SPORADIC MECHANISM OF THE ANTIPHOSPHOLIPID SYNDROME

APLS是一种散发性和不可预测的自身免疫性疾病 血栓形成导致流产、静脉血栓、中风， 年轻人的突然死亡。 唯一可用的临床测试是 检测狼疮抗凝剂的非特异性筛选试验，或 抗磷脂autoabs，但不能预测哪些患者将发展 危及生命的疾病。 因此，患者不接受 抗凝治疗，直至发生严重血栓事件。 然后，他们被留在潜在危险的抗凝治疗方案， 生活，没有保证，他们需要它。有一个明显的任务 为了更好的预测测试和更具体的治疗， 这种综合征的潜在凝血障碍 一个关键方面 疾病模型必须解决的一个问题是 发生的血栓形成事件的性质。 本申请将评估散发性血栓形成的可能模型， 抗凝血蛋白S的暂时性功能缺陷。 功能性蛋白S缺乏是由于蛋白S与一种 蛋白S抑制剂，C4BP，补体和 凝血系统 C4BP对蛋白S的功能性抑制作用 最近许多作者在APLS患者中发现， 与凝血事件有关 申请人确定β 2-GPI， 抗磷脂自身抗体的主要靶抗原，结合蛋白S 并逆转C4BP对蛋白S的抑制。 一种抗β 2- GPI ab抑制其与蛋白质的相互作用， 蛋白S缺乏。申请人假设一个子集 病原性抗磷脂autoabs抑制相互作用， β 2-GPI和蛋白S，导致间歇性血栓形成， 高补体活性和过量的C4BP，如在 狼疮发作和怀孕。 申请人将定义蛋白S，β 2-GPI， 和C4BP的分子水平。 Beta2-GPI和C4BP具有同源性 与补体控制蛋白超家族相关的区域。 这些可能是蛋白质S结合位点，将被靶向于 诱变实验旨在寻找致病的表位， 抗体结合。 衍生自蛋白质S-结合区的肽 β 2-GPI可能作为抗原用于更特异的临床检测， 致病性抗磷脂autoabs或作为一种新的基础， 治疗剂 申请人还将评估 性激素结合球蛋白（SHBG）区域的蛋白S。 妊娠是APLS患者血栓形成的危险因素， 蛋白S功能与口服避孕药的使用有关。 因此，性激素可能调节 这些蛋白质将在本申请中进行阐述。

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 autoabs, but do not predict which patients will develop life-threatening disease. Because of this, patients do not receive anticoagulent 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 temporally related to clotting events. The applicants determined that beta2-GPI, the major target antigen for antiphospholipid autoabs, binds protein S and reverses inhibition of protein S by C4BP. A monoclonal anti-beta2- GPI ab inhibits its interaction with protein and causes functional protein S deficiency in vitro. The applicants hypothesize that a subset of pathogenic antiphospholipid autoabs inhibits 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 will 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 autoabs or as a basis for a novel therapeutic agent. The applicants 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.