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The aim of this study was to characterize the evolution of\n ACPA<\/jats:styled-content>\n s by sequencing the plasmablast antibody repertoire at serial time points in patients with established\n RA<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Blood samples were obtained at up to 4 serial time points from 8 individuals with established\n RA<\/jats:styled-content>\n who were positive for\n ACPA<\/jats:styled-content>\n s by the anti\u2013cyclic citrullinated peptide test.\n CD<\/jats:styled-content>\n 19+\n CD<\/jats:styled-content>\n 3\u2212IgD\u2212\n CD<\/jats:styled-content>\n 14\u2212\n CD<\/jats:styled-content>\n 20\u2212\n CD<\/jats:styled-content>\n 27+\n CD<\/jats:styled-content>\n 38++ plasmablasts were isolated by single\u2010cell sorting and costained with citrullinated peptide tetramers to identify\n ACPA<\/jats:styled-content>\n \u2010expressing plasmablasts. Cell\u2010specific oligonucleotide barcodes were utilized, followed by large\u2010scale sequencing and bioinformatics analysis, to obtain error\u2010corrected, paired heavy\u2010 and light\u2010chain antibody gene sequences for each B cell.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Bioinformatics analysis revealed 170 persistent plasmablast lineages in the\n RA<\/jats:styled-content>\n blood, of which 19% included multiple isotypes. Among IgG\u2010 and IgA\u2010expressing plasmablasts, significantly more IgA\u2010expressing than IgG\u2010expressing persistent lineages were observed (\n P<\/jats:italic>\n < 0.01). Shared complementarity\u2010determining region 3 sequence motifs were identified across subjects. A subset of the plasmablast lineages included members derived from later time points with divergent somatic hypermutations that encoded antibodies that bind an expanded set of citrullinated antigens. Furthermore, these recombinant, differentially mutated plasmablast antibodies formed immune complexes that stimulated higher macrophage production of tumor necrosis factor (TNF) compared to antibodies representing earlier time point\u2013derived lineage members that were less mutated.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n These findings demonstrate that established\n RA<\/jats:styled-content>\n is characterized by a persistent IgA\n ACPA<\/jats:styled-content>\n response that exhibits ongoing affinity maturation. This observation suggests the presence of a persistent mucosal antigen that continually promotes the production of IgA plasmablasts and their affinity maturation and epitope spreading, thus leading to the generation of\n ACPA<\/jats:styled-content>\n s that bind additional citrullinated antigens and more potently stimulate macrophage production of\n TNF<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.40587","type":"journal-article","created":{"date-parts":[[2018,6,21]],"date-time":"2018-06-21T07:59:47Z","timestamp":1529567987000},"page":"1946-1958","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Affinity Maturation Drives Epitope Spreading and Generation of Proinflammatory Anti\u2013Citrullinated Protein Antibodies in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Serra E.","family":"Elliott","sequence":"first","affiliation":[{"name":"Stanford University, Stanford, California and VA Palo Alto Health Care System Palo Alto California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kongpachith","sequence":"additional","affiliation":[{"name":"Stanford University, Stanford, California and VA Palo Alto Health Care System Palo Alto California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nithya","family":"Lingampalli","sequence":"additional","affiliation":[{"name":"Stanford University, Stanford, California and VA Palo Alto Health Care System Palo Alto California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Z.","family":"Adamska","sequence":"additional","affiliation":[{"name":"Stanford University, Stanford, California and VA Palo Alto Health Care System Palo Alto California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan J.","family":"Cannon","sequence":"additional","affiliation":[{"name":"Stanford University, Stanford, California and VA Palo 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