Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis

Abstract

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis

“…This may change as a recent publication has defined autoantigens recognized by AECA. Mutoh et al, have identified two autoantigens expressed on ECs by applying an elegant serological identification system based on a retroviral expression system and flow cytometry (165). In this system, a cDNA library of ECs was retrovirally transfected into a rat myeloma cell line and AECA-positive clones were sorted by flow cytometry (165,166).…”

“…Mutoh et al, have identified two autoantigens expressed on ECs by applying an elegant serological identification system based on a retroviral expression system and flow cytometry (165). In this system, a cDNA library of ECs was retrovirally transfected into a rat myeloma cell line and AECA-positive clones were sorted by flow cytometry (165,166). This yielded endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) as bona fide autoantigens (165).…”

“…In this system, a cDNA library of ECs was retrovirally transfected into a rat myeloma cell line and AECA-positive clones were sorted by flow cytometry (165,166). This yielded endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) as bona fide autoantigens (165). In a cohort study, the authors found that approximately 1 in 3 patients with TAK produce autoantibodies against either antigen.…”

“…In a cohort study, the authors found that approximately 1 in 3 patients with TAK produce autoantibodies against either antigen. Remarkably, both molecules that are recognized by autoantibodies negatively regulate endothelial cell function, undermining the protective role of the endothelial layer (165). The authors propose that the autoantibodies disrupt the barrier function of ECs, opening the intimal surface to immune cell infiltration.…”

Treatment of Giant Cell Arteritis and Takayasu Arteritis—Current and Future

“…Individual case reports on the use of rituximab reporting favorable outcomes are limited by reporting bias [3,88]. Very recently, autoantibodies against endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) were detected in 34.6% and 36.5% of patients with TA, respectively, with minimal overlap (3.8%) [89]. The antigens EPCR and SR-BI function as negative regulators of endothelial activation.…”