Oxidative Stress and Autoimmunity

描述（由申请人提供）：环境化学品是自身免疫性疾病（AD）的致病因子。我们的长期目标是阐明脂质过氧化衍生的醛（LPDAs）和活性氮（RNS）在化学暴露诱导和/或加剧的AD发展中的作用。活性氧和氮物质（RONS）的产生增加与AD的发病机制有关，已知大量化学物质会产生RONS。相应地，在全身性AD中也报告了脂质过氧化和蛋白质硝化增加。我们假设LPDA和RNS的产生增加通过共价结合和/或氧化引起内源性大分子（包括蛋白质）的结构改变，从而导致新抗原的形成。抗原加工后，这些新抗原可通过刺激T和B淋巴细胞引发自身免疫应答，最终导致AD，如系统性红斑狼疮（SLE）。这一假设将通过四个具体目标进行测试：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易感（MRL+/+）和耐药（B6 C3 F1）小鼠暴露于三氯乙烯（TCE，一种已知可引起脂质过氧化/RNS的环境化学品）来实现。LPDA-蛋白加合物（在肝、肾和脾中）及其相应抗体的形成将与自身免疫应答相关。氧化应激在自身免疫中的作用将通过铁超负荷、N-乙酰半胱氨酸给药和使用CYP 2 E1敲除MRL +/+小鼠进一步确定; 2）确定TCE诱导的RNS在自身免疫中的作用。利用iNOS抑制剂和iNOS基因敲除MRL +/+小鼠，我们将评估RNS导致自身免疫的潜力; 3）阐明脂质过氧化导致自身免疫的机制。利用LPDA-蛋白加合物，将阐明T细胞在自身免疫中的作用; 4）确定SLE患者血清中的氧化/亚硝化应激特征。使用SLE患者的血清，将建立氧化应激标志物和疾病进展之间的联系。我们的研究应该建立氧化应激作为一种致病机制的广告，并打开重要的途径，通过发展的疾病标志物的临床干预和医学监测，并将提供一个途径，机制为基础的风险评估。 与公共卫生的相关性：自身免疫性疾病是一种病因不明的严重病理状态。我们的目标是阐明氧化和亚硝化应激在这些疾病的发展中的作用。这项研究的结果将为这些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.