Systemic lupus erythematosus affects women ten times more often than men. Many observations made in patients with systemic lupus and in animal models of this disease suggest that sex hormones, estrogen in particular, may augment expression of disease. Despite the pronounced gender bias, s strong clinical suspicion that estrogen exacerbates disease, and some phenomenologic data on estrogen effects in mice, we do not understand how estrogen affects autoantibody production. We propose the following two hypotheses: 1) that estrogen alters thresholds for B cell activation and apoptosis by regulating expression of members of the bcl-2 gene family and the fas signaling cascade and 2) that estrogen alters survival of germinal center B cells. We will test these hypotheses in mouse models. First, in a transgenic mouse with three populations of anti-DNA B cells, one ignorant, one anergic and one deleted, we will determine how estrogen alters cell fate decisions, and whether changes in cell fate correlate with changes in expression of anti-apoptotic or pro-apoptotic genes. Second, we will determine if estrogen alters survival of germinal center B cells in both a transgenic model in which autoreactive B cells arise by somatic mutation and in a non-transgenic model in which B cell apoptosis is induced by soluble antigen. Finally, we will determine is estrogen acts directly on B cells by create a double transgenic mouse with a dominant negative receptor expressed in the B cell compartment to determine if this alters survival of naive or antigen activated B cells.
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