Xenobiotics, Lipid Peroxidation and Autoimmunity

描述（由申请人提供）：自身免疫性疾病（ADs），如系统性红斑狼疮（SLE）和硬皮病是严重的病理状况，其中针对自身抗原的免疫反应会导致结构和/或功能损伤。这些疾病的病因在很大程度上是未知的，尽管遗传、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ad发展中的作用。lpo衍生的活性醛（LPDAs），如丙二醛（MDA）、4-羟基壬烯醛（HNE）和4-羟基己烯醛（HHE），共价修饰蛋白质形成lpda蛋白加合物，但它们引发自身免疫反应的潜力尚未阐明。我们假设LPDAs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（lda修饰的蛋白）通过刺激T淋巴细胞和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，对lpda蛋白加合物的抗体持续增加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。这一假设将通过追求三个特定目的来验证：1)研究在已知引起脂质过氧化的环境化学物质（三氯乙烯和百草枯）处理过的自身免疫易感性（MRL+/+）和抗性（B6C3F1）小鼠中lpda蛋白加合物形成的动力学；2)通过定量特异性抗体（针对lpda蛋白加合物）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，建立LPDAs增加与自身免疫发展之间的联系；3)开始建立LPO引起自身免疫的机制。实验将用于阐明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及模型化学物质的研究，旨在确立LPO是ad的致病机制，并通过开发疾病标志物为临床干预、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.