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• 批准号: 2006347
• 负责人: POJEN P CHEN
• 金额: $ 19.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-25 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2006347
• 关键词: anticoagulants; autoantibody; autoimmune disorder; blood coagulation tests; cardiolipins; clinical research; enzyme linked immunosorbent assay; glycoproteins; human subject; immunoglobulin G; immunological substance; immunopathology; laboratory mouse; monoclonal antibody; phospholipids; prothrombin; systemic lupus erythematosus; thrombosis

In systemic lupus erythematosus (SLE), antiphospholipid antibodies (APA), detected either by ELISA (anticardiolipin antibodies, A C A) or by an inhibitory effect on phospholipid-dependent in vitro blood coagulation (lupus anticoagulant, LAC), are strongly associated with recurrent thrombosis, fetal loss, thrombocytopenia and neurological pathology (the "antiphospholipid syndrome" APS). When acquired coagulation abnormalities of APS occur in the absence of SLE, it is referred to as primary APS. To date, the role of APA in immunopathogenesis of APS remains unclear. Analyses of APA indicate that they are composed of immunologically and functionally distinct antibody species. Considering that some individuals with persistently elevated serum ACA and LAC do not experience thrombotic problems, we hypothesize that only certain APA in APS patients may cause thrombosis, and that such thrombogenic APA is necessary, but not sufficient for, induction of pathologic thrombosis. The potentially thrombogenic antibodies may possess unique binding specificity and affinity to phospholipid and/or cofactor(s), not appreciated with present analyses of polyclonal heterogeneous APA in plasma samples. To test these hypotheses, we plan to: 1 Generate monoclonal IgG APA from APS patients with high titers of serum APA and recurrent thrombosis, and characterize the binding specificities and affinities of the monoclonal APA; 2) Determine the functional properties of monospecific APA by in vitro blood clotting assays and an in vivo thrombosis model in mice; 3) Study the mechanisms by which thrombogenic and anticoagulant APA exert their effects; The results from these studies will help to define various subsets of APA in APS patients with recurrent thrombosis, and to advance our understanding about the role of APA in thrombosis associated with APS. If some thrombogenic APA are found, their immunological characteristics and pathogenic mechanisms will be revealed.

在系统性红斑狼疮（SLE）中，抗磷脂抗体（阿帕）， 通过ELISA（抗心磷脂抗体，A C A）或通过 对磷脂依赖性体外凝血抑制作用 （狼疮抗凝剂，LAC），与复发性 血栓形成、胎儿丢失、血小板减少症和神经病理学（ “抗磷脂综合征”APS）。 当获得性凝血异常时 在没有SLE的情况下发生的APS，称为原发性APS。到 迄今为止，阿帕在APS免疫发病机制中的作用尚不清楚。 对阿帕的分析表明，它们由免疫和 功能上不同的抗体种类。考虑到有些人 血清ACA和LAC持续升高的患者不会发生血栓形成 问题，我们假设APS患者中只有某些阿帕可能导致 血栓形成，这种血栓形成阿帕是必要的，但不是充分的 用于诱导病理性血栓形成。潜在的血栓形成 抗体可以具有独特的结合特异性和亲和力， 磷脂和/或辅因子，目前的分析没有认识到， 血浆样品中的多克隆异质阿帕。为了验证这些假设， 我们计划： 1从具有高滴度血清的APS患者产生单克隆IgG阿帕 阿帕和复发性血栓形成，并表征结合特异性 和单克隆阿帕的亲和力; 2)通过体外实验确定单特异性阿帕的功能特性 小鼠中的凝血测定和体内血栓形成模型; 3)研究血栓形成和抗凝阿帕发挥作用的机制 其影响; 这些研究的结果将有助于定义阿帕的各种子集 在APS患者复发性血栓形成，并提高我们的理解， 阿帕在APS相关血栓形成中的作用。如果一些 血栓形成阿帕的发现，其免疫学特性， 致病机制将被揭示。