{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T03:46:41Z","timestamp":1793245601254,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,9,24]],"date-time":"2018-09-24T00:00:00Z","timestamp":1537747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010063676"],"award-info":[{"award-number":["R01\u2010AR\u2010063676"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["U01\u2010AI\u2010101981"],"award-info":[{"award-number":["U01\u2010AI\u2010101981"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["U19\u2010AI\u201011049103"],"award-info":[{"award-number":["U19\u2010AI\u201011049103"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["UH2\u2010AR\u2010067676"],"award-info":[{"award-number":["UH2\u2010AR\u2010067676"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2018,11]]},"abstract":"\n Objective<\/jats:title>\n \n Rheumatoid arthritis (\n RA<\/jats:styled-content>\n ) is characterized by the activation of B cells that produce anti\u2013citrullinated protein antibodies (\n ACPA<\/jats:styled-content>\n s) and rheumatoid factors (\n RF<\/jats:styled-content>\n s), but the mechanisms by which tolerance is broken in these B cells remain incompletely understood. We undertook this study to investigate whether\n ACPA<\/jats:styled-content>\n + and\n RF<\/jats:styled-content>\n + B cells break tolerance through distinct molecular mechanisms.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We developed antigen\u2013tetramers to isolate\n ACPA<\/jats:styled-content>\n + and\n RF<\/jats:styled-content>\n + B cells and performed single\u2010cell\n RNA<\/jats:styled-content>\n sequencing on 2,349 B cells from 6\n RA<\/jats:styled-content>\n patients and 1 healthy donor to analyze their immunoglobulin repertoires and transcriptional programs. Prominent immunoglobulins were expressed as monoclonal antibodies and tested for autoantigen reactivity.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n ACPA<\/jats:styled-content>\n + and\n RF<\/jats:styled-content>\n + B cells were enriched in the peripheral blood of\n RA<\/jats:styled-content>\n patients relative to healthy controls. Characterization of patient\u2010derived monoclonal antibodies confirmed\n ACPA<\/jats:styled-content>\n and\n RF<\/jats:styled-content>\n targeting of tetramer\u2010specific B cells at both antigen\u2010inexperienced and affinity\u2010matured B cell stages.\n ACPA<\/jats:styled-content>\n + B cells used more class\u2010switched isotypes and exhibited more somatic hypermutations relative to\n RF<\/jats:styled-content>\n + B cells, and these differences were accompanied by down\u2010regulation of\n CD<\/jats:styled-content>\n 72 and up\u2010regulation of genes that promote class\u2010switching and T cell\u2013dependent responses. In contrast,\n RF<\/jats:styled-content>\n + B cells expressed transcriptional programs that stimulate rapid memory reactivation through multiple innate immune pathways. Coexpression analysis revealed that\n ACPA<\/jats:styled-content>\n + and\n RF<\/jats:styled-content>\n + B cell\u2013enriched genes belong to distinct transcriptional regulatory networks.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our findings suggest that\n ACPA<\/jats:styled-content>\n + and\n RF<\/jats:styled-content>\n + B cells are imprinted with distinct transcriptional programs, which suggests that these autoantibodies associated with increased inflammation in\n RA<\/jats:styled-content>\n arise from 2 different molecular mechanisms.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.40578","type":"journal-article","created":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T02:55:40Z","timestamp":1527821740000},"page":"1732-1744","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["T Cell\u2013Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Daniel R.","family":"Lu","sequence":"first","affiliation":[{"name":"Stanford University, Stanford, California, and VA Palo Alto Health Care System Palo Alto California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"McDavid","sequence":"additional","affiliation":[{"name":"University of Rochester Medical Center Rochester New York"}],"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 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