Oxidative Stress and Autoimmunity

描述（由申请人提供）：环境化学物质与自身免疫性疾病（ADs）的病原体有关。我们的长期目标是阐明脂质过氧化衍生醛（LPDAs）和活性氮（RNS）在化学暴露诱导和/或加剧ad发展中的作用。活性氧和活性氮（RONS）的增加与ad的发病机制有关，并且已知大量化学物质会产生活性氧和活性氮。相应的，脂质过氧化和蛋白质硝化的增加也在系统性ad中被报道。我们假设LPDAs和RNS的增加通过共价结合和/或氧化导致内源性大分子（包括蛋白质）的结构改变，从而导致新抗原的形成。经过抗原处理后，这些新抗原可通过刺激T淋巴细胞和B淋巴细胞引发自身免疫反应，最终导致系统性红斑狼疮（SLE）等ad。这一假设将通过四个具体目标来验证：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+/+）和抗性（B6C3F1）小鼠暴露于三氯乙烯（TCE，一种已知引起脂质过氧化/RNS的环境化学物质）来实现。lpda蛋白加合物（肝脏、肾脏和脾脏）及其相应抗体的形成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CYP2E1敲除MRL +/+小鼠进一步确定；2)建立TCE诱导的RNS在自身免疫中的作用。使用iNOS抑制剂和iNOS敲除MRL +/+小鼠，我们将评估RNS在导致自身免疫中的潜力；3)阐明脂质过氧化引起自身免疫的机制。利用lda蛋白加合物，阐明T细胞在自身免疫中的作用；4)明确SLE患者血清中氧化/亚硝化应激特征。利用SLE患者的血清，将建立氧化应激标志物与疾病进展之间的联系。我们的研究将确立氧化应激作为ad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，为基于机制的风险评估提供途径。

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.