PATHOPHYSIOLOGY OF ANTIPHOSPHOLIPID AUTOANTIBODIES

某些患者出现抗磷脂自身抗体(APL) 系统性红斑狼疮、其他自身免疫性疾病 APL综合征。他们的存在与增加的风险有关 血栓形成，反复的胎儿丢失，以及血小板减少。它被认为是 这些自身抗体可能通过以下途径直接致病 干扰发生在皮肤表面的止血反应 血小板和血管内皮细胞。最近有报道称， APL不仅识别磷脂，而且识别一种复合体 由磷脂和血浆蛋白β2组成的抗原- 糖蛋白I(β2GPI)。有趣的是，Beta2GPI与 以前归因于APL的生物学特性，即结合到 阴离子磷脂与凝血酶原酶活性的抑制。我们有 最近证明了某些APL抑制的能力 凝血酶原激活，即狼疮的抗凝活性，是 取决于Beta2GPI的存在。据推测， 抗磷脂抗体通过增强 β2GPI与磷脂的结合，从而抑制 止血系统的磷脂依赖反应。长期的 这项拟议研究的目标是确定 急性早幼粒细胞白血病可能导致血栓形成。拟议的研究将集中于 APL对β2GPI与磷脂相互作用的影响 在结合研究和止血反应方面。第一个目标是 定量表征APL对β_2GPI结合的影响 到磷脂膜。将仅对Beta2GPI的结合进行量化 通过90度光散射和荧光能量传递。这个 APL对这种结合的影响将使用非平衡来确定 结合分析和荧光各向异性测量。第二个目标 是为了确定APL和Beta2GPI抑制 激活凝血酶原，并将此信息合并到 凝血酶原激活的定量模型。第三个目标是 确定在APL存在或不存在的情况下，Beta2GPI对 蛋白C途径的磷脂依赖反应，即 凝血酶/血栓调节蛋白对蛋白C和蛋白C/蛋白的激活作用 S灭活因子Va和VIIIa。蛋白C的抑制作用 β2GPI和APL在B2GPI与磷脂相互作用中的途径 膜可能有助于了解急性早幼粒细胞白血病的病理生理学 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.