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The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (<jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b) derived from <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> synovial plasma cells and address the question of antigen cross\u2010reactivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>IgG\u2010secreting cells were isolated from <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full\u2010length <jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b (n = 93) and also as germline\u2010reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the <jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b to promote osteoclastogenesis were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four unrelated anti\u2013citrullinated protein autoantibodies (<jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>s), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>. The <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>s recognized &gt;3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients. The plasma cell\u2013derived <jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that the high level of cross\u2010reactivity among <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40699","type":"journal-article","created":{"date-parts":[[2018,8,28]],"date-time":"2018-08-28T06:26:21Z","timestamp":1535437581000},"page":"196-209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell\u2013Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"71","author":[{"given":"Johanna","family":"Steen","sequence":"first","affiliation":[{"name":"Karolinska Institutet Karolinska University Hospital  Stockholm 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