オカモト　ユウコ   Okamoto Yuuko   岡本　祐子    所属   医学部 医学科（東京女子医科大学病院）    職種   講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	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.
掲載誌名	正式名：Journal of autoimmunity 略　 称：J Autoimmun ISSNコード：10959157/08968411
掲載区分	国外
巻・号・頁	117,pp.102581
著者・共著者	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
担当区分	筆頭著者
発行年月	2021/02
概要	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