PMID- 34369110 OWN - NLM STAT- MEDLINE DCOM- 20220217 LR - 20221016 IS - 2326-5205 (Electronic) IS - 2326-5191 (Print) IS - 2326-5191 (Linking) VI - 74 IP - 1 DP - 2022 Jan TI - Association of Sputum Neutrophil Extracellular Trap Subsets With IgA Anti-Citrullinated Protein Antibodies in Subjects at Risk for Rheumatoid Arthritis. PG - 38-48 LID - 10.1002/art.41948 [doi] AB - 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-1beta (IL-1beta), 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. CI - (c) 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. FAU - Okamoto, Yuko AU - Okamoto Y AD - University of Colorado, Aurora, and Tokyo Women's Medical University School of Medicine, Tokyo, Japan. FAU - Devoe, Stephanie AU - Devoe S AD - University of Colorado, Aurora. FAU - Seto, Nickie AU - Seto N AD - National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. FAU - Minarchick, Valerie AU - Minarchick V AD - University of Colorado, Aurora. FAU - Wilson, Timothy AU - Wilson T AUID- ORCID: 0000-0003-2989-133X AD - University of Colorado, Aurora. FAU - Rothfuss, Heather M AU - Rothfuss HM AD - University of Wyoming, Laramie. FAU - Mohning, Michael P AU - Mohning MP AD - National Jewish Health, Denver, Colorado. FAU - Arbet, Jaron AU - Arbet J AD - University of Colorado, Aurora. FAU - Kroehl, Miranda AU - Kroehl M AD - University of Colorado, Aurora. FAU - Visser, Ashley AU - Visser A AD - University of Colorado, Aurora. FAU - August, Justin AU - August J AD - University of Colorado, Aurora. FAU - Thomas, Stacey M AU - Thomas SM AD - National Jewish Health, Denver, Colorado. FAU - Charry, Laura Lenis AU - Charry LL AD - University of Colorado, Aurora. FAU - Fleischer, Chelsie AU - Fleischer C AD - University of Colorado, Aurora. FAU - Feser, Marie L AU - Feser ML AD - University of Colorado, Aurora. FAU - Frazer-Abel, Ashley A AU - Frazer-Abel AA AD - University of Colorado, Aurora. FAU - Norris, Jill M AU - Norris JM AD - University of Colorado, Aurora. FAU - Cherrington, Brian D AU - Cherrington BD AD - University of Wyoming, Laramie. FAU - Janssen, William J AU - Janssen WJ AD - National Jewish Health, Denver, Colorado. FAU - Kaplan, Mariana J AU - Kaplan MJ AUID- ORCID: 0000-0003-2968-0815 AD - National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland. FAU - Deane, Kevin D AU - Deane KD AUID- ORCID: 0000-0003-2211-4861 AD - University of Colorado, Aurora. FAU - Holers, V Michael AU - Holers VM AUID- ORCID: 0000-0002-5634-7746 AD - University of Colorado, Aurora. FAU - Demoruelle, M Kristen AU - Demoruelle MK AUID- ORCID: 0000-0002-2563-5155 AD - University of Colorado, Aurora. LA - eng GR - HD090541/Eunice Kennedy Shriver National Institute of Child Health and Human Development/ GR - R21 HD090541/HD/NICHD NIH HHS/United States GR - AI101981/National Institute of Allergy and Infectious Diseases/ GR - HL140039/HL/NHLBI NIH HHS/United States GR - U01 AI101981/AI/NIAID NIH HHS/United States GR - U01 AI101990/AI/NIAID NIH HHS/United States GR - R35 HL140039/HL/NHLBI NIH HHS/United States GR - ZIAAR041199/Intramural Research Program, NIAMS/ GR - AI101990/National Institute of Allergy and Infectious Diseases/ GR - AR51749/AR/NIAMS NIH HHS/United States GR - R01 AR051749/AR/NIAMS NIH HHS/United States GR - GM103432/GM/NIGMS NIH HHS/United States GR - R56 AR051749/AR/NIAMS NIH HHS/United States GR - AR066712/AR/NIAMS NIH HHS/United States GR - R01 AR076450/AR/NIAMS NIH HHS/United States GR - NH/NIH HHS/United States GR - ZIA AR041199/ImNIH/Intramural NIH HHS/United States GR - K23 AR066712/AR/NIAMS NIH HHS/United States GR - P20 GM103432/GM/NIGMS NIH HHS/United States GR - AR076450/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20211125 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (Anti-Citrullinated Protein Antibodies) SB - IM CIN - Arthritis Rheumatol. 2022 Jan;74(1):10-12. PMID: 34369664 CIN - Arthritis Rheumatol. 2022 Jul;74(7):1299. PMID: 35289128 MH - *Anti-Citrullinated Protein Antibodies MH - Arthritis, Rheumatoid/*immunology MH - *Extracellular Traps MH - Female MH - Humans MH - Male MH - Risk Factors MH - *Sputum PMC - PMC8712364 MID - NIHMS1731176 EDAT- 2021/08/10 06:00 MHDA- 2022/02/19 06:00 PMCR- 2022/10/07 CRDT- 2021/08/09 07:12 PHST- 2021/04/08 00:00 [received] PHST- 2021/08/03 00:00 [accepted] PHST- 2021/08/10 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2021/08/09 07:12 [entrez] PHST- 2022/10/07 00:00 [pmc-release] AID - ART41948 [pii] AID - 10.1002/art.41948 [doi] PST - ppublish SO - Arthritis Rheumatol. 2022 Jan;74(1):38-48. doi: 10.1002/art.41948. Epub 2021 Nov 25.