TY - JOUR
T1 - Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis
AU - Mutoh, Tomoyuki
AU - Shirai, Tsuyoshi
AU - Ishii, Tomonori
AU - Shirota, Yuko
AU - Fujishima, Fumiyoshi
AU - Takahashi, Fumiaki
AU - Kakuta, Yoichi
AU - Kanazawa, Yoshitake
AU - Masamune, Atsushi
AU - Saiki, Yoshikatsu
AU - Harigae, Hideo
AU - Fujii, Hiroshi
N1 - Funding Information:
KAKENHI Grant Numbers 16H06642 and 18K16136 for T.S. and research grants from the Kanae Foundation and Nanbyo Medical Foundation for T.S.
Funding Information:
The authors thank Prof. Masato Nose for technical advice and critical reading of this manuscript. We also thank Ms. Yayoi Aoyama (Tohoku University Hospital) for technical assistance for immunohistochemistry and Ms. Chikako Fushimi for technical assistance for flow cytometry and Western blotting. This work was supported by JSPS
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15088-0
DO - 10.1038/s41467-020-15088-0
M3 - Article
C2 - 32152303
AN - SCOPUS:85081287845
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1253
ER -