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    Cellular regulation of mercury-induced autoimmunity

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    Genre
    Thesis/Dissertation
    Date
    2009
    Author
    Jha, Vibha
    Advisor
    Monestier, Marc
    Committee member
    Tsygankov, Alexander Y.
    Buttaro, Bettina A.
    Cohen, Philip L.
    Denny, Michael F.
    Department
    Microbiology and Immunology
    Subject
    Health Sciences, Immunology
    Anti-cd3
    Autoimmunity
    Lag-3
    Mercury
    Murine
    Regulatory T Cells
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/1536
    
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    DOI
    http://dx.doi.org/10.34944/dspace/1518
    Abstract
    Etiological agents causing autoimmune diseases largely remain unknown. However, several lines of evidence suggest that environmental factors such as heavy metals (arsenic, lead and mercury) play a crucial role in the development of autoimmune disorders. In our model of mercury-induced autoimmunity, administration of subtoxic doses of HgCl2 to genetically susceptible strains of mice result in an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hypergammaglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of HgCl2 (tolerogenic dose). Previous studies from our lab had demonstrated that CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) control the induction and maintenance of tolerance to mercury. We investigated the therapeutic role of Tregs in our model by utilizing agents that are known to stimulate in vivo expansion of Tregs. We studied two such agents, CD3-specific non-Fc receptor-binding [(Fab’)2 fragment] monoclonal antibody (Anti-CD3) and immune complexes containing recombinant IL-2 and anti-IL-2 monoclonal antibody (IC). In our model, treatment of mice with Anti-CD3 had no effect on Treg population. Administration of Anti-CD3 with the tolerogenic dose prevented induction of tolerance and failed to improve the maintenance period of tolerance. Anti-CD3 in presence of mercury activated the immune-system causing splenomegaly and expansion of B cell population. Overall, in contrast to its protective role in other experimental autoimmune disease models, Anti-CD3 exacerbated mercury-induced autoimmune syndrome. Treatment of mice with IC resulted in selective expansion of Tregs with a modest decrease in IgE levels and autoantibody production. Administration of IC with the tolerogenic dose led to a reduction in autoantibody response, thus IC was able to extend the maintenance period of tolerance to mercury. Lymphocyte Activation Gene-3 (LAG-3) is an inhibitory molecule that maintains lymphocyte homeostatic balance by controlling effector T cell expansion and contributing to the suppressive functions of Tregs. Thus, with the goal to understand the impact of homeostatic balance on Hg-induced autoimmunity, we investigated the role of LAG-3 in our model. Administration of an anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in levels of serum IgE. Additionally, LAG-3-deficient B6.SJL mice exhibited an increased susceptibility to mercury-induced autoimmunity whereas, wild type controls suffered only from a mild disease. Moreover, adoptive transfer of wild-type CD4+ T cells protected LAG-3-deficient mice from mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.
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