Our long-term goal is to elucidate the mechanism(s) by which environmental chemicals induce diseases so that preventive therapies and/or interventions can be devised. Trichloroethene (trichloroethylene, TCE), an environmental contaminant, is implicated in causing autoimmune-like diseases. However, no systematic studies have yet established its potential in inducing/exacerbating such diseases, or elucidated the mechanism(s) to TCE-induced autoimmunity, which is the focus of this application. Based upon the literature and our preliminary studies, we hypothesize that TCE and/or its metabolites bind to endogenous protein(s). These protein adducts elicit T and B cell responses that escape the normal tolerance to self-protein(s), leading to autoimmune-like diseases. This hypothesis will be tested by pursuing four Specific Aims: 1) To determine the autoimmune potential of TCE by conducting dose-and time-dependent studies in female MRL+/+ mice; autoimmune responses will be assessed by measuring autoantibodies and TCE-specific antibodies, circulating immune complexes, alterations in T cell functions, and by examining morphological changes. 2) To address the contribution of TCE metabolites to the induced autoimmunity, autoimmune responses to TCE-metabolites will be examined. 3) To identify the protein adduct(s) [antigen(s)] of TCE responsible for autoimmune responses. Protein adduct(s) will be purified from major tissues and characterized, and their autoimmune potential will be tested in mice. 4) To examine the role of T cells in TCE-induced autoimmune response. T cell responses (e.g., cell proliferation and the production of cytokines) to TCE and its protein-adducts(s) will be assessed. These studies should establish that TCE induces autoimmunity and provide insights into the mechanism(s) responsible for these responses. Our results will be important in designing strategies to prevent or reduce autoimmune responses to TCE and other related industrial chemicals. Furthermore, elucidating the mechanism(s) of TCE-induced autoimmunity will open avenues for early detection, medical interventions or therapies to prevent or manage various chemical-induced autoimmune diseases.
