SPORADIC MECHANISM OF THE ANTIPHOSPHOLIPID SYNDROME

描述：(改编自申请人的摘要)-APLS是一种 散发性和不可预测的血栓形成的自身免疫性疾病 流产、静脉血栓、中风和年轻人猝死 人民。唯一可用的临床检测是非特异性筛查。 检测狼疮抗凝剂或抗磷脂的检测 自身抗体，但不能预测哪些患者会发展成生命- 有威胁的疾病。正因为如此，患者不会收到 抗凝治疗，直到发生严重血栓事件。 然后他们被留在有潜在危险的抗凝剂方案中 生活，没有保证他们需要它。有一项明显的授权 为了更好的预测性测试和更具体的治疗 这种综合症中潜在的凝血功能紊乱。一个关键的方面 疾病模型必须解决的问题之一是零星的 血栓形成事件的性质。 该应用程序将评估散发性血栓形成的可能模型， 一过性功能缺陷的抗凝蛋白S。 功能蛋白S缺乏症是一种蛋白过度结合所致 S蛋白抑制剂，C4BP，补体和补体的双重调节 凝结系统。C4BP对S蛋白的功能抑制作用 最近由许多作者在APLS患者中发现，并暂时性地 与凝血事件有关。申请人确定Beta2-GPI， 抗磷脂自身抗体的主要靶抗原结合 并逆转C4BP对S蛋白的抑制作用。单克隆体 抗β2-GPI抗体抑制其与S蛋白的相互作用 导致体外功能蛋白S缺乏症。申请者 假设致病的抗磷脂自身抗体的一个子集 抑制β2-GPI与S蛋白的相互作用，引起 高补体活性状态下的间歇性血栓形成 过量的C4BP，例如在狼疮发作和怀孕期间发现的。 申请人建议定义蛋白质S、β2-之间的相互作用 GPI和C4BP在分子水平上。β2-GPI和C4BP具有同源性 与补体控制蛋白超家族相关的区域。 这些可能是S蛋白的结合位点，并将在 旨在寻找致病表位的诱变实验 抗体结合在一起。S蛋白结合区的多肽 β2-GPI可作为更具特异性的临床检测的抗原。 致病性抗磷脂自身抗体或作为一种新的基础 治疗剂。他们还将评估性行为的意义 蛋白S上的激素结合球蛋白(SHBG)区域怀孕是一种风险 急性早幼粒细胞白血病血栓形成因素及S蛋白功能减退 与口服避孕药的使用有关。因此，可能的调制 通过性激素，这些蛋白质之间的相互作用将被解决 在此应用程序中。

DESCRIPTION: (Adapted from the applicant's abstract)-The APLS is an autoimmune disease of sporadic and unpredictable thrombosis which leads to miscarriages, venous clots, strokes, and sudden death of young people. The only clinical tests available are nonspecific screening assays which detect a lupus anticoagulant or antiphospholipid autoantibodies, but do not predict which patients will develop life- threatening disease. Because of this, patients do not receive anticoagulant therapy until after a serious thrombotic event occurs. Then they are left on potentially dangerous anticoagulant regimens for life, with no assurance that they need it. There is an obvious mandate for better predictive testing and for more specific therapies aimed at the underlying coagulation disorder in this syndrome. A critical aspect of the problem that must be addressed by a disease model is the sporadic nature of the thrombotic events that occur. This application will evaluate a likely model for sporadic thrombosis, transient functional deficiency of the anticoagulant protein S. Functional protein S deficiency results from excessive binding by a protein S inhibitor, the C4BP, a dual regulator of the complement and coagulation systems. Functional inhibition of protein S by C4BP has been recently found in patients with APLS by many authors and is temporally related to clotting events. The applicants determined that beta2-GPI, the major target antigen for antiphospholipid autoantibodies, binds protein S and reverses inhibition of protein S by C4BP. A monoclonal anti-beta2-GPI antibody inhibits its interaction with protein S and causes functional protein S deficiency in vitro. The applicants hypothesize that a subset of pathogenic antiphospholipid autoantibodies inhibit interaction between beta2-GPI and protein S, causing intermittent thrombosis during states of high complement activity and excess C4BP, such as are found during lupus flare and pregnancy. The applicants propose to define interactions between protein S, beta2- GPI, and C4BP on a molecular level. Beta2-GPI and C4BP share homologous regions associated with the complement control protein superfamily. These are likely protein S-binding sites and will be targeted in mutagenesis experiments aimed at finding epitopes to which pathogenic antibodies bind. Peptides derived from the protein S-binding region of beta2-GPI might serve as antigens for a more specific clinical assay for pathogenic antiphospholipid autoantibodies or as a basis for a novel therapeutic agent. They will also evaluate the significance of the sex hormone-binding globulin (SHBG) region on protein S. Pregnancy is a risk factor for thrombosis in APLS, and decrease in protein S function is associated with oral contraceptive use. Therefore, possible modulation by sex-hormones of interactions between these proteins will be addressed in this application.