The etiology of autoimmune diseases is unknown, but previous exposure to environmental pathogens is thought to play an important role. In this application, the connection between Coxsackie virus infection and the prevalent autoimmune disease Insulin Dkependent Diabetes Mellitus is investigated. Coxsackie virus has been implicated to be causally associated with diabetes, but the pathway from infection to disease has not been defined. In the current project, three mechanistic hypotheses are tested experimentally to determine how the virus induces disease. The first hypothesis tested is that the virus shares a pathogenic similarity with the host, so that upon infection, the immune response to the virus also recognizes the host. This potential antigenic similarity has recently been demonstrated between the Coxsackie virus P2-C antigen and the pancreatic islet antigen glutamic acid decarboxylase, a target antigen strongly associated with pathogenesis of diabetes in both humans and spontaneous animal models. A second possible mechanism for the initiation of autoimmunity is that virus infection of the pancreas leads to immune activation and the elicitation of host defense molecules "bystander damage" hypothesis then predicts that these released antigens could cause the priming of na&iuml;ve islet-specific T cells. Lastly, previous exposure to pathogens causes the immune system to accumulate memory to those agents. The third hypothesis predicts that the re- exposure to the same or similar antigens causes reactivation of those specificities and a pathogenic T cells response is initiated, destroying the pancreatic beta cells. In the proposed experiments, specific predictions of these three mechanistic hypotheses will be approached experimentally using a murine system in which diabetes-prone strains are infected with the Coxsackie virus and either studied directly for the development of pancreatic islet sensitization or used as donors in a series of adoptive transfer protocols designed specifically to address each mechanism. They anticipate that these studies will lead to increased understanding of the mechanism of virus induced autoimmunity.