{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T13:49:39Z","timestamp":1782913779915,"version":"3.54.5"},"reference-count":44,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["09150172110053"],"award-info":[{"award-number":["09150172110053"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["AdG2019\u2010884796"],"award-info":[{"award-number":["AdG2019\u2010884796"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006315","name":"ReumaNederland","doi-asserted-by":"publisher","award":["LLP5"],"award-info":[{"award-number":["LLP5"]}],"id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Rheumatoid arthritis (RA) is characterized by anti\u2010modified protein antibodies (AMPAs), including anti\u2010citrullinated protein antibodies (ACPA), anti\u2010carbamylated protein antibodies (anti\u2010CarP), and anti\u2010acetylated protein antibodies (AAPA). In contrast to other AMPAs, AAPA IgM is found in healthy individuals, raising questions about its role in early immune responses. We investigated whether AAPA IgM serves as a precursor for other AMPAs, marking the initial breach of tolerance in RA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>AAPA IgM levels were measured in cord blood and serum of children up to three years old to assess whether it represents a natural (auto)antibody. To evaluate whether AAPA IgM presence precedes other AMPAs, we longitudinally measured AAPA and ACPA IgM in individuals before RA onset. To assess whether AAPA IgM\u2013expressing B cells display a naive phenotype and carry germline\u2010encoded B cell receptors (BCRs), single cells were sorted and sequenced.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>AAPA IgM was not detected in early life, but before RA onset, significantly more individuals were AAPA IgM positive (27.3%) compared to ACPA IgM positive (11.7%). Toward disease onset, ACPA IgM positivity increased to 51.2%, whereas AAPA IgM positivity remained stable. Furthermore, AMPAs developed in individuals who were AAPA IgM negative. Regarding B cell characteristics, germline\u2010encoded BCRs were identified among both AAPA\u2010 and ACPA\u2010expressing B cells in patients with RA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AMPA responses in RA do not appear to arise solely from AAPA IgM, as suggested by the lack of association between predisease AMPA IgM positivity and later AMPA evolution. This is further supported by the presence of germline\u2010configured ACPA BCRs, suggesting multiple possible starting points for AMPA responses.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70259-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70259","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T12:04:42Z","timestamp":1782129882000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of\n                    <scp>IgM<\/scp>\n                    Anti\u2010acetylated Protein Antibodies and B Cells in the Origin of Antimodified Protein Autoimmunity in Rheumatoid Arthritis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5238-1138","authenticated-orcid":false,"given":"Aegli","family":"Athanasiadou","sequence":"first","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8900-1285","authenticated-orcid":false,"given":"Sanne","family":"Kroos","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"van de Wetering","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rian","family":"Schopmeijer","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carin","family":"van der Keur","sequence":"additional","affiliation":[{"name":"Department of Immunology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Eikmans","sequence":"additional","affiliation":[{"name":"Department of Immunology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Willem\u2010Alexander Children's Hospital Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-3863","authenticated-orcid":false,"given":"Solbritt","family":"Rantap\u00e4\u00e4\u2010Dahlqvist","sequence":"additional","affiliation":[{"name":"Department of Public Health and Clinical Medicine Ume\u00e5 University  Ume\u00e5 Sweden"},{"name":"Department of Rheumatology Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 E. M.","family":"Toes","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M.","family":"Slot","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"van der Woude","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000001006"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204154"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206785"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20018"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200008)43:8<1831:AID-ANR19>3.0.CO;2-6"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30537"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11223"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212052"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40760"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40587"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.172006"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214950"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216499"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201559"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-021-02609-5"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224553"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq230"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-025-03591-y"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119298"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.10.6589"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29943"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2015.02.001"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2012.03.005"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2907"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.110234"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.42098"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02185.x"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00389"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2024-004411"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.80217"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13206"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22279"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3702"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27628"},{"key":"e_1_2_7_36_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2024.103241","article-title":"Selective activation of na\u00efve B cells with unique epitope specificity shapes autoantibody formation in celiac disease","volume":"146","author":"Das S","year":"2024","journal-title":"J Autoimmun"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1086907"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900799"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.03.22.644346"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209991"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169149"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.03.035"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780301102"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-025-03543-6"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-220546"}],"container-title":["Arthritis &amp; 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