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品诱发疾病的机制，以便设计预防性治疗和/或干预措施。三氯乙烯（三氯乙烯，TCE），一种环境污染物，涉及引起自身免疫样疾病。然而，尚未有系统的研究确定其诱导/加重此类疾病的潜力，或阐明TCE诱导自身免疫的机制，这是本申请的重点。基于文献和我们的初步研究，我们假设TCE和/或其代谢产物与内源性蛋白质结合。这些蛋白加合物引起T和B细胞应答，其逃避对自身蛋白的正常耐受，导致自身免疫样疾病。将通过以下四个特定目的来检验这一假设：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;将通过测量自身抗体和TCE特异性抗体、循环免疫复合物、T细胞功能改变以及检查形态学变化来评估自身免疫应答。2)为了解决TCE代谢物对诱导的自身免疫的贡献，将检查对TCE代谢物的自身免疫反应。3)鉴定TCE的蛋白加合物[抗原]，负责自身免疫反应。将从主要组织中纯化蛋白加合物并进行表征，并在小鼠中测试其自身免疫潜力。4)探讨T细胞在TCE诱导的自身免疫反应中的作用。T细胞应答（例如，细胞增殖和细胞因子的产生）对TCE及其蛋白加合物的影响。这些研究应该确定TCE诱导自身免疫，并提供对这些反应的机制的见解。我们的研究结果将是重要的设计策略，以防止或减少自身免疫反应TCE和其他相关的工业化学品。此外，阐明TCE诱导的自身免疫性的机制将为早期检测、医学干预或治疗开辟途径，以预防或管理各种化学诱导的自身免疫性疾病。

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.