オカモト　ユウコ   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	Association of Sputum Neutrophil Extracellular Trap Subsets With IgA Anti-Citrullinated Protein Antibodies in Subjects at Risk for Rheumatoid Arthritis.
掲載誌名	正式名：Arthritis & rheumatology (Hoboken, N.J.) 略　 称：Arthritis Rheumatol ISSNコード：23265205/23265191
掲載区分	国外
巻・号・頁	74(1),pp.38-48
著者・共著者	Okamoto Yuko, Devoe Stephanie, Seto Nickie, Minarchick Valerie, Wilson Timothy, Rothfuss Heather M, Mohning Michael P, Arbet Jaron, Kroehl Miranda, Visser Ashley, August Justin, Thomas Stacey M, Charry Laura Lenis, Fleischer Chelsie, Feser Marie L, Frazer-Abel Ashley A, Norris Jill M, Cherrington Brian D, Janssen William J, Kaplan Mariana J, Deane Kevin D, Holers V Michael, Demoruelle M Kristen
担当区分	筆頭著者
発行年月	2022/01/01
概要	OBJECTIVE:Mechanisms leading to anti-citrullinated protein antibody (ACPA) generation in rheumatoid arthritis (RA) are hypothesized to originate in the lung. We undertook this study to understand associations between neutrophil extracellular trap (NET) formation in the lung and local ACPA generation in subjects at risk of developing RA.METHODS:Induced sputum was collected from 49 subjects at risk of developing RA, 12 patients with RA, and 18 controls. Sputum neutrophils were tested for ex vivo NET formation, and sputum-induced NET formation of control neutrophils was measured using immunofluorescence imaging. Sputum macrophages were tested for ex vivo endocytosis of apoptotic and opsonized cells. Levels of ACPA, NET remnants, and inflammatory proteins were quantified in sputum supernatant.RESULTS:Spontaneous citrullinated histone H3 (Cit-H3)-expressing NET formation was higher in sputum neutrophils from at-risk subjects and RA patients compared to controls (median 12%, 22%, and 0%, respectively; P < 0.01). In at-risk subjects, sputum IgA ACPA correlated with the percentage of neutrophils that underwent Cit-H3+ NET formation (r = 0.49, P = 0.002) and levels of Cit-H3+ NET remnants (r = 0.70, P < 0.001). Reduced endocytic capacity of sputum macrophages was found in at-risk subjects and RA patients compared to controls. Using a mediation model, we found that sputum inflammatory proteins were associated with sputum IgA ACPA through a pathway mediated by Cit-H3+ NET remnants. Sputum-induced Cit-H3+ NET formation also correlated with sputum levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor in at-risk subjects, suggesting a causal relationship.CONCLUSION:These data support a potential mechanism for mucosal ACPA generation in subjects at risk of developing RA, whereby inflammation leads to increased citrullinated protein-expressing NETs that promote local ACPA generation.
DOI	10.1002/art.41948
PMID	34369110