CELLULAR AND MOLECULAR MECHANISMS OF AUTOIMMUNITY

University Of California San Francisco, San Francisco CA

Investigators

Abstract

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.