The broad objectives of this project are to define the cellular and biochemical abnormalities that contribute to the development of autoimmunity in Fas- and Fas ligand-mutant mouse strains, which are animal models of systemic autoimmune diseases with human counterparts. Our underlying hypothesis is that autoimmunity in these mutant mice is due to a failure of self antigen-reactive lymphocytes to die upon repeated antigen encounter. The project has three specific aims. 1. Survival and responses of Fas-deficient CD4+ T lymphocytes: The goal of these studies is to examine the patterns of activation and survival of Fas (and Fas ligand)-deficient CD4+ T cells, which are known to play an obligatory role in the development of autoimmunity in these models. Transgenic mice expressing a single T cell receptor of known specificity bred into Fas and FasL-mutant strains will be used as sources of monospecific lymphocytes. Responses of T cells to antigen, differentiation into effector and memory cells, and persistence upon repeated antigen exposure will be examined. The roles of growth factors in inducing T cell death, and the mechanisms that control sensitivity to cell death, will be analyzed. 2. Responses of autoreactive T cells to endogenous self antigens in vivo: The role of self antigen-reactive T cells in inducing autoimmune reactions will be studied by adoptive transfer experiments. The in vivo survival, activation, and pathologic effects of autoreactive T cells will be examined. The development and pathologic effects of autoreactive T cells will be analyzed. 3. Functions of lpr lymphocytes in autoantibody production: The role of cell death in controlling antibody responses will be examined. The differentiation of Fas-deficient B cells into antibody secretors and memory cells will be studied, and antagonists to inhibit B cell activation will be tested. These studies will elucidate the mechanisms of autoimmunity in two well- defined animals models, and are relevant to all autoimmune disorders attributable to a failure of lymphocyte death. The studies will also suggest potential therapeutic strategies for such diseases.
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