Mercury Induced Autoimmunity

Scripps Research Institute, The, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Exposure to xenobiotics can produce aberrant immune reactions, including autoimmunity. Exposure of mice to the heavy metal mercury leads to systemic autoimmunity with characteristic lymphadenopathy, hypergammaglobulinemia, autoantibodies and immune complex disease. In both idiopathic and mercury-induced autoimmunity (mHglA) reductions in IFN-gamma levels are associated with reductions in both autoantibody levels and immune-complex mediated pathology. Prior studies have revealed that genes, which control IFN-gamma expression, such as IL-4, IL-12, STAT4 and ICE, do not significantly influence the development of mHglA. However absence of genes involved in IFN-gamma function (IFN-gamma, IFN-gamma receptor, IRF-1) suppresses development of mHglA, suggesting that specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction control disease expression. These observations underlie the hypothesis that mHgIA is dependent upon IFN-gamma and that the severity of disease is regulated by molecular and cellular events downstream of IFN-gamma expression. This hypothesis will be addressed by four specific aims:- 1) Determination of the Site and Kinetics of IFN-gamma Production in mHglA, 2) Determination of the Cellular Requirements Leading to IFN-gamma Dependent mHglA, 3) Determination of the Genetic Requirements Leading to lFN-gamma Dependent mHglA, and 4) Examination of the Suppression of the IFN-gamma Response as a Therapy for IFN-gamma Dependent mHglA. Identification of the role that IFN-gamma plays in the development of induced murine systemic autoimmunity should prove applicable to murine models of idiopathic systemic autoimmunity and to human lupus.