瓜氨酸化
单核细胞
自身抗体
免疫学
流式细胞术
抗体
中性粒细胞胞外陷阱
类风湿性关节炎
化学
医学
炎症
生物化学
瓜氨酸
氨基酸
精氨酸
作者
Mekha A. Thomas,Pankaja Naik,Hong Wang,Yura Jang,Tory P. Johnson,Ashley M. Curran,Jonathan D Crawford,Shaghayegh Jahanbani,William H. Robinson,Chan Hyun Na,Erika Darrah
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2022-05-01
卷期号:208 (1_Supplement): 104.01-104.01
标识
DOI:10.4049/jimmunol.208.supp.104.01
摘要
Abstract Citrullination is recognized as a key pathogenic process in rheumatoid arthritis (RA), as evidenced by the formation of anti-citrullinated protein antibodies (APCAs) in the majority of patients; however, the mechanisms that result in citrullinated autoantigen generation are not fully understood. Although the citrullinating enzyme peptidylarginine deiminase IV (PAD4) is predominantly expressed by neutrophils and monocytes, the contribution of monocytes to the citrullinated autoantigen pool has been underexplored. In this study, we utilized multiple complementary methods including flow cytometry, immunofluorescence, and transmission electron microscopy, which revealed a predominantly extranuclear localization of PAD4 in monocytes with a fraction present on the cell surface. Surface PAD4 was enzymatically active and citrullinated both extracellular fibrinogen and endogenous surface proteins in a calcium dose–dependent manner. In addition, human monoclonal ACPAs cloned from patients with RA recognized fibrinogen citrullinated by monocyte-surface PAD4. Mass spectrometry analysis of citrullinated proteins from the cell surface fraction revealed CD11b to be a novel PAD4 substrate. Citrullinated CD11b was recognized by autoantibodies in 60% of ACPA+ RA patients compared to 6% of healthy controls (p=0.0021) and 0% of ACPA− RA patients (p≤0.001). Taken together, our study demonstrates that PAD4 is expressed on the surface of monocytes in an enzymatically active state that renders the monocyte surface a novel site of citrullinated autoantigen generation in RA. Supported by funds received from Bristol-Myers Squibb.
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