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Perchloroethylene Exposure and Autoimmunity

全氯乙烯暴露和自身免疫

基本信息

批准号：
8701671
负责人：
M. FIROZE KHAN
金额：
$ 17.5万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701671
关键词：
4 hydroxynonenal Address Affinity Aldehydes Animals Antibodies Antibody Formation Antigen-Antibody Complex Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Binding Blood capillaries Cardiolipins Chemicals Common Epitope Data Deposition Dermal Disease Environment Environmental Pollution Evaluation Exanthema Exhibits Exposure to Female Generations Glomerulonephritis Goals Human Immune response Industry Kidney Lead Link Lipid Peroxidation Malondialdehyde Measures Metabolism Metals Modality Mus Nuclear Occupational Organ Population Prevention Preventive Proteins Proteomics Role Scleroderma Serum Skin Specificity Symptoms Systemic Lupus Erythematosus Tetrachloroethylene Textiles Therapeutic Tissues Toxic effect Vasculitis adduct arteriole base capillary design high reward high risk innovation macromolecule mouse model novel strategies prevent public health relevance research study response sound

项目摘要

DESCRIPTION (provided by applicant): Tetrachloroethylene (perchloroethylene; PCE) is a widely used dry-cleaning, fabric-finishing and metal degreasing agent. Large number of humans are exposed to this chemical either occupationally or through the environment. Besides its organ toxicity, PCE exposure has been implicated in inducing autoimmunity and/or autoimmune diseases (ADs), as evident from high levels of anti-nuclear antibodies, rashes, scleroderma and systemic lupus erythematosus (SLE)-like symptoms. The focus of this proposal is to establish that PCE exposure induces/exacerbates an autoimmune response and to elucidate the putative mechanism(s) of such response. We hypothesize that PCE can induce an autoimmune response through two possible mechanisms: 1) via PCE metabolism where metabolite-adducted proteins can act as neoantigens, and/or 2) via lipid peroxidation (LPO) where LPO-derived reactive aldehydes (LPDAs) such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA) can form LPDA-protein adducts and elicit an autoimmune response. Generation of neoantigen(s) via either of these mechanisms can elicit the production of antibodies against such neoantigen(s). These antibodies are expected to exhibit diverse specificities, particularly towards cellular macromolecule(s) to which PCE metabolites or LPDAs are bound and those macromolecules which share common epitopes. The binding of antibodies to these macromolecules would be detrimental to tissues and/or organs and eventually lead to ADs. Using female MRL +/+ and NZB/WF1 mice (autoimmune-prone) and B6C3F1 mice (non-autoimmune), the potential of PCE in inducing and/or exacerbating ADs will be evaluated by determining the markers of autoimmunity in the serum [anti-nuclear (ANA)-, anti-single stranded DNA (anti- ssDNA)-, anti-double stranded DNA (anti-dsDNA)-, anti-cardiolipin- and anti-Scl70-antibodies, and circulating immune complexes], and morphological assessment of tissues, especially kidneys (glomerulonephritis, vasculitis and deposition of immune complexes) and skin (perivascular infiltrates, thickening of the walls of dermal arterioles and capillaries). We will also evaluate te role of innate immune response in the progression to PCE-induced autoimmunity (Aim 1). Furthermore, to elucidate the mechanism(s) of PCE-induced autoimmunity and support our hypothesis, we will characterize trichloroacylated-protein adducts and LPDA- protein adducts using proteomic approaches in the tissues and/or serum of PCE-treated mice for quantitation and evaluation of their autoimmune potential. Antibodies to trichloroacylated-protein adducts and LPDA- protein adducts will also analyze for correlation with autoimmunity markers (Aim 2). These studies will establish that PCE induces and/or accelerates an autoimmune response and will also provide a link between PCE exposure, adducted proteins and autoimmunity. These studies will eventually help in designing strategies to prevent or reduce ADs resulting from exposure to PCE or related environmental/occupational agents.

描述（申请人提供）：四氯乙烯（全氯乙烯；PCE）是一种广泛使用的干洗、织物整理和金属脱脂剂。许多人因职业或环境而接触这种化学物质。除了其器官毒性外，四氯乙烯暴露还可能诱发自身免疫和/或自身免疫性疾病 (AD)，这一点从高水平的抗核抗体、皮疹、硬皮病和系统性红斑狼疮 (SLE) 样症状中可见一斑。该提案的重点是确定四氯乙烯暴露会诱发/加剧自身免疫反应，并阐明此类反应的假定机制。我们假设 PCE 可以通过两种可能的机制诱导自身免疫反应：1）通过 PCE 代谢，其中代谢物加合蛋白可以充当新抗原，和/或 2）通过脂质过氧化（LPO），其中 LPO 衍生的反应性醛（LPDA），例如 4-羟基壬烯醛（HNE）和丙二醛 (MDA) 可形成 LPDA 蛋白加合物并引发自身免疫反应。通过这些机制中的任一种产生新抗原可以引发针对此类新抗原的抗体的产生。这些抗体预计表现出不同的特异性，特别是针对与 PCE 代谢物或 LPDA 结合的细胞大分子以及具有共同表位的那些大分子。抗体与这些大分子的结合将对组织和/或器官有害，并最终导致AD。使用雌性 MRL +/+ 和 NZB/WF1 小鼠（易发生自身免疫）和 B6C3F1 小鼠（非自身免疫），通过测定血清中的自身免疫标志物 [抗核 (ANA)-、抗单链 DNA (抗 ssDNA)-、抗双链 DNA（抗 dsDNA）、抗心磷脂和抗 Scl70 抗体以及循环免疫复合物]，以及组织的形态学评估，特别是肾脏（肾小球肾炎、血管炎和免疫复合物沉积）和皮肤（血管周围浸润、真皮小动脉壁增厚和毛细血管）。我们还将评估先天免疫反应在 PCE 诱导的自身免疫进展中的作用（目标 1）。此外，为了阐明 PCE 诱导的自身免疫的机制并支持我们的假设，我们将使用蛋白质组学方法在 PCE 处理的小鼠的组织和/或血清中表征三氯酰化蛋白加合物和 LPDA 蛋白加合物，以定量和评估其自身免疫潜力。三氯酰化蛋白加合物和 LPDA 蛋白加合物的抗体也将分析与自身免疫标记物的相关性（目标 2）。这些研究将确定 PCE 诱导和/或加速自身免疫反应，并将提供 PCE 暴露、加合蛋白和自身免疫之间的联系。这些研究最终将有助于设计预防或减少因接触四氯乙烯或相关环境/职业因素而导致的 AD 的策略。