ANTICARDIOLIPIN ANTIBODIES AND OXIDIZED PHOSPHOLIPIDS

抗心磷脂抗体和氧化磷脂

• 批准号: 2638090
• 负责人: Joseph L. Witztum
• 金额: $ 35.82万
• 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/2638090
• 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《调查者摘要》)：患有 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/或狼疮抗凝剂和临床经验 复发性静脉或动脉血栓形成，胎儿死亡和 自身免疫性血小板减少症。抗磷脂升高的患者 抗体(APL)会增加中风和心肌梗死的风险。 然而，APL升高的诊断因显著的变异而受挫。 甚至在专家实验室和临床管理之间的化验结果 由于缺乏解释原因的潜在假设而受到阻碍 抗体应该形成对磷脂等普遍存在的化合物，许多 应在各种设置中出现低于APL的情况。一个新的假设是 提出这一点可以解释部分(如果不是大多数)APL抗体的病因。 APL抗体被认为是针对氧化的表位的。 磷脂和/或针对分解产物之间的共价加合物 氧化磷脂和相关蛋白质。推论是最多的 APL不针对天然的、未经修饰的磷脂。假说 提示体内的脂质过氧化增强，无论是局部的还是 广义的，导致磷脂的氧化，从而产生新的 免疫原性表位。由此产生的自身抗体具有各种各样的 生物后果。为了验证这些假说，一组APL小鼠 脾靶向心磷脂和磷脂酰丝氨酸的单克隆化 载脂蛋白E缺陷小鼠，它们都有高滴度的自身抗体 氧化的低密度脂蛋白和心磷脂将被生成。这些抗体是针对 氧化磷脂的表位将被用来确定表观 以及它们是作为狼疮抗菌药物还是诱导剂 改变了生物行为。最后，这些信息和理解将 用于开发更标准化的分析方法，这些方法将应用于 选定的患者群体。对这些假说的验证可能导致 只是为了提高检测高危人群的能力，但会建议 对这些抗体病因学的解释以及可能的新发现 治疗方式(例如，抗炎和/或抗氧化剂 干预)。