Various human autoimmune diseases, including the rheumatologic diseases ankylosing spondylitis and rheumatoid arthritis, have been associated with etiologies triggered by infectious processes. Unfortunately, there are few animal models useful for the study of autoimmunity resulting directly from an infectious disease. Infection of mice with the protozoan parasite Trypanosoma cruzi, the agent of human Chagas' disease, constitutes a particularly good system because the acute and chronic pathology is virtually identical to that seen in the human. The most common (and most serious) adverse effect of chronic infection with this parasite is the development of cardiomyopathy. Because parasites are rarely found at autopsy in the heart tissues of chagasic patients who succumb to heart failure, an autoimmune basis has been proposed to be responsible for disease pathogenesis. This hypothesis has been supported by extensive experimentation in which cross-reactive T. cruzi and mammalian antigens have been identified, and the development of chagasic pathology has been induced by the transfer of T cells from infected mice to naive recipients. Although we and others have identified T. cruzi antigens potentially involved in autoimmune pathogenesis, the approaches used have been indirect. Using an immunologic screening strategy, we propose to identify mammalian heart antigens that are targets of the immune response during T. cruzi infection by directly cloning the genes that encode them. The humoral and cellular immune responses to these putative autoantigens will be investigated and their potential roles in Chagas' disease pathogenesis determined. If these studies implicate antigen-specific autoimmune responses in disease pathogenesis, we will attempt to induce disease in naive recipients via the transfer of autoantigen-specific antibodies or T cells - the ultimate confirmatory test for antigen-specific autoimmunity.
Showing the most recent 10 out of 248 publications
