PATHOPHYSIOLOGY OF ANTIPHOSPHOLIPID AUTOANTIBODIES

磷脂自身抗体（aPL）发生在某些患者， 系统性红斑狼疮，其他自身免疫性疾病，以及原发性 aPL综合征 他们的存在与增加的风险有关， 血栓形成、复发性流产和血小板减少症。 据认为 这些自身抗体可以通过以下方式发挥直接的致病作用： 干扰发生在血管表面的止血反应， 血小板和血管内皮细胞。 最近有报道称 aPL不识别单独磷脂，而是一种复合物 抗原由磷脂和血浆蛋白β 2- 糖蛋白I（β 2GPI）。 有趣的是，beta2 GPI具有一定的相关性， 以前归因于aPL的生物学特性，即，结合 阴离子磷脂和凝血酶原酶活性的抑制。 我们有 最近证明，某些aPL抑制 凝血酶原活化即，它们的狼疮抗凝活性， 这取决于beta2 GPI的存在。 它是假设 抗磷脂抗体发挥其致病作用，通过增强 β 2GPI与磷脂的结合，从而抑制 止血系统的磷脂依赖性反应。 长期 拟议研究的目的是确定机制， aPL可引起血栓形成素质。 拟议的研究将侧重于 关于aPL对β 2GPI和磷脂的相互作用的影响， 在结合研究和止血反应中。 第一个目标是 定量表征aPL对β 2GPI结合的影响 到磷脂膜。 将定量单独β 2GPI的结合 通过90度光散射和荧光能量转移。 的 aPL对这种结合的影响将用非平衡法来确定 结合测定和荧光各向异性测量。 第二个目的 是为了确定aPL和beta2 GPI抑制 激活凝血酶原，并将此信息纳入一个 凝血酶原激活的定量模型。 第三个目标是 在存在或不存在aPL的情况下，测定β 2GPI对 蛋白C途径的磷脂依赖性反应，即，的 凝血酶/血栓调节蛋白激活蛋白C和蛋白C/蛋白 因子Va和VIIIa的S失活。 蛋白C的抑制 β 2GPI和aPL对B2 GPI与磷脂相互作用的影响 膜可以提供对aPL的病理生理学的洞察 综合征，并提出新的治疗策略。

Autoantibodies to phospholipids (aPL) occur in certain patients with systemic lupus erythematosus, other autoimmune diseases, and the primary aPL syndrome. Their presence is associated with an increased risk of thrombosis, recurrent fetal loss, and thrombocytopenia. It is thought that these autoantibodies may exert a direct pathogenic effect by interfering with hemostatic reactions that occur on the surface of platelets and vascular endothelial cells. It has recently been reported that aPL do not recognize phospholipid alone, but rather a complex antigen comprised of phospholipid and the plasma protein beta2- glycoprotein I (beta2GPI). Interestingly, beta2GPI has certain relevant biological properties previously attributed to aPL, i.e., binding to anionic phospholipids and inhibition of prothrombinase activity. We have recently demonstrated that the ability of certain aPL to inhibit prothrombin activation i.e., their lupus anticoagulant activity, is dependent upon the presence of beta2GPI. It is hypothesized that antiphospholipid antibodies exert their pathogenic effects by enhancing the binding of beta2GPI to phospholipids, thereby inhibiting phospholipid-dependent reactions of the hemostatic system. The long-term objective of the proposed research is to define the mechanisms by which aPL may cause a thrombotic diathesis. The proposed studies will focus on the effect of aPL on the interactions of beta2GPI and phospholipids, both in binding studies and hemostatic reactions. The first aim is to characterize quantitatively the effect of aPL on the binding of beta2GPI to phospholipid membranes. Binding of beta2GPI alone will be quantitated by 90 degrees light scattering and fluorescence energy transfer. The effect of aPL on this binding will be determined using nonequilibrium binding assays and fluorescence anisotropy measurements. The second aim is to determine the mechanism by which aPL and beta2GPI inhibit the activation of prothrombin, and incorporate this information into a quantitative model of prothrombin activation. The third aim is to determine the effects of beta2GPI, in the presence or absence of aPL, on phospholipid-dependent reactions of the protein C pathway, i.e., the thrombin/thrombomodulin activation of protein C and the protein C/protein S inactivation of factors Va and VIIIa. Inhibition of the protein C pathway by beta2GPI and aPL on the interaction of B2GPI with phospholipid membranes may provide insight into the pathophysiology of the aPL syndrome and suggest novel therapeutic strategies.