AUTOIMMUNE MECHANISMS OF THROMBOSIS

描述(由申请人提供)： 抗磷脂综合征(APS)代表了免疫系统和免疫系统之间的接口 系统和血液凝固。在APS中，异常的免疫反应会导致 对阴离子有明显特异性的自身抗体的制备 磷脂。这些自身抗体与这两种疾病密切相关 动脉和静脉血栓形成。对APS病理生理学的新认识 发现大多数自身抗体 与该综合征相关的是针对一些 与磷脂结合的血浆蛋白，如β2-糖蛋白I(β2GPI)， 而不仅仅是磷脂。越来越多的证据支持这一观点 自身抗体直接影响APS患者的血栓形成素质。 最近的数据表明，自身抗体介导的一个重要机制 血栓形成是组织因子(TF)途径的上调， 正常凝血的生理性触发因素和脑出血的一个重要触发因素 血栓形成。这些观察结果使我们假设Tf增加 外周血单核细胞活性是高凝状态的重要原因 APS。这一假设将通过以下具体目标进行检验。 目标1是识别和表征特定的自身抗体 体外增强正常单核细胞的转铁蛋白活性，重点是抗-β2GPI 组织因子途径抑制物(TFPI)自身抗体和自身抗体， 因子VIIa/Tf和因子Xa的关键抑制物。全血转铁蛋白 APS患者的活动度将被测量以确定是否某些 自身抗体与循环单核细胞转铁蛋白升高有关 活着。目标2和目标3将决定将军 自身抗体增强单核细胞转铁蛋白活性的机制。目标2是 为了确定抗体对a)数量表达的影响 转录因子mRNA和蛋白；b)转录因子分子的定性功能状态 在单核细胞表面。这一目标的实验也将检验 某些药物可阻断单核细胞转铁蛋白的表达 对其他刺激也能抑制单核细胞转铁蛋白的表达 由APS自身抗体诱导。目标3是确定自身抗体 通过阻断TFPI的作用来增强TF活性。总而言之，建议的 实验将确定能够诱导单核细胞转铁蛋白的自身抗体 活动和所涉及的一般机制。这些数据将是 有助于将未来的研究重点放在特定的途径上 抗体介导的单核细胞活化和高凝状态及其设计 新的治疗策略。

DESCRIPTION (provided by applicant): The Antiphospholipid Syndrome (APS) represents an interface between the immune system and blood coagulation. In APS, an abnormal immune response leads to the production of autoantibodies with an apparent specificity for anionic phospholipids. These autoantibodies are strongly associated with both arterial and venous thrombosis. New insights into the pathophysiology of APS have been provided by the discovery that most of the autoantibodies associated with the syndrome are directed against a number of phospholipid-binding plasma proteins, such as beta2-glycoprotein I (beta2GPI), rather than phospholipids alone. A growing body of evidence supports the view that autoantibodies directly contribute to the thrombotic diathesis in APS. Recent data suggest that an important mechanism of autoantibody-mediated thrombosis is upregulation of the tissue factor (TF) pathway, the physiological trigger of normal coagulation and an important trigger in thrombosis. These observations lead us to hypothesize that increased TF activity on blood monocytes is an important cause of hypercoagulability in APS. This hypothesis will be tested through the following specific aims. Aim 1 is to identify and characterize the particular autoantibodies that increase TF activity on normal monocytes in vitro, focusing on anti-beta2GPI autoantibodies and autoantibodies to tissue factor pathway inhibitor (TFPI), a critical inhibitor of both factor VIIa/TF and factor Xa. Whole blood TF activity in APS patients will be measured to determine if certain autoantibodies are associated with increased TF on circulating monocytes in vivo. Aims 2 and 3 will determine the general mechanisms by which autoantibodies increase monocyte TF activity. Aim 2 is to determine the effects of antibodies on a) the quantitative expression of TF mRNA and protein and b) the qualitative functional status of TF molecules on the monocyte surface. Experiments in this aim will also examine whether certain pharmacological agents that block monocyte TF expression in response to other stimuli are also capable of inhibiting monocyte TF expression induced by APS autoantibodies. Aim 3 is to determine whether autoantibodies enhance TF activity by blocking the effects of TFPI. Together, the proposed experiments will identify autoantibodies capable of inducing monocyte TF activity and the general mechanisms that are involved. These data will be useful in focusing future research efforts on specific pathways of antibody-mediated monocyte activation and hypercoagulability and in designing new therapeutic strategies.