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，是这些患者死亡的主要原因。传统的危险因素无法完全识别SLE患者是否会发展为早期动脉粥样硬化，提示狼疮患者动脉粥样硬化存在其他狼疮特异性危险因素和途径。最近，肝素辅助因子II （HCII，一种凝血酶调节剂）缺陷小鼠显示出明显的内膜增生，HCII缺乏加速了apoe缺陷小鼠主动脉斑块的形成。值得注意的是，HCII与皮肤硫酸酯（DS）结合后，凝血酶的失活能力增强了1000倍以上，皮肤硫酸酯是动脉壁中主要的抗血栓糖胺聚糖。此外，在一些患者中发现抗凝血酶抗体（Ab）与ATH相关。此外，我们发现某些患者的某些抗凝血酶Ab可以阻碍抗凝血酶的失活。此外，SLE是一种自身免疫性疾病，其特征是存在多种自身抗体。综合这些发现，我们推测一些狼疮患者具有抗凝血酶Ab，阻碍动脉壁HCII的凝血酶失活，导致宿主患者凝血酶不调节，促进动脉粥样硬化。为了验证这一假设，具体目的是：1)对颈动脉超声检查有斑块的狼疮患者、匹配的无斑块狼疮患者和匹配的健康对照进行IgG抗凝血酶Ab的血清学分析。我们将利用从特征明确的有或无动脉粥样硬化的患者收集的血液样本来确定IgG抗凝血酶Ab是否与SLE患者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ATH的存在和/或进展相关，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，旨在建立SLE中ATH的风险预测模型。2)选定患者单克隆抗凝血酶抗体IgG的产生及免疫学特性分析。3)抗凝血酶Ab对HCII致凝血酶失活的功能分析。动脉粥样硬化是狼疮患者的一个主要问题，目前的数据表明一些狼疮特异性的危险因素和动脉粥样硬化途径。我们怀疑一些狼疮患者有抗体阻碍动脉壁凝血酶的调节，导致凝血酶不调节，促进宿主患者动脉粥样硬化。该应用程序将利用收集的血液样本，这些样本来自有或没有记录的动脉粥样硬化的患者，以检验这一重要和新颖的假设。

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.