Exposure to toxins and chemicals can produce aberrant immune reactions which may include autoimmunity. Responses of inbred, congenic and hybrid mice following exposure to the heavy metal mercury has revealed a number of strain dependent immunopathologic sequlae including lymphadenopathy, hypergammaglobulinemia, and immune complex disease. Mercury also induces an MHC restricted autoantibody response inmice that predominantly targets the nucleolar protein fibrillarin. It has been argued that MHC-linked expression of particular cytokines, defining T helper cell types 1 or 2, are key controlling elements in heavy metal-induced immunopathology. While the importance of cytokines in this model is not disputed, it is possible that mercury induced immune aberrations, and autoantibody production in particular, are not strictly controlled by individual cytokines. The hypothesis to be tested is that mercury-induced activation of lymphoid cells and their interaction, through cytokines and cell surface receptors and accessory molecules, leads to lymphokkproliferation and hypergammaglobulinemia. In hosts bearing the appropriate genotypes this can lead to immune complex disease and autoantibody production, irrespective of the accompanying cytokine profile. In vitro studies will examine the interplay between cell type, cytokine profile, and cell surface receptor expression to identify the components required for mercury-induced lymphiod cell activation and lymphoproliferation. These observations will then be confirmed and extended within vivo studies using wildtype and gene knockout mice to define the roles of T cells subsets (CD4, CD8, TH1, TH2), B cells, MHC class I and class II expression, IL-4 and INF-gamma cytokine expression in mercury-induced immunopathology, particularly immune-complex disease and autoantibody production. Identification of the mechanisms of mercury-induced lymphoid cell activation and immunopathogenesis should provide important insights into the pathogenesis of chemical- induced autoimmunity, and may identify potential targets for intervention.
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