A common property of environmental pollutants is that they are mildly immunosuppressive. Studies of several gene knockout mice reveal an interesting association between a mildly suppressed T cell response with systemic autoimmune diseases. In addition, CD95 ligand (FasL) expression in some strains of these mice is impaired. Because FasL is critically involved in regulating peripheral tolerance, there may be a link between autoimmune diseases and a moderate T cell response that is insufficient for activation of the FasL gene. Here, we propose that there are two thresholds of T cell activation. When moderately stimulated, T cells can be activated to the low (1st) threshold, which permits the induction of CD40L, (low level of) IL-2, IL-4, and other components that help T and B cell immune response. The high (2nd) activation threshold can only be achieved by a strong stimulation through both TCR and IL-2R. FasL is produced to induce apoptosis of the activated B and T cells (activation-induced cell death, or AICD). In the absence of the FasL-mediated down regulation, activated B cells become efficient antigen-presenting cells for self-antigens and excellent responders to T cell help. Such an exacerbating condition, induced by recurrent and moderate activation, should favor the development of auto-reactive T cells and autoantibody production over time. Many environmental agents are mildly immunosuppressive and hosts chronically exposed to these agents may not effectively harness the FasL to contain their autoreactive clones. We hypothesize that this is a major and general mechanism that fosters systemic autoimmunity in host chronically exposed to environmental agents and that IL-2, FasL, and AICD are biomarkers for this mechanism. Preliminary studies demonstrate that IL-2 induces critical transcription factors for FasL gene expression and that environmental agents depress AICD and presumably IL-2 production. We have three specific aims. (1) To test the hypothesis that environmental agents, lead, mercury, diethystilbestrol, polycyclic aromatic hydrocarbons and trichloroethylene suppress IL-2 production, FasL expression, and AICD. (2) To determine how they affect B cell death. And (3) to test whether autoimmune disease caused by exposure to environmental agents can be ameliorated by IL-2 supplement and ectopic FasL expression.
