Viruses, host responses, and autoimmunity

Conceptually, the initiation of autoimmune disease can be described as a th ree-stage process involving both genetic and environmental influences. This process begins with the development of an autoimmune cellular repertoire, followed by activation of these autoreactive cells in response to a localiz ed target and, finally, the immune system's failure to regulate these self reactive constituents. Viruses have long been associated with inciting auto immune disorders. Two mechanisms have been proposed to explain how a viral infection can overcome immunological tolerance to self-components and initi ate an organ-specific autoreactive process; these mechanisms are molecular mimicry and bystander activation. Both pathways, as discussed here, could p lay pivotal roles in the development of autoimmunity without necessarily ex cluding each other. Transgene technology has allowed us and others to exami ne more closely the roles of these mechanisms in mice and to dissect the re quirements for initiating disease. These results demonstrate that bystander activation is the most likely explanation for disease development. Additio nal evidence suggests a further role for viruses in the reactivation and ch ronicity of autoimmune diseases. In this scenario, a second invasion by a p reviously infecting virus may restimulate already existing autoreactive lym phocytes, and thereby contribute to the diversity of the immune response.