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However, composition and functionality of the associated autoreactive B cell repertoire have not been directly assessed. We aimed to selectively investigate citrullinated autoantigen\u2013specific B cell receptors (<jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content>s) involved in <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> and initiate studies on their pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Blood samples were obtained from patients in a University of Minnesota cohort with <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content>\u2010positive <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> (n = 89). Tetramer sets bearing citrullinated filaggrin peptide cfc1 or citrullinated \u03b1\u2010enolase peptide were constructed to specifically capture autoreactive B cells from the unaltered, polyclonal repertoire in <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients. Citrullinated peptide tetramer\u2013bound B cells were subjected to flow cytometric cell sorting and single\u2010cell <jats:italic><jats:styled-content style=\"fixed-case\">IGH<\/jats:styled-content><\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">IGK<\/jats:styled-content><\/jats:italic>, and <jats:italic><jats:styled-content style=\"fixed-case\">IGL<\/jats:styled-content><\/jats:italic> gene sequencing for B cell lineage determinations. <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content> gene sequences were also expressed as recombinant monoclonal antibodies (<jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b) for direct evaluation of citrullinated autoantigen binding and effector functionality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using citrullinated peptide tetramer enrichment to investigate single autoreactive blood B cells, we identified biased V\u2010region gene usage and conserved junction arrangements in <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content>s from <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients. Parsimonious clustering of related immunoglobulin gene nucleotide sequences revealed clonal expansions of rare individual B cell clades, in parallel with divergent sequence mutations. Correspondingly, recombinant <jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b generated from such <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content> lineages demonstrated citrulline\u2010dependent cross\u2010reactivity extending beyond the citrullinated peptides used for B cell capture. A pair of citrullinated autoantigen\u2013specific <jats:styled-content style=\"fixed-case\">mA<\/jats:styled-content>b with cross\u2010reactive binding profiles also promoted arthritis in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest that broad <jats:styled-content style=\"fixed-case\">ACPA<\/jats:styled-content> specificities in <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> arise from a restricted repertoire of evolving citrulline\u2010multispecific B cell clades with pathogenic potential.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40590","type":"journal-article","created":{"date-parts":[[2018,6,21]],"date-time":"2018-06-21T07:51:09Z","timestamp":1529567469000},"page":"1933-1945","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Pathogenic Citrulline\u2010Multispecific B Cell Receptor Clades in Rheumatoid 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