver enzymes, resulting in a structurally novel protein that is recognised as a foreign antigen by the immune system. This can provoke the development of autoantibodies and activated T cels, which can cause hepatic necrosis.