Oxidative Stress and Autoimmunity

描述(申请人提供)：环境化学物质被认为是自身免疫性疾病(ADS)的致病因素。我们的长期目标是阐明脂质过氧化衍生的醛(LPDA)和活性氮物种(RNS)在化学暴露诱导和/或加重ADS的发展中所起的作用。活性氧和氮物种(RON)的产生增加与ADS的发病机制有关，已知有大量的化学物质产生RON。相应地，系统性ADS中也有增加的脂质过氧化和蛋白质硝化的报道。我们假设，LPDA和RNS的产生增加会通过共价结合和/或氧化引起包括蛋白质在内的内源性大分子的结构变化，从而形成新的抗原。经过抗原处理后，这些新的抗原可以通过刺激T和B淋巴细胞来激发自身免疫反应，最终导致ADS，如系统性红斑狼疮(SLE)。这一假设将通过四个具体目标进行检验：1)描述氧化应激和自身免疫之间的联系。这将通过将自身免疫倾向(MRL/)和抵抗力(B6C3F1)小鼠暴露于三氯乙烯(TCE，一种已知会导致脂质过氧化/RNS的环境化学物质)来实现。LPDA蛋白加合物的形成(在肝、肾和脾)及其相应的抗体将与自身免疫反应相关。氧化应激在自身免疫中的作用将通过铁超载、N-乙酰半胱氨酸给药和使用CYP2E1基因敲除的MRL/小鼠来进一步确定；2)建立TCE诱导的RNS在自身免疫中的作用。利用诱导型一氧化氮合酶抑制剂和诱导型一氧化氮合酶基因敲除的MRL/小鼠，我们将评估RNS在导致自身免疫中的潜力；3)阐明脂质过氧化导致自身免疫的机制(S)。利用LPDA蛋白加合物，T细胞在自身免疫中的作用将被阐明；4)确定SLE患者血清中的氧化/亚硝化应激信号。利用SLE患者的血清，氧化应激标志物和疾病进展之间的联系将被建立。我们的研究应该建立氧化应激作为ADS的致病机制，并通过疾病标志物的开发为临床干预和医学监测开辟重要途径，并将为基于机制的风险评估提供途径。 与公共卫生相关：自身免疫性疾病是一种原因不明的严重病理疾病。我们的目标是阐明氧化和亚硝化应激在此类疾病发展中的作用。这项研究的结果将为此类疾病的预防和管理提供重要的见解。

DESCRIPTION (provided by applicant): Environmental chemicals are implicated as causative agents of autoimmune diseases (ADs). Our long-term goal is to elucidate the role of lipid peroxidation-derived aldehydes (LPDAs) and reactive nitrogen species (RNS) in the development of ADs induced and/or exacerbated by chemical exposure. Increased production of reactive oxygen and nitrogen species (RONS) has been implicated in the pathogenesis of ADs, and a large number of chemicals are known to produce RONS. Correspondingly, increased lipid peroxidation and protein nitration are also reported in systemic ADs. We hypothesize that increased production of LPDAs and RNS causes structural alterations to endogenous macromolecules, including proteins, through covalent binding and/or oxidation, resulting in the formation of neoantigens. Following antigen processing, these neoantigens can elicit autoimmune responses by stimulating T and B lymphocytes, eventually leading to ADs such as systemic lupus erythematosus (SLE). This hypothesis will be tested through four specific aims to: 1) Delineate the link between oxidative stress and autoimmunity. This will be achieved by exposing autoimmune-prone (MRL+/+) and -resistant (B6C3F1) mice to trichloroethene (TCE, an environmental chemical known to cause lipid peroxidation/RNS). Formation of LPDA-protein adducts (in liver, kidney and spleen) and their corresponding antibodies will be correlated with autoimmune response. The role of oxidative stress in autoimmunity will be further established through iron overload, N-acetylcysteine administration and use of CYP2E1 knockout MRL +/+ mice; 2) Establish the role of RNS induced by TCE in autoimmunity. Using iNOS inhibitors and iNOS knockout MRL +/+ mice, we will evaluate the potential of RNS in leading to autoimmunity; 3) Elucidate the mechanism(s) of autoimmunity resulting from lipid peroxidation. Utilizing LPDA-protein adducts, the role of T cells in autoimmunity will be elucidated; 4) Define oxidative/nitrosative stress signature in the sera of SLE patients. Using sera from SLE patients, a link between oxidative stress markers and disease progression will be established. Our studies should establish oxidative stress as a pathogenic mechanism of ADs, and open important avenues for clinical intervention and medical surveillance through the development of disease markers, and will provide an avenue for mechanism-based risk assessment. Relevance to Public Health: Autoimmune diseases are serious pathological conditions with unknown cause. Our goal is to elucidate the role of oxidative and nitrosative stress in the development of such diseases. The results of this study will provide important insight into the prevention and management of such diseases.