ANTICARDIOLIPIN ANTIBODIES, BETA 2GI AND THROMBOSIS

抗心磷脂抗体、β2GI 和血栓形成

• 批准号: 2226205
• 负责人: SANDOR S SHAPIRO
• 金额: $ 29.19万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2226205
• 关键词: anticoagulants; cardiolipins; chemical binding; disease /disorder model; disease /disorder proneness /risk; enzyme complex; enzyme linked immunosorbent assay; epitope mapping; glycoprotein structure; glycoproteins; human subject; immunoglobulins; intermolecular interaction; laboratory mouse; laboratory rabbit; molecular site; monoclonal antibody; mutant; phospholipids; protein sequence; protein structure function; synthetic peptide; systemic lupus erythematosus; thrombosis

Lupus anticoagulants (LACs) and anticardiolipin antibodies (ACAs) are defined as immunoglobulins reactive directly against anionic phospholipids, or having a requirement for anionic phospholipids for their reactivity. LACs are recognized by their prolongation of phospholipid- dependent coagulation tests, while ACAs are generally measured in ELISA assays. Although LACs and ACAs are related phenomena, there is reason to believe that these two activities frequently reside in separate immunoglobulin subpopulations. Nevertheless, the presence of either phenomenon is associated with an increased risk of thrombosis, spontaneous abortion (in women of child-bearing age), thrombocytopenia, as well as several other manifestations that have sometimes been referred to collectively as the "antiphospholipid antibody syndrome". Since the discovery that beta2-glycoprotein l (beta2Gl) is a necessary component in the reactivity of the majority of ACAs and, possibly, LACs, the nature of the interaction of these antibodies with beta2Gl, with phospholipid, and with the beta2Gl-phospholipid complex has assumed major importance. The aims of this proposal are: 1) To identify the specific areas and critical amino acid residues in beta2Gl involved in binding of cardiolipin (CL) and other anionic phospholipids. 2) To identify the epitopes in beta2Gl, CL, and the beta2Gl-CL complex to which LACs/ACAs bind. 3) To study the functional characteristics of epitope-specific LAC/ACA subpopulations, and to correlate epitope-specificities with the risk of thrombosis. These studies will make use of expression mutants of beta2Gl, monoclonal antibodies to beta2Gl, synthetic peptides mimicking surface characteristics of the beta2Gl molecule, and an animal thrombosis model in which to test the thrombogenic potential of antibody subpopulations. We believe that an understanding of the assembly of the beta2Gl-CL complex and the isolation and determination of the functional characteristics of epitope-specific subpopulations of LACs/ACAs will lead to a better understanding of the mechanisms giving rise to the thromboembolic risk and other clinical manifestations associated with the presence of these antibodies.

狼疮抗凝剂 (LAC) 和抗心磷脂抗体 (ACA) 定义为直接与阴离子反应的免疫球蛋白 磷脂，或需要阴离子磷脂才能发挥作用 反应性。 LAC 通过延长磷脂-来识别 依赖凝血测试，而 ACA 通常在 ELISA 中测量 化验。尽管 LAC 和 ACA 是相关现象，但有理由 相信这两项活动经常存在于不同的地方 免疫球蛋白亚群。尽管如此，任何一个的存在 现象与血栓形成、自发性血栓形成的风险增加有关。 流产（育龄妇女）、血小板减少症以及 有时提到的其他几种表现形式 统称为“抗磷脂抗体综合征”。自从 发现β2-糖蛋白l（beta2Gl）是 大多数 ACA 和可能的 LAC 的反应性， 这些抗体与β2Gl、与磷脂的相互作用，以及 β2Gl-磷脂复合物具有重要的重要性。这 该提案的目的是： 1) 识别特定区域和关键氨基酸残基 beta2Gl 参与心磷脂 (CL) 和其他阴离子的结合 磷脂。 2) 鉴定 beta2Gl、CL 和 beta2Gl-CL 复合物中的表位 LAC/ACA 结合。 3) 研究表位特异性LAC/ACA的功能特性 亚群，并将表位特异性与风险相关联 血栓形成。 这些研究将利用 beta2Gl、单克隆抗体的表达突变体 β2Gl 抗体，合成肽模拟表面 β2Gl分子的特征以及动物血栓形成模型 用于测试抗体亚群的血栓形成潜力。我们 相信对 beta2Gl-CL 复合物组装的理解 以及功能特性的分离和测定 LAC/ACA 的表位特异性亚群将带来更好的结果 了解引起血栓栓塞风险的机制以及 与这些症状相关的其他临床表现 抗体。