FRI0189 ENDOTHELIAL PROTEIN C RECEPTOR AND SCAVENGER RECEPTOR CLASS B TYPE 1 NEGATIVELY REGULATE ENDOTHELIAL ACTIVATION AND REPRESENT NOVEL AUTOANTIGENS IN TAKAYASU ARTERITIS
Authors: T. Shirai, T. Mutoh, H. Fujii, T. Ishii, H. Harigae
Journal: Annals of the Rheumatic Diseases (2020)

Background: Takayasu arteritis (TAK) is a chronic granulomatous vasculitis and affects large vessels in young female. It has been recognized that high numbers of patients with TAK possessed autoantibodies against vascular endothelium, which are called anti-endothelial cell antibodies (AECAs). Although their target antigens had not been identified for a long time, we utilized an expression cloning system for specific identification of cell-surface antigens and successufully identified endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) as major novel autoantigens in TAK. It was possible that identified novel autoantibodies were utilized for clinical application and elucidating pathomechanisms of TAK. Objectives: To reveal the clinical impact and pathogenic potential of novel autoantibodies in TAK Methods: Three hundred twenty-five patients with autoimmune diseases were enrolled: 80, TAK; 10, giant cell arteritis (GCA); and 235, other autoimmune diseases. The expressions of EPCR and SR-BI were examined in the aortic tissue from several diseases by immunohistochemistry. The presence of novel autoantibodies was measured in TAK and other autoimmune diseases. Clinical characteristics of patients with these autoantibodies were evaluated in TAK. To investigate the pathogenetic potential of these novel autoantibodies, vascular endothelial cells from umbilical vein, aortic artery, and pulmonary artery were examined for the endothelial cell activation. The effects of the novel autoantibodies upon the differentiation of immune cells were also evaluated. Results: In non-inflammatory aortic tissue, the expressions of EPCR and SR-BI were observed in the endothelium of vasa vasorum. Their expressions in the endothelium were augumented in TAK tissue. Novel autoantibodies against EPCR or SR-BI were detected in 34.6 % or 36.5 % of cases, respectively in TAK, and overlap was obsereved only in two cases, indicating their exclusive nature. These autoantibodies were specific for TAK among autoimmune rheumatic diseases, and they were not detected in patients with GCA with cranial involvement, suggesting different pathomechanisms among these diseases. The clinical characteristics of patients with anti-EPCR autoantibodies included high prevalence of stroke and ulcerative colitis. Surprisingly, anti-EPCR autoantibodies were also detected in patients with primary ulcerative colitis, suggesting their common pathomechanisms with TAK. Serial measurement of these novel autoantibodies revealed their correlation with disease activity of TAK. In machanistic studies, EPCR and SR-BI functioned as negative regulators of endothelial activation and chemokine production. EPCR further functioned in human T cells and ameliorated Th17 differentiation. Autoantibodies against EPCR and SR-BI blocked the functions of their targets, thereby promoting pro-inflammatory phenotype. Conclusion: EPCR and SR-BI are preferentially expressed in the endothelium of vaso vasorum and upregulated in TAK tissue. Autoantibodies against EPCR or SR-BI are specific for TAK among autoimmune rheumatic conditions and detected in about 70 % of TAK, suggesting their usefulness for the diagnosis, subclassification, and monitoring of TAK. Autoantibodies inhibit the resolution of activated immune responses and thus would lead to the chronic vascular inflammation. References: [1]Shirai T et al. Arthritis Res Ther 2012;14:R157. [2]Shirai T et al. Clin Dev Immunol 2013;2013:453058. [3]Shirai T et al. J Neuroinflammation. 2013;10:128 Disclosure of Interests: None declared