Immune Tolerance And Autoimmunity
The immune system generates significant numbers of lymphocytes whose antigen receptors bind "self" molecules strongly enough to engender immune activity against self components. Indeed, the random processes responsible for antigen receptor diversity, coupled with genetic polymorphism in most structural genes, makes generation of such "autoreactive" receptors unavoidable. The random processes responsible for antigen-receptor diversity, coupled with genetic polymorphism in most structural genes, makes generation of such autoreactive receptors unavoidable. The avoidance of pathogenic autoreactivity, despite this likelihood of developing receptors capable of binding to self molecules, is collectively termed immunologic tolerance.
How cells bearing potentially autoreactive receptors are controlled remains an area of intense investigation, but several mechanisms clearly play important roles. Many autoreactive clones are eliminated before they mature in the marrow and thymus, because when immature B or T cells have their antigen receptor occupied they undergo deletion via apoptotic cell death. In contrast, mature lymphocytes resist death induced via receptor ligation. Regardless of the exact mechanisms involved, these so-called central deletion mechanism provide a means to screen and eliminate incipient autoreactive cells before they completely mature. However, these central tolerance mechanisms, while clearly an important element of immunologic tolerance, are insufficient to fully explain the lack of auto-reactivity. For example, some self molecules are expressed only in tissues found outside of the thymus or bone marrow, precluding exposure of developing lymphocytes. Thus, a variety of peripheral tolerance mechanisms are believed to be important in successful avoidance of self reactivity. These include the functional inactivation of lymphocytes through anergy, the blockage or prevention of appropriate second signals, discussed above, and the sequestration of certain self components in areas where lymphocytes do not recirculate, such as the chamber of the eye.
If the immune system fails to appropriately eliminate or control self-reactive cells, they may cause life-threatening autoimmune disease. These diseases may involve cell-mediated responses, humoral responses, or both. Examples of autoimmunity include: type I diabetes, where individuals make an immune response against their insulin-producing cells, destroying them and resulting in abnormal sugar metabolism; myasthenia gravis, where one makes antibodies against normal molecules that control neuromuscular activity, resulting in weakness and paralysis; and systemic lupus erythematosus, where antibodies to many normal body constituents are made, resulting in widespread symptoms. Some autoimmune diseases lead to the deposition of antibody-antigen aggregates called immune complexes in the kidney, lungs, or joints. Because these complexes will trigger complement and other inflammatory processes, they can result in severe damage to the affected areas.
Age-associated changes involving immune tolerance. Age-associated changes in the susceptibility to autoimmune phenomena are well-established. Indeed, epidemiological evidence shows that the incidence of various autoimmune diseases peaks at certain ages. Thus, while many other risk factors are also involved, elucidating the links between various autoimmune syndromes and age forms an important immunologic problem. Because the mechanisms that mediate immune tolerance per se are poorly understood, it is even more difficult to establish how age-associated factors can influence susceptibility. Clearly, shifts in the production, selection, and homeostatic processes that govern lymphocyte activity may play a role, but causal relationships await further research.
MICHAEL P. CANCRO
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