The monocyte cell surface is a unique site of autoantigen generation in rheumatoid arthritis

• 成果类型: Article
• 署名作者: Thomas, Mekha A.; Naik, Pooja; Wang, Hong; Giles, Jon T.; Girgis, Alexander A.; Kim, Seok - Young; Johnson, Tory P.; Curran, Ashley M.; Crawford, Jonathan D.; Jahanbani, Shaghayegh; Bingham, Clifton O.; Robinson, William H.; Na, Chan Hyun; Darrah, Erika
• 署名单位: Johns Hopkins University; Columbia University; Johns Hopkins University; Johns Hopkins University; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS); Stanford University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Palo Alto Health Care System
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13492
• DOI: 10.1073/pnas.2304199121
• 发表日期: 2024-04-23
• 关键词: peptidylarginine deiminase; synovial-fluid; citrullinated fibrinogen; histone deimination; arginine deiminases; diagnostic impact; structural basis; antibodies; autoantibodies; inhibition

摘要

Although anti- citrullinated protein autoantibodies (ACPAs) are a hallmark serological feature of rheumatoid arthritis (RA), the mechanisms and cellular sources behind the generation of the RA citrullinome remain incompletely defined. Peptidylarginine deiminase IV (PAD4), one of the key enzymatic drivers of citrullination in the RA joint, is expressed by granulocytes and monocytes; however, the subcellular localization and contribution of monocyte- derived PAD4 to the generation of citrullinated autoantigens remain underexplored. In this study, we demonstrate that PAD4 displays a widespread cellular distribution in monocytes, including expression on the cell surface. Surface PAD4 was enzymatically active and capable of citrullinating extracellular fibrinogen and endogenous surface proteins in a calcium dose-dependent manner. Fibrinogen citrullinated by monocyte- surface PAD4 could be specifically recognized over native fibrinogen by a panel of eight human monoclonal ACPAs. Several unique PAD4 substrates were identified on the monocyte surface via mass spectrometry, with citrullination of the CD11b and CD18 components of the Mac- 1 integrin complex being the most abundant. Citrullinated Mac- 1 was found to be a target of ACPAs in 25% of RA patients, and Mac- 1 ACPAs were significantly associated with HLA- DRB1 shared epitope alleles, higher C- reactive protein and IL- 6 levels, and more erosive joint damage. Our findings implicate the monocyte cell surface as a unique and consequential site of extracellular and cell surface autoantigen generation in RA.