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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Program Officer
Mastin, Patrick
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
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

Showing the most recent 10 out of 30 publications