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Moreover, autoantibodies develop against proteins with different posttranslational modifications and native proteins without obvious unifying characteristics of the antigens. We undertook this study to broadly evaluate autoantibody binding in seronegative and seropositive <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> to identify novel features of reactivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An array was created using a total of 172,828 native peptides, citrulline\u2010containing peptides, and homocitrulline\u2010containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared between cyclic citrullinated peptide (<jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>)\u2013positive <jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>+, <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>+<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>\u2212, <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>\u2212<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>+, and <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>\u2212<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>\u2212 serum from <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients (n = 48) and controls (n = 12). IgG\u2010bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e., unstable 3\u2010dimensional structure. Binding to IgG\u2010derived peptides was specifically evaluated. Enzyme\u2010linked immunosorbent assay confirmed key results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Broadly, <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>+<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>+ patients had high citrulline\u2010specific IgG binding to array peptides and <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>+<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>\u2212 and <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>\u2212<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>+ patients had modest citrulline\u2010specific IgG binding (median Z scores 3.02, 1.42, and 0.75, respectively; <jats:italic>P<\/jats:italic> &lt; 0.0001). All <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> groups had low homocitrulline\u2010specific binding. <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>+<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>+ patients had moderate IgG binding to native peptides (median Z score 2.38; <jats:italic>P<\/jats:italic> &lt; 0.0001). The highest IgG binding was to citrulline\u2010containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen in endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from <jats:styled-content style=\"fixed-case\">CCP<\/jats:styled-content>+<jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content>+ patients targeted citrulline\u2010containing IgG\u2010derived peptides.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Disordered antigens, which are frequently citrullinated, and common epitopes for <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>s and <jats:styled-content style=\"fixed-case\">RF<\/jats:styled-content> are potentially unifying features for <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> autoantibodies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41074","type":"journal-article","created":{"date-parts":[[2019,8,9]],"date-time":"2019-08-09T02:28:09Z","timestamp":1565317689000},"page":"262-272","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Disordered Antigens and Epitope Overlap Between Anti\u2013Citrullinated Protein Antibodies and Rheumatoid Factor in <scp>Rheumatoid Arthritis<\/scp>"],"prefix":"10.1002","volume":"72","author":[{"given":"Zihao","family":"Zheng","sequence":"first","affiliation":[{"name":"University of Wisconsin\u2010Madison"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aisha M.","family":"Mergaert","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2010Madison"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren M.","family":"Fahmy","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2010Madison"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mandar","family":"Bawadekar","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2010Madison"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlyn L.","family":"Holmes","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2010Madison"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene M.","family":"Ong","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2010Madison and University of Wisconsin Carbone Comprehensive Cancer Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan J.","family":"Bridges","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2010Madison and William S. 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