Oxidative Stress and Autoimmunity

摘要 氧化应激(OS)与自身免疫性疾病(ADS)的发病机制有关，包括 系统性红斑狼疮(SLE)和大量环境化学物质被认为是引起OS的原因。 我们的长期目标是阐明操作系统在环境诱导的广告开发中的作用 并利用这些信息设计预防或治疗策略。三氯乙烯(TCE) 与导致广告有关，包括人类的SLE样疾病。此前，我们已经建立了一个 TCE介导的OS与自身免疫反应/系统性红斑狼疮的相关性这种竞争性的延续 应用程序的前提是TCE暴露会影响各种操作系统响应路径，从而导致 致病反应。我们假设TCE诱导的氧化应激导致PARP-1和PARP-1的损伤 NRF-2的表达，导致有害的炎症/自身免疫反应。此外，脂质衍生的反应 醛(LDRA)引起内源蛋白质的结构修饰，导致形成 新的抗原，通过淋巴细胞激活，有助于ADS。为了检验我们的假设，以下是具体的 提出AIMS：AIM 1将定义PARP-1激活在TCE介导的自身免疫/SLE中的作用，并将 检验TCE诱导的PARP-1激活导致促炎反应和 对系统性红斑狼疮/自身免疫性的易感性较高。这一目标的研究将建立PARP-1之间的明确联系 激活和TCE介导的自身免疫/SLE，决定了PARP-1的调节消除了TCE-1- 介导自身免疫应答并检测PARP-1‘S作为核因子-kB介导的辅活化子的潜能 促炎介质/细胞因子的转录。目标2将确定受损的Nrf2表达发挥作用 在三氯乙烯介导的系统性红斑狼疮的发病机制中起关键作用，并将检验减少表达的假设 Nrf2的表达加剧了TCE介导的狼疮性肾炎的发展。NRF2的激活可能会减弱 炎症与疾病发病机制。这一目标的研究将证实，缺乏NRF2会加剧 TCE介导的自身免疫反应，并确定抗氧化剂萝卜硫素(SFN)改善 TCE通过上调Nrf2介导的SLE。目标3将阐明脂质衍生的反应醛(LDRAs) 有助于三氯乙烯介导的系统性红斑狼疮，并将检验LDRA修饰内源蛋白的假设 结果形成新的抗原，通过激活淋巴细胞可以引发自身免疫反应。 我们将确定LDRA蛋白加合物促进T细胞，特别是Th17细胞的增殖，并诱导 炎性细胞因子。此外，我们将表征LDRA-蛋白质加合物(蛋白质组学方法)和 确定它们的自身免疫潜力。我们的研究将坚定地确立OS在诱导和/或 自身免疫/系统性红斑狼疮的恶化，将描绘出新的发病机制，并将作为一种 翻译策略的垫脚石，以防止对三氯乙烯和其他化学品/药物的自身免疫反应 已知会通过操作系统造成毒性。

Abstract Oxidative stress (OS) has been implicated in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), and a large number of environmental chemicals are known to cause OS. Our long-term goal is to elucidate the role of OS in the development of ADs that are induced by environmental chemicals, and use this information to design preventive or therapeutic strategies. Trichloroethene (TCE) has been implicated in causing ADs, including SLE-like diseases in humans. Previously, we have established an association between TCE-mediated OS and autoimmune response/SLE. This competitive continuation application is based on the premise that TCE exposure affects diverse OS-responsive pathways to lead to a pathogenic response. We hypothesize that TCE-induced oxidative stress causes impairment in PARP-1 and Nrf-2 expression, leading to a harmful inflammatory/autoimmune response. Furthermore, lipid-derived reactive aldehydes (LDRAs) cause structural modifications to endogenous proteins, resulting in the formation of neoantigens which, via lymphocyte activation, contribute to ADs. To test our hypothesis, the following specific aims are proposed: Aim 1 will define the role of PARP-1 activation in TCE-mediated autoimmunity/SLE and will test the hypothesis that TCE-induced activation of PARP-1 leads to a pro-inflammatory response and confers higher susceptibility for SLE/autoimmunity. Studies in this aim will establish a clear link between PARP-1 activation and TCE-mediated autoimmunity/SLE, determine that modulation of PARP-1 abrogates TCE- mediated autoimmune response, and examine PARP-1's potential to act as a coactivator of NF-kB-mediated transcription of pro-inflammatory mediators/cytokines. Aim 2 will determine that impaired Nrf2 expression plays a critical role in the pathogenesis of TCE-mediated SLE, and will test the hypothesis that reduced expression of Nrf2 exacerbates the development of TCE-mediated lupus nephritis. Nrf2 activation will likely attenuate inflammation and disease pathogenesis. Studies in this aim will establish that absence of Nrf2 exacerbates TCE-mediated autoimmune response, and also determine that antioxidant sulforaphane (SFN) ameliorates TCE-mediated SLE by upregulating Nrf2. Aim 3 will elucidate that lipid-derived reactive aldehydes (LDRAs) contribute to TCE-mediated SLE, and will test the hypothesis that LDRA modification of endogenous proteins results in the formation of neo-antigens, which by activating lymphocytes can elicit an autoimmune response. We will determine that LDRA-protein adducts aggravate T cell proliferation, especially Th17 cells, and induce inflammatory cytokines. Furthermore, we will characterize LDRA-protein adducts (proteomic approaches) and determine their autoimmune potential. Our studies will firmly establish a role for OS in the induction and/or exacerbation of autoimmunity/SLE, will delineate novel mechanisms of pathogenesis, and will serve as a stepping stone to translational strategies to prevent autoimmune responses to TCE and other chemicals/drugs known to cause toxicity via OS.