XENOBIOTIC ACCELERATION OF AUTOIMMUNITY

Scripps Research Institute, La Jolla CA

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Abstract

Exposure to toxins such has heavy metals can be associated with aberrant immune reactions, including autoimmunity in humans and animals. Healthy mice exposed to mercury, silver or gold exhibit a variety of genetically restricted immunopathological responses that range from lymphoproliferation to systematic autoimmune disease. Although there is little information on the immunopathological effects on environmentally relevant exposure to these heavy metals, the immune activating potential of heavy metals suggest that low level exposure in hosts genetically predisposed to develop autoimmunity may accelerate the appearance of features of autoimmune disease. To test this possibility, preautoimmune BXSB, MRL and (NZBxNZW)F1 mice will be exposed to a range of mercury concentration to determine the effect of dosage, age and time of exposure in eliciting features of autoimmunity. Mice will be tested for the in vivo appearance of pathological responses that characterize the spontaneous appearance of autoimmunity in these strains, such as hypergammaglobulinemia, autoantibodies of defined specificity to chromatin and sub-chromatin structures, changes in cytokine expression, lymphoid cell activation and proliferation, immune-complex disease and proteinuria. These studies will test the hypothesis that mercury accelerates the onset of systemic autoimmunity by stimulating autoreactive mature T cells to proliferate. Mercury-induced T cell activation should lead to enhanced T-B cell collaboration and production of autoantibodies. Analysis of the effect of environmentally relevant concentrations of mercury to alter the natural history of systemic autoimmune disease will provide a greater understanding of the role of environmental exposure to xenobiotics in the exacerbation of human autoimmune disease.