Oxidative Stress and Autoimmunity

摘要 氧化应激（OS）与自身免疫性疾病（AD）的发病机制有关，包括 系统性红斑狼疮（SLE）和大量的环境化学物质已知引起OS。 我们的长期目标是阐明OS在环境因素诱导的AD发生中的作用， 化学品，并使用这些信息来设计预防或治疗策略。三氯乙烯（TCE） 与引起AD有关，包括人类的SLE样疾病。此前，我们已建立了一个 TCE介导的OS与自身免疫反应/SLE之间的相关性。这种竞争性的延续 应用是基于这样的前提，即TCE暴露会影响多种OS响应途径， 致病反应我们假设TCE诱导的氧化应激导致PARP-1受损， nrf-2表达，导致有害的炎症/自身免疫反应。此外，脂质衍生的反应性 醛（LDRA）引起内源性蛋白质的结构修饰，导致形成 新抗原，其通过淋巴细胞活化导致AD。为了验证我们的假设，以下具体 提出了以下目标：目标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活化导致促炎反应并赋予 对SLE/自身免疫的易感性更高。这方面的研究将建立PARP-1之间的明确联系 活化和TCE介导的自身免疫性/SLE，确定PARP-1的调节消除TCE- 介导的自身免疫反应，并检查PARP-1作为NF-κ B介导的自身免疫反应的共激活剂的潜力。 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TCE介导的SLE发病机制中起关键作用，并将检验表达减少的假设， Nrf2的过度表达加剧了TCE介导的狼疮性肾炎的发展。Nrf2激活可能会减弱 炎症和疾病发病机制。这方面的研究将确定Nrf2的缺乏会加重 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。目的3阐明脂质衍生的反应性醛（LDRAs） 有助于TCE介导的SLE，并将测试的假设，LDRA修饰的内源性蛋白质 导致新抗原的形成，新抗原通过激活淋巴细胞可以引发自身免疫应答。 我们将确定LDRA-蛋白加合物加剧T细胞增殖，特别是Th17细胞，并诱导T细胞增殖。 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）， 决定自身免疫能力我们的研究将坚定地确立OS在诱导和/或 自身免疫/SLE的恶化，将描绘新的发病机制，并将作为一种新的治疗方法。 预防对TCE和其他化学品/药物的自身免疫反应的转化策略的垫脚石 已知通过操作系统导致毒性。

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.