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.
| Pollard, K Michael; Christy, Joseph M; Cauvi, David M et al. (2018) Environmental Xenobiotic Exposure and Autoimmunity. Curr Opin Toxicol 10:15-22 |
| Pollard, K Michael; Escalante, Gabriela M; Huang, Hua et al. (2017) Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN. J Immunol 199:3739-3747 |
| Toomey, Christopher B; Cauvi, David M; Hamel, John C et al. (2014) Cathepsin B regulates the appearance and severity of mercury-induced inflammation and autoimmunity. Toxicol Sci 142:339-49 |
| Pollard, Kenneth M; Cauvi, David M; Toomey, Christopher B et al. (2013) Interferon-? and systemic autoimmunity. Discov Med 16:123-31 |
| Pollard, K Michael; Hultman, Per; Toomey, Christopher B et al. (2012) Definition of IFN-?-related pathways critical for chemically-induced systemic autoimmunity. J Autoimmun 39:323-31 |
| Cauvi, David M; Toomey, Christopher B; Pollard, K Michael (2012) Depletion of complement does not impact initiation of xenobiotic-induced autoimmune disease. Immunology 135:333-43 |
| Pollard, Kenneth M; Hultman, Per; Toomey, Christopher B et al. (2011) ?2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity. J Immunotoxicol 8:228-37 |
| Pollard, K Michael; Hultman, Per; Kono, Dwight H (2010) Toxicology of autoimmune diseases. Chem Res Toxicol 23:455-66 |
| Toomey, Christopher B; Cauvi, David M; Song, Wen-Chao et al. (2010) Decay-accelerating factor 1 (Daf1) deficiency exacerbates xenobiotic-induced autoimmunity. Immunology 131:99-106 |
| Havarinasab, S; Pollard, K M; Hultman, P (2009) Gold- and silver-induced murine autoimmunity--requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity. Clin Exp Immunol 155:567-76 |
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