Autoantibodies Against Thrombin in Lupus Atherosclerosis

描述(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。传统的危险因素不能完全识别哪些SLE患者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额外的狼疮特异性危险因素(S)和途径(S)。最近，肝素辅因子II(一种凝血酶的调节剂)缺陷的小鼠表现出显著的内膜增生，并且HCII缺陷加速了载脂蛋白E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对凝血酶的灭活作用增强了1000多倍。硫酸皮肤素是动脉壁中主要的抗血栓糖胺多糖。此外，在一些患者中，发现抗凝血酶抗体(Ab)与ATH有关。此外，我们还发现某些患者的抗凝血酶抗体可以阻止抗凝血酶灭活凝血酶。此外，系统性红斑狼疮是一种自身免疫性疾病，其特征是存在各种自身抗体。综合这些发现，我们推测一些狼疮患者存在抗凝血酶抗体，这种抗体可以阻止HCII在动脉壁中的凝血酶失活，导致无调控的凝血酶促进宿主患者的动脉粥样硬化。1)对有斑块的狼疮患者、无斑块的狼疮患者和匹配的健康对照组进行血清免疫球蛋白抗体的检测。我们将利用从有或没有明确证明的动脉粥样硬化的特征良好的患者收集的血液样本来确定抗凝血酶抗体是否与SLE患者ATH的存在和/或进展有关。如果Ig G抗凝血酶抗体被证实与狼疮患者ATH的存在和/或进展有关，则狼疮患者的Ig G抗凝血酶抗体效价将作为另一种新的生物标志物被纳入目前资助的两项研究中，这两项研究旨在建立SLE患者ATH的风险预测模型。2)抗凝血酶单抗的制备及免疫学特性鉴定。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：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，一些狼疮特有的危险因素(S)和途径(S)在患者中导致动脉粥样硬化。我们怀疑一些狼疮患者存在抗体，这些抗体阻碍了动脉壁凝血酶的调节，导致未调节的凝血酶促进宿主患者的动脉粥样硬化。这项应用将利用从有或不有有记录的动脉粥样硬化的特征良好的患者收集的血液样本来检验这一重要的新假说。

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.