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This study was undertaken to address the molecular basis of the specificity and cross\u2010reactivity of <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>s from patients with <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Antibodies isolated from <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross\u2010reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen\u2010binding fragment (Fab) of the monoclonal <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content> E4 in complex with 3 different citrullinated peptides were determined using x\u2010ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis of the crystal structures of a monoclonal <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content> from human <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> serum in complex with citrullinated peptides revealed key residues of several complementarity\u2010determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data show, for the first time, how <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>s derived from human <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> serum recognize citrulline. The specific citrulline recognition and backbone\u2010mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\u2010specific <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>s.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40698","type":"journal-article","created":{"date-parts":[[2018,8,28]],"date-time":"2018-08-28T17:29:27Z","timestamp":1535477367000},"page":"210-221","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Structural Basis of Cross\u2010Reactivity of Anti\u2013Citrullinated Protein Antibodies"],"prefix":"10.1002","volume":"71","author":[{"given":"Changrong","family":"Ge","sequence":"first","affiliation":[{"name":"Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingze","family":"Xu","sequence":"additional","affiliation":[{"name":"Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibo","family":"Liang","sequence":"additional","affiliation":[{"name":"Karolinska Institutet, Stockholm, Sweden, and Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"L\u00f6nnblom","sequence":"additional","affiliation":[{"name":"Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna L.","family":"Lundstr\u00f6m","sequence":"additional","affiliation":[{"name":"Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman A.","family":"Zubarev","sequence":"additional","affiliation":[{"name":"Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burcu","family":"Ayoglu","sequence":"additional","affiliation":[{"name":"KTH Royal Institute of Technology  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Nilsson","sequence":"additional","affiliation":[{"name":"KTH Royal Institute of Technology  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Skogh","sequence":"additional","affiliation":[{"name":"Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alf","family":"Kastbom","sequence":"additional","affiliation":[{"name":"Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianne","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[{"name":"Karolinska Institutet and Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Klareskog","sequence":"additional","affiliation":[{"name":"Karolinska Institutet and Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 E. 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