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界面。 系统和血液凝固。在APS中，异常的免疫反应导致 产生对阴离子具有明显特异性的自身抗体， 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APS病理生理学的新见解 发现大多数自身抗体 与综合症相关的是针对一些 磷脂结合血浆蛋白，如β 2-糖蛋白I（β 2GPI）， 而不是单独的磷脂。越来越多的证据支持这一观点 自身抗体直接导致APS的血栓形成素质。 最近的数据表明，一个重要的机制，自身抗体介导的 血栓形成是组织因子（TF）途径的上调， 正常凝血的生理触发和 血栓形成这些观察结果使我们假设TF增加 对血液单核细胞的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。 目的1是鉴定和表征特定自身抗体， 体外增加TF对正常单核细胞活性，重点是抗β 2 GPI 自身抗体和组织因子途径抑制物（TFPI）的自身抗体， 因子VIIa/TF和因子Xa的关键抑制剂。全血TF 将测量APS患者的活性，以确定某些 自身抗体与循环单核细胞上TF增加相关， vivo.目标2和3将决定一般 自身抗体增加单核细胞TF活性的机制。目标二是 以确定抗体对a）以下的定量表达的影响： TF mRNA和蛋白以及B）TF分子的定性功能状态 在单核细胞表面。这方面的实验还将研究 某些药物阻断单核细胞TF表达， 对其他刺激也能抑制单核细胞TF表达 由APS自身抗体诱导。目的3是确定自身抗体是否 通过阻断TFPI的作用增强TF活性。在一起，拟议的 实验将鉴定能够诱导单核细胞TF的自身抗体 活动和所涉及的一般机制。这些数据将 有助于将未来的研究工作集中在特定的途径上， 抗体介导的单核细胞活化和高凝状态， 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.