Xenobiotics, Lipid Peroxidation and Autoimmunity

描述（由申请人提供）：自身免疫性疾病（AD），如系统性红斑狼疮（SLE）和硬皮病是严重的病理状态，其中针对自身抗原的免疫应答导致结构和/或功能损伤。 这些疾病的病因在很大程度上是未知的，虽然遗传，激素，营养和环境因素可能有助于其发病机制。 脂质过氧化（LPO）是细胞损伤的主要因素，也与AD的发病机制有关。 我们的长期目标是阐明LPO在化学暴露诱导和/或加剧的AD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）共价修饰蛋白质以形成LPDA-蛋白质加合物，但其引发自身免疫应答的潜力尚未阐明。 我们假设LPDA的共价结合导致内源性大分子（包括蛋白质）的结构改变，从而导致新抗原的形成。 抗原加工后，这些新抗原（LPDA修饰的蛋白质）通过刺激T和B淋巴细胞引发自身免疫反应，导致SLE和硬皮病等疾病。 此外，持续增加抗体LPDA-蛋白加合物可能导致免疫复合物的形成，其在组织中的沉积可能是AD的致病机制。 这一假设将通过以下三个具体目标进行检验：1）研究环境化学品处理的自身免疫易感（MRL+/+）和自身免疫抵抗（B6 C3 F1）小鼠中LPDA-蛋白加合物形成的动力学（三氯乙烯和百草枯）已知会引起脂质过氧化; 2）通过定量特异性抗体，建立LPDA增加与自身免疫发展之间的联系（对LPDA-蛋白质加合物）和各种自身抗体、循环免疫复合物以及主要组织（包括肝、肾、脾和皮肤）的形态学评估;和3）开始建立由LPO引起的自身免疫的机制。 将进行实验以阐明T细胞在LPDA诱导的自身免疫中的作用。 我们的研究与自身免疫易感和耐药的小鼠和模型化学品应建立LPO作为AD的致病机制，并打开重要的途径，临床干预，通过发展疾病标志物的医学监测，和风险评估。

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.