Session Type: ACR Abstract Session
Session Time: 11:00AM-12:30PM
Background/Purpose: Takayasu arteritis (TAK) is a chronic vasculitis which predominantly affects large vessels. Although anti-endothelial cell antibodies (AECA) had been reported to be involved in vascular inflammation in TAK, their target antigens remained unclear. We had constructed an expression cloning system for specific identification of cell-surface antigens, which we named SARF. The aim of this study was to identify autoantigens expressed on the cell surface and to clarify their pathogenic relevance in TAK.
Methods: AECA activity against human umbilical vein endothelial cells (HUVEC) was measured and prototype AECA for SARF was determined. HUVEC cDNA library was inserted into rat myeloma cells by using retroviral vector, and cells expressing proteins derived from cDNA library of HUVEC were incubated with prototype AECA-IgG. Cells bound to AECA-IgG were sorted by flow cytometry, and inserted cDNA in sorted cells was analyzed to identify autoantigens. The prevalence of autoantibodies identified was measured among collagen diseases, and the clinical characteristics of patients with TAK were evaluated according to the presence of autoantibodies. To examine the pathogenic roles of identified autoantibodies, the activation of HUVEC and differentiation of Th17 cells were evaluated.
Results: We performed SARF by using nine TAK sera, and successfully completed in three patients. Four clones bound to the prototype AECA were established, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) were identified as novel autoantigens in TAK. Among 52 TAK patients, anti-EPCR or anti-SR-BI activity was observed in 18 (34.6%) or 19 (36.5%) patients, respectively, with minimal overlap. Their presence was mostly specific for TAK in collagen diseases. TAK was classified into 3 subtypes based on the activity of autoantibodies. Anti-EPCR positive group showed high prevalence of stroke, ulcerative colitis, and type II lesion. Anti-SR-BI positive group presented higher levels of inflammatory markers, type V lesion, and older age at onset. Aortic regurgitation (AR) was rare in anti-SR-BI group. Double-negative group presented higher rates of surgery for AR. In mechanistic studies, EPCR and SR-BI negatively regulated the upregulation of adhesion molecules on HUVEC upon stimulation. The expression of EPCR was induced upon Th17 differentiation, and its agonist suppressed Th17 differentiation. These functions of autoantigens were inhibited by autoantibodies, which resulted in the activation of endothelial cells and the promotion of Th17 differentiation.
Conclusion: EPCR and SR-BI were identified as novel autoantigens in TAK, and these autoantibodies were observed in 67.3% of TAK patients. These autoantibodies blocked the negative regulatory effects of their targets, and thus would contribute to the chronicity of vascular inflammation in TAK.
To cite this abstract in AMA style:Mutoh T, Shirai T, Ishii T, Shirota Y, Harigae H, Fujii H. Endothelial Protein C Receptor and Scavenger Receptor Class B Type 1 Negatively Regulate Vascular Inflammation and Are Major Autoantigens in Takayasu Arteritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/endothelial-protein-c-receptor-and-scavenger-receptor-class-b-type-1-negatively-regulate-vascular-inflammation-and-are-major-autoantigens-in-takayasu-arteritis/. Accessed November 24, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/endothelial-protein-c-receptor-and-scavenger-receptor-class-b-type-1-negatively-regulate-vascular-inflammation-and-are-major-autoantigens-in-takayasu-arteritis/