Mercury (Hg) toxicity affects numerous organ systems including the immune system. The immunotoxicity of Hg is complex, in that, immunosuppression and immunostimulation occur upon exposure to this metal, and both of these outcomes may have adverse effects on human health. This proposal is constructed around the conceptual framework that Hg is an environmental agent that contributes to the development of autoimmune disease. Animal studies have established a connection between experimental exposure to Hg and lupus-like autoimmune disease. Similarly, case reports demonstrating a correlation between accidental Hg exposure and either the onset or the severity of autoimmune disease symptoms support a link between Hg intoxication and the etiology of human autoimmune disease. From this perspective, Hg is one of the few suspected environmental agents where a link between exposure to the agent and autoimmune disease has been indicated. However, the mechanisms whereby Hg initiates, potentiates, or perpetuates autoimmune responses have not been established. In particular, there is a dearth of information regarding the biochemical/molecular mechanisms involved in Hg-mediated autoimmunity. Accordingly, the long-term goal of our research is to identify biochemical/molecular mechanisms underlying Hg-mediated autoimmune disease. Non-cytotoxic concentrations of Hg2+ interfere with the CD95 apoptotic signaling pathway and also interfere with protein tyrosine mediated signaling. Thus, this proposal focuses on lymphocyte signaling pathways involved in the regulation of CD95-induced apoptosis. Since CD95-mediated apoptosis is involved in the regulation of peripheral tolerance, dysregulation of CD95-signaling by Hg may be one factor (together with other genetic or environmental factors) that contributes to autoimmune disease. The hypothesis guiding this proposal is that Hg2+ disrupts CD95-mediated apoptosis, which contributes to a breakdown in peripheral tolerance to autoantigens leading to the development of autoimmune disease. Using cell lines and human CD4+ lymphoblasts this hypothesis will be tested by determining; 1) the influence of Hg2+ on components of the CD95 apoptotic machinery and 2) the effects of Hg2+ on non-receptor kinase signaling pathways that may interact with and regulate CD95. A third specific aim will employ a mouse model to test whether disruption of CD95-mediated cell death by Hg intoxication in vivo enhances the survival of autoreactive T lymphocytes.
