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岡本 祐子
Department School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine Position Assistant Professor |
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| Article types | Original article |
| Language | English |
| Peer review | Peer reviewed |
| Title | Subjects at-risk for future development of rheumatoid arthritis demonstrate a PAD4-and TLR-dependent enhanced histone H3 citrullination and proinflammatory cytokine production in CD14hi monocytes. |
| Journal | Formal name：Journal of autoimmunity Abbreviation：J Autoimmun ISSN code：10959157/08968411 |
| Domestic / Foregin | Foregin |
| Volume, Issue, Page | 117,pp.102581 |
| Author and coauthor | Okamato Yuko, Ghosh Tusharkanti, Okamoto Tsukasa, Schuyler Ronald P, Seifert Jennifer, Charry Laura Lenis, Visser Ashley, Feser Marie, Fleischer Chelsie, Pedrick Chong, August Justin, Moss Laurakay, Bemis Elizabeth A, Norris Jill M, Kuhn Kristine A, Demoruelle M Kristen, Deane Kevin D, Ghosh Debashis, Holers V Michael, Hsieh Elena W Y |
| Authorship | Lead author |
| Publication date | 2021/02 |
| Summary | The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3). Intracellular citrullination of H3 in neutrophils and T cells is known to regulate immune cell function by promoting neutrophil extracellular trap formation and citrullinated autoantigen release as well as regulating the Th2/Th17 T cell phenotypic balance. However, the roles of H3 citrullination in other immune cells are not fully elucidated. We aimed to explore H3 citrullination and cytokine/metabolomic signatures in peripheral blood immune cells from subjects prior to and after the onset of RA, at baseline and in response to ex vivo toll-like receptor (TLR) stimulation. Here, we analyzed 13 ACPA (+) subjects without arthritis but at-risk for future development of RA, 14 early RA patients, and 13 healthy controls. We found significantly elevated H3 citrullination in CD14hi monocytes, as well as CD1c+ dendritic cells and CD66+ granulocytes. Unsupervised analysis identified two distinct subsets in CD14hi monocytes characterized by H3 modification and unique cytokine/metabolomic signatures. CD14hi monocytes with elevated TLR-stimulated H3 citrullination were significantly increased in ACPA (+) at-risk subjects. These cells were skewed to produce TNFα, MIP1β, IFNα, and partially IL-12. Additionally, they demonstrate peptidyl arginine deiminase 4 (PAD4) mediated upregulation of the glycolytic enzyme PFKFB3. These CD14hi monocytes with elevated H3 citrullination morphologically formed monocyte extracellular traps (METs). |
| DOI | 10.1016/j.jaut.2020.102581 |
| PMID | 33310262 |