ANTICARDIOLIPIN ANTIBODIES AND OXIDIZED PHOSPHOLIPIDS

抗心磷脂抗体和氧化磷脂

• 批准号: 2030750
• 负责人: Joseph L. Witztum
• 金额: $ 30.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2030750
• 关键词: anticoagulants; antigen antibody reaction; atherosclerosis; autoantibody; autoimmune disorder; blood vessel occlusion; cardiolipins; guinea pigs; human tissue; immunologic assay /test; laboratory mouse; laboratory rabbit; method development; monoclonal antibody; oxidation

DESCRIPTION (Adapted from Investigator's Abstract): Patients with the antiphospholipid syndrome (APS) have autoantibodies to certain phospholipids such as cardiolipin and/or the lupus anticoagulant and clinically experience recurrent venous or arterial thrombosis, history of fetal death and autoimmune thrombocytopenia. Patients with increased antiphospholipid antibodies (aPL) have increased risk of stroke and of myocardial infarction. However, diagnosis of elevated aPL has been frustrated by marked variation in assay results even between expert laboratories, and clinical management has been hampered by lack of an underlying hypothesis to explain why antibodies should form to such ubiquitous compounds as phospholipids, much less that aPL should occur in a variety of settings. A novel hypothesis is put forth that explains the etiology of some, if not most, aPL antibodies. It is proposed that aPL antibodies are directed against epitopes of oxidized phospholipids and/or against covalent adducts between breakdown products of oxidized phospholipids and associated proteins. A corollary is that most aPL are not directed to native, unmodified phospholipids. The hypothesis suggests that enhanced lipid peroxidation in vivo, either localized or generalized, leads to oxidation of phospholipids which creates new immunogenic epitopes. The resultant autoantibodies than have a variety of biological consequences. To test these hypotheses, a panel of aPL murine monoclonals directed at cardiolipin and phosphatidylserine using the spleens of apoE-deficient mice, which have a high titer of autoantibodies to both oxidized LDL and cardiolipin will be generated. These antibodies to epitopies of oxidized phospholipids will be used to determine the epitipes to which they bind and whether they act as lupus antiboagulants or induce altered biologic behavior. Finally this information and understanding will be used to develop more standardized assays which will be applied to selected patient populations. Validation of these hypotheses could lead not only to improved ability to detect high-risk individuals, but would suggest explanations for the etiology of these antibodies and possibly new therapeutic modalities (e.g., anti-inflammatory and/or antioxidant interventions).

描述（改编自研究者摘要）： 抗磷脂综合征（APS）具有针对某些磷脂的自身抗体 如心磷脂和/或狼疮抗凝剂， 复发性静脉或动脉血栓形成、胎儿死亡史和 自身免疫性血小板减少症 抗磷脂抗体升高的患者 抗体（aPL）增加了中风和心肌梗塞的风险。 然而，aPL升高的诊断因显著的变异而受挫。 即使在专家实验室和临床管理之间， 由于缺乏一个基本假设来解释为什么 抗体应该形成这种普遍存在的化合物，如磷脂， 更少aPL应该发生在各种环境中。 一个新的假设是， 提出了解释一些，如果不是大多数，aPL抗体的病因。 提出aPL抗体是针对氧化的表位， 磷脂和/或抗磷脂的分解产物之间的共价加合物， 氧化磷脂和相关蛋白质。 一个必然的结果是， aPL不涉及天然的、未改性的磷脂。 的假设 表明，增强脂质过氧化作用在体内，无论是局部或 一般来说，导致磷脂氧化，产生新的 免疫原性表位 所产生的自身抗体具有多种 生物后果。 为了验证这些假设，一组aPL小鼠 使用脾脏针对心磷脂和磷脂酰丝氨酸的单克隆抗体 apoE缺陷小鼠，它们对这两种抗体都有高滴度的自身抗体， 将产生氧化的LDL和心磷脂。 这些抗体 氧化磷脂的表位将用于确定表位 以及它们是否作为狼疮抗凝血剂或诱导 改变生物行为。 最后，这些信息和理解将 用于开发更标准化的检测方法， 选择患者人群。 验证这些假设可能导致 只是提高了检测高风险个体的能力，但这表明 解释这些抗体的病因，可能是新的 治疗方式（例如，抗炎和/或抗氧化剂 干预）。