The Fas/APO-1 cytotoxic pathway plays an important role in the regulation of peripheral immunity. Our recent studies have demonstrated that activated murine macrophages express FasR, and in addition to their important regulatory role as "professional" antigen presenting cells (APC) which participate in the activation of CD4+ T cells, the macrophages themselves are susceptible to Th1- mediated cell death through FasR/FasL interactions. In normals, potentially autoreactive CD4+ T cells can destroy the APC through the Fas pathway and thereby prevent an autoimmune response. We hypothesize that in Fas-deficient mice, there is a failure of T cell-mediated macrophage apoptosis thus prolonging expression and presentation of self peptides and initiating or potentiating an autoimmune response.

Our current studies explore the expression and function of Fas on dendritic cells, extremely potent professional APC. Our data reveal that dendritic cells express high levels of Fas, but unlike other APC populations, are resistant to Fas mediated apoptosis. Current studies are directed at delineating the molecular basis of this reistance as well as the physiologic significance of Fas resistance in this APC population.

In conjunction with studies in the murine system, we are initiating studies of antigen presenting cell apoptosis in humans and are examining the role of Fas on monocyte/macrophages and dendritic cells isolated from peripheral blood of SLE patients and normal controls.