Xenobiotics, Lipid Peroxidation and Autoimmunity

描述(申请人提供)：自身免疫性疾病(ADS)，如系统性红斑狼疮(SLE)和硬皮病，是针对自身抗原的免疫反应导致结构和/或功能损害的严重病理状况。这些疾病的病因在很大程度上是未知的，尽管遗传、激素、营养和环境因素可能与它们的发病机制有关。脂质过氧化(LPO)是细胞损伤的主要因素，也参与了ADS的发病机制。我们的长期目标是阐明LPO在化学暴露诱导和/或加剧的ADS发展中的作用。LPO衍生的反应性醛(LPDA)，如丙二醛(MDA)、4-羟基壬烯醛(HNE)和4-羟基己烯醛(HHE)，可以共价修饰蛋白质形成LPDA-蛋白质加合物，但它们诱导自身免疫反应的可能性尚未阐明。我们假设LPDA的共价结合会引起包括蛋白质在内的内源性大分子的结构变化，从而导致新抗原的形成。在抗原处理后，这些新抗原(LPDA修饰的蛋白质)通过刺激T和B淋巴细胞而引发自身免疫反应，并导致SLE和硬皮病等疾病。此外，LPDA蛋白加合物抗体的持续增加可能导致免疫复合体的形成，其沉积在组织中可能是ADS的致病机制。为验证这一假说，将达到三个特定目标：1)研究用已知可引起脂质过氧化的环境化学品(三氯乙烯和百草枯)处理的自身免疫易发小鼠(MRL+/+)和耐药小鼠(B6C3F1)中LPDA蛋白加合物的形成动力学；2)通过对特异性抗体(针对LPDA蛋白质加合物)和各种自身抗体、循环免疫复合物的定量以及包括肝、肾、脾和皮肤在内的主要组织的形态评估，建立LPDA增加与自身免疫之间的联系；以及3)开始建立LPO引起自身免疫的机制(S)。将进行实验以阐明T细胞在LPDA诱导的自身免疫中的作用。我们对自身免疫易感和耐药小鼠和模型化学物质的研究应该建立LPO作为ADS的致病机制，并为临床干预、通过开发疾病标记物进行医学监测和风险评估开辟重要途径。

DESCRIPTION (provided by applicant): Autoimmune diseases (ADs) such as systemic lupus erythematosus (SLE) and scleroderma are serious pathological conditions in which immune responses against autoantigens cause structural and/or functional damage. The etiology of these diseases is largely unknown, although genetic, hormonal, nutritional and environmental factors may contribute to their pathogenesis. Lipid peroxidation (LPO), a major contributor to cellular damage, is also implicated in the pathogenesis of ADs. Our long-term goal is to elucidate the role of LPO in the development of ADs induced and/or exacerbated by chemical exposure. LPO-derived reactive aldehydes (LPDAs) such as malondialdehyde (MDA), 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), covalently modify proteins to form LPDA-protein adducts, but their potential to elicit an autoimmune response has not been elucidated. We hypothesize that covalent binding of LPDAs cause structural alterations to endogenous macromolecules, including proteins, resulting in the formation of neoantigens. After antigen processing, these neoantigens (LPDA-modified proteins) elicit autoimmune responses by stimulating T and B-lymphocytes and leading to diseases like SLE and scleroderma. Further, persistent increases in antibodies to LPDA-protein adducts may lead to formation of immune complexes whose deposition in tissues could be a pathogenic mechanism of ADs. This hypothesis will be tested by pursuing three Specific Aims: 1) To study the kinetics of formation of LPDA-protein adducts in autoimmunity-prone (MRL+/+) and -resistant (B6C3F1) mice treated with environmental chemicals (trichloroethene and paraquat) known to cause lipid peroxidation; 2) To establish a link between increased LPDAs and the development of autoimmunity, by quantitating specific antibodies (to LPDA-protein adducts) and various autoantibodies, circulating immune complexes and by morphological assessment of major tissues, including liver, kidney, spleen and skin; and 3) To begin to establish the mechanism(s) of autoimmunity resulting from LPO. Experiments will be performed to elucidate the role of T cells in LPDA-induced autoimmunity. Our studies with autoimmune-prone and -resistant mice and the model chemicals should establish LPO as pathogenic mechanism of ADs, and open important avenues for clinical intervention, medical surveillance through the development of disease markers, and risk assessment.