Anticardiolipin Antibodies and Oxidized Phospholipids

抗心磷脂抗体和氧化磷脂

• 批准号: 6784162
• 负责人: Joseph L. Witztum
• 金额: $ 42.37万
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784162
• 关键词: anticoagulants; antigen antibody reaction; antioxidants; antiphospholipid syndrome; atherosclerosis; autoantibody; autoimmune disorder; blood coagulation; blood vessel occlusion; cardiolipins; clinical research; discoid lupus erythematosus; human tissue; laboratory mouse; monoclonal antibody; oxidation; peroxidation; phage display; protein C; protein S; systemic lupus erythematosus

Patients with the antiphospholipid antibody syndrome (APS) have autoantibodies to certain phospholipids (aPL) such as cardiolipin and/or the lupus anticoagulant and clinically experience recurrent venous or arterial thrombosis, history of fetal death and autoimmune thrombocytopenia. Increased aPL also appear to predict increased risk of stroke and myocardial infarction in otherwise healthy men as well. However, controversy exists about the target antigens of aPL, and even university laboratories cannot agree who has elevated aPL titers. In turn, clinical management is hampered by lack of an underlying hypothesis to explain why antibodies should form to such ubiquitous compounds as PL. We have developed the novel hypothesis that many aPL are directed against epitopes of oxidized PL (OxPL) and/or against covalent adducts of OxPL and associated PL binding proteins, such as beta2GPI. Our hypothesis suggests that states of enhanced lipid peroxidation, as occurs in inflammation or atherosclerosis, leads to oxidation of PL (such as in LDL or in membranes of apoptotic or dying cells) which creates neo self-determinants and immunogenic epitopes. The resultant autoantibodies can then target such neoepitopes in many tissues, and may have a variety of biological consequences. Cardiolipin (CL) is the most common PL used to test for aPL. We have shown that APS plasma bind exclusively to OxCL, or to OxCL adducts with beta2GPI, and not to native CL. We propose to further test our hypothesis by determining if antibodies to other OxPL are also present in sera from patients and mice with lupus- like syndromes. We will generate a panel of such aOxPL murine monoclonals from (NZWxBXSB) F1 males. Similar Fab and scFv antibodies will be generated from a human phage-display library. We will determine the epitopes to which they bind and their impact on in vitro and in vivo coagulation, with an emphasis on the Protein C pathway. We will treat lupus-prone mice with potent antioxidants to see if changes in aPL titers and/or other clinical parameters occur. Understanding the etiology of even some of the aPL should lead not only to development of more standardized assays, which should improve our ability to detect high risk individuals, but also to consideration of new therapeutic modalities for patients with aPL and APS (e.g. aggressive anti-inflammatory and/or antioxidant interventions).

抗磷脂抗体综合征（APS）患者具有针对某些磷脂（aPL）（如心磷脂和/或狼疮抗凝剂）的自身抗体，临床上会出现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。 aPL增加似乎也预示着其他健康男性中风和心肌梗死的风险增加。 然而，关于aPL的靶抗原存在争议，甚至大学实验室也不能同意谁具有升高的aPL滴度。反过来，临床管理是阻碍了缺乏一个潜在的假设来解释为什么抗体应该形成这样的普遍存在的化合物PL。 我们提出了一种新的假设，即许多aPL是针对氧化PL（OxPL）的表位和/或针对OxPL和相关PL结合蛋白（如β 2GPI）的共价加合物。 我们的假设表明，在炎症或动脉粥样硬化中发生的增强的脂质过氧化状态导致PL的氧化（例如在LDL中或在凋亡或死亡细胞的膜中），这产生了新的自身决定簇和免疫原性表位。 然后，所得的自身抗体可以靶向许多组织中的此类新表位，并且可能具有多种生物学后果。心磷脂（CL）是用于检测aPL的最常见PL。 我们已经表明，APS血浆仅结合OxCL，或OxCL与β 2GPI的加合物，而不是天然CL。 我们建议通过确定其他OxPL的抗体是否也存在于患有狼疮样综合征的患者和小鼠的血清中来进一步检验我们的假设。 我们将从（NZWxBXSB）F1雄性产生一组此类aOxPL鼠单克隆抗体。 类似的Fab和scFv抗体将从人噬菌体展示文库产生。我们将确定它们结合的表位及其对体外和体内凝血的影响，重点是蛋白C途径。 我们将用有效的抗氧化剂治疗狼疮易感小鼠，以观察aPL滴度和/或其他临床参数是否发生变化。 了解某些aPL的病因不仅可以开发更标准化的检测方法，提高我们检测高危个体的能力，还可以考虑对aPL和APS患者进行新的治疗方式（例如积极的抗炎和/或抗氧化干预）。

项目成果

Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.

• DOI: 10.1084/jem.20031763
• 发表时间: 2004-12-06
• 期刊: The Journal of experimental medicine
• 作者: Chang MK;Binder CJ;Miller YI;Subbanagounder G;Silverman GJ;Berliner JA;Witztum JL
• 通讯作者: Witztum JL

Circulating autoantibodies to oxidized cardiolipin correlate with isoprostane F(2alpha)-VI levels and the extent of atherosclerosis in ApoE-deficient mice: modulation by vitamin E.

ApoE 缺陷小鼠中氧化心磷脂循环自身抗体与异前列烷 F(2α)-VI 水平和动脉粥样硬化程度相关：维生素 E 的调节。

• DOI: 10.1182/blood.v97.2.459
• 发表时间: 2001
• 期刊: Blood
• 影响因子: 20.3
• 作者: Praticò,D;Tangirala,RK;Hörkkö,S;Witztum,JL;Palinski,W;FitzGerald,GA
• 通讯作者: FitzGerald,GA