Autoantibodies Against Thrombin in Lupus Atherosclerosis

描述（由申请人提供）： 动脉粥样硬化（ATH）在系统性红斑狼疮（SLE）患者中增加，并且是这些患者死亡的主要原因。传统的危险因素不能完全确定SLE患者是否会发生早期动脉粥样硬化，这表明在狼疮患者中存在其他狼疮特异性危险因素和动脉粥样硬化途径。最近，肝素辅因子II（HCII，凝血酶的调节剂）缺陷小鼠显示出突出的内膜增生，HCII缺陷加速apoE缺陷小鼠的主动脉斑块形成。值得注意的是，在与硫酸皮肤素（DS）结合后，HCII对凝血酶的失活增强了1,000倍以上，硫酸皮肤素是动脉壁中主要的抗血栓形成糖胺聚糖。此外，抗凝血酶抗体（Ab）被发现与ATH在一些患者。此外，我们还发现某些患者体内的抗凝血酶抗体可阻碍抗凝血酶对凝血酶的灭活。此外，SLE是一种自身免疫性疾病，其特征在于存在多种自身抗体。结合，这些发现使我们假设，一些狼疮患者具有抗凝血酶Ab，其阻碍动脉壁中HCII引起的凝血酶失活，导致不受调节的凝血酶，从而促进宿主患者的动脉粥样硬化。为验证这一假设，我们的具体目标是：1）对颈动脉超声显示有斑块的狼疮患者、无斑块的狼疮患者和健康对照者进行IgG抗凝血酶Ab的血清学分析。我们将利用从有或无动脉粥样硬化记录的患者中收集的血液样本来确定IgG抗凝血酶Ab是否与SLE患者中ATH的存在和/或进展相关。如果IgG抗凝血酶Ab被证实与狼疮患者中ATH的存在和/或进展相关，则狼疮患者的IgG抗凝血酶Ab滴度将作为另一种新的生物标志物纳入目前资助的两项研究中，旨在开发SLE中ATH的风险预测模型。2)来自所选患者的单克隆IgG抗凝血酶Ab的产生和免疫学表征。3)抗凝血酶抗体对HCII灭活凝血酶的功能分析。公共卫生相关性：与公共卫生的相关性动脉粥样硬化是狼疮患者的一个主要问题，目前的数据表明患者动脉粥样硬化的一些狼疮特异性风险因素和途径。我们怀疑某些狼疮患者体内的抗体阻碍了动脉壁中凝血酶的调节，导致不受调节的凝血酶促进宿主患者的动脉粥样硬化。本申请将利用从具有或不具有记录的动脉粥样硬化的良好表征的患者中收集的血液样本来检查这一重要且新颖的假设。

DESCRIPTION (provided by applicant): Atherosclerosis (ATH) is increased in patients with Systemic Lupus Erythematosus (SLE), and is a major cause of death in these patients. Traditional risk factors are unable to completely identify SLE patients who will develop early atherosclerosis, suggesting additional lupus-specific risk factor(s) and pathway(s) for atherosclerosis in lupus patients. Very recently, heparin cofactor II (HCII, a regulator of thrombin)-deficient mice were shown to display prominent intimal hyperplasia, and HCII deficiency accelerated aortic plaque formation in apoE-deficient mice. Of note, inactivation of thrombin by HCII is enhanced by more than 1,000-fold after binding to dermatan sulfate (DS), which is the predominant antithrombotic glycosaminoglycan in arterial walls. Additionally, anti-thrombin antibodies (Ab) were found to be associated with ATH in some patients. Moreover, we found that some anti-thrombin Ab in certain patients could hinder inactivation of thrombin by antithrombin. Furthermore, SLE is an autoimmune disease characterized by the presence of a variety of autoantibodies. Combined, these findings led us to hypothesize that some lupus patients have anti-thrombin Ab that hinder thrombin inactivation by HCII in arterial walls, leading to unregulated thrombin that promotes atherosclerosis in the host patients. To test this hypothesis, the specific aims are: 1) Serological analyses of IgG anti-thrombin Ab in lupus patients with plaques on carotid ultrasound, the matched lupus patients without plaques, and the matched healthy controls. We will utilize collected blood samples from well-characterized patients with or without documented atherosclerosis to determine whether IgG anti-thrombin Ab are associated with either the presence and/or progression of ATH in SLE patients. If IgG anti-thrombin Ab are confirmed to be associated with either the presence and/or progression of ATH in lupus patients, the IgG anti-thrombin Ab titers of lupus patients will be incorporated as another novel biomarker into the two currently funded studies that aim to develop a risk prediction model for ATH in SLE. 2) Generation and Immunological characterization of monoclonal IgG anti-thrombin Ab from chosen patients. 3) Functional analyses of the anti-thrombin Ab on thrombin inactivation by HCII. PUBLIC HEALTH RELEVANCE: Relevance to Public Health Atherosclerosis is a major problem for lupus patients, and current data suggest some lupus-specific risk factor(s) and pathway(s) for atherosclerosis in patients. We suspect that some lupus patients have antibodies that hinder regulation of thrombin in arterial walls, leading to unregulated thrombin that promotes atherosclerosis in the host patients. This application will utilize collected blood samples from well-characterized patients with or without documented atherosclerosis to examine this important and novel hypothesis.