The etiopathogenesis of autoimmunity.

Acquisition by mammals of an adaptive immune system was an evolutionary leap, but occurred at the cost of autoimmunity. The necessity for self-recognition was appreciated in 1900, but autoimmune disease did not become a clinical reality until the 1950s-still the perimeters are indistinct. Autoimmune responses recapitulate the complex events of normal immune responses but cannot shut down. Immune tolerance is established during repertoire development centrally in thymus or bone marrow by deletion of self-reactive immunocytes, and is supplemented peripherally by regulatory T cells (Tregs). A startling discovery is the autoimmune regulator AIRE gene that enables expression of organ-specific autoantigens for intrathymic deletional tolerance of T cells. The origins, activities, and markers of Tregs are under intensive investigation. Of genes implicated in autoimmune, only few are characterized; contributions of environment are similarly uncertain. Time-latency considerations implicate stochastic factors or chance in the etiopathogenesis of autoimmunity, whether they are somatic mutations or successive random gene-environment interactions. Solutions to etiopathogenesis require novel experimental models and finely designed gene-environment studies on human populations. Perhaps immunomodulatory therapies will effect cures before causes are fully understood.