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.
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.
