ANTICARDIOLIPIN ANTIBODIES, BETA 2GI AND THROMBOSIS

狼疮抗凝剂(LACS)和抗心磷脂抗体(ACAs)是 定义为直接与阴离子反应的免疫球蛋白 磷脂，或有阴离子磷脂的要求 反应性。Lacs是通过延长磷脂- 依赖凝血试验，而ACAs通常用酶联免疫吸附试验测定 化验。尽管LACS和ACAS是相关的现象，但有理由 我认为这两个活动经常分别驻留在 免疫球蛋白亚群。然而，无论是哪一种情况 这一现象与血栓形成的风险增加有关，自发性 堕胎(育龄妇女)、血小板减少症以及 有时被提及的其他几种表现形式 统称为“抗磷脂抗体综合征”。自.以来 发现β2-糖蛋白L(Beta2G1)是血管紧张素转换酶的必需成分 大多数ACAs的反应性，可能还有Lacs，其性质 这些抗体与Beta2Gl、磷脂和 随着Beta2Gl-磷脂复合体的出现，它扮演了重要的角色。这个 这项建议的目的是： 1)确定特定区域和关键氨基酸残基 β2Gl参与心磷脂与其他阴离子的结合 磷脂。 2)确定Beta2Gl、CL和Beta2Gl-CL复合体T0的表位 LACS/ACAS绑定的。 3)研究表位特异性LAC/ACA的功能特性 亚群，并将表位特异性与发病风险联系起来。 血栓形成。 这些研究将利用Beta2Gl的表达突变体，单克隆 抗Beta2Gl抗体，模拟表面的合成肽 β2Gl分子的特性和动物血栓形成模型的建立 用来检测抗体亚群的血栓形成能力。我们 相信对Beta2Gl-CL络合物组装的理解 以及功能特性的分离和测定 Lacs/ACAs表位特异性亚群将导致更好的 了解导致血栓栓塞症风险的机制和 与这些疾病相关的其他临床表现 抗体。

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.