Mechanism(s) of TCE-Mediated Autoimmunity

描述（由申请人提供）：我们的长期目标是阐明环境化学物质诱发疾病的机制，以便设计预防性治疗和/或干预措施。三氯乙烯（三氯乙烯，TCE）是一种环境污染物，与引起自身免疫性疾病有关。然而，目前还没有系统的研究确定其在诱导/加重此类疾病中的潜力，或阐明tce诱导自身免疫的机制，这是本应用的重点。根据文献和我们的初步研究，我们假设TCE和/或其代谢物与内源性蛋白质结合。这些蛋白质加合物引起T细胞和B细胞的反应，从而逃避对自身蛋白质的正常耐受，导致自身免疫样疾病。这一假设将通过追求四个特定目标来验证：1)通过在雌性MRL+/+小鼠中进行剂量和时间依赖性研究来确定TCE的自身免疫潜力；自身免疫反应将通过测量自身抗体和tce特异性抗体、循环免疫复合物、T细胞功能的改变以及检查形态学变化来评估。2)为了研究TCE代谢物在诱导自身免疫中的作用，我们将研究自身免疫对TCE代谢物的反应。3)鉴定与自身免疫反应相关的TCE蛋白加合物[抗原]。蛋白质加合物将从主要组织中纯化并表征，其自身免疫潜力将在小鼠中进行测试。4)探讨T细胞在tce诱导的自身免疫反应中的作用。将评估T细胞对TCE及其蛋白加合物的反应（例如，细胞增殖和细胞因子的产生）。这些研究应确立TCE诱导自身免疫，并对这些反应的机制提供见解。我们的研究结果将在设计预防或减少对TCE和其他相关工业化学品的自身免疫反应的策略方面具有重要意义。此外，阐明tce诱导的自身免疫机制将为早期发现、医疗干预或治疗开辟道路，以预防或管理各种化学诱导的自身免疫疾病。

DESCRIPTION (provided by applicant): 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.