{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:12:19Z","timestamp":1790781139012,"version":"4.1.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Immunology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by joint and systemic inflammation. Anti-citrullinated protein antibodies (ACPAs) define an at-risk stage that precedes clinically apparent inflammatory arthritis (clinical RA) onset, yet the molecular mechanisms driving progression remain poorly understood. Here, we applied single-cell multi-omics to profile B cells longitudinally collected from ACPA+ individuals who either convert to clinical RA (Converters) or do not (Nonconverters). We identified a striking expansion of CXCR5+CD69+ activated naive B cells (aNAVs) uniquely in Converters prior to clinical RA. These aNAVs exhibited a pro-inflammatory, senescent transcriptional program and persist through to clinical RA. In Converters, aNAVs expressed polyreactive, autoreactive IgM with distinctive V-J gene rearrangements that dominate the BCR repertoire. Furthermore, in Converters most IgM+ aNAVs were developmentally arrested in the peripheral blood, while a subset undergoes class switching and follows divergent somatic hypermutation trajectories. Mechanistically, aNAVs infiltrated RA synovium and served as potent antigen presenting cells to activate both anti-citrullinated antigen CD4+ and CD8+ T cells in an HLA-dependent manner. Chronic exposure to citrullinated antigens and CpG synergistically drove aNAV activation and senescence. These findings establish a mechanistic link between naive B cell senescence and clinical RA development in ACPA+ individuals, providing a rationale for therapeutically targeting aNAV B cells for the prevention of RA.<\/jats:p>","DOI":"10.1101\/2025.10.14.682430","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T22:55:18Z","timestamp":1760568918000},"source":"Crossref","is-referenced-by-count":4,"title":["Senescent Activated Naive B Cells Promote Anti-Citrullinated Antigen T Cell Responses and the Transition to Clinical Rheumatoid Arthritis"],"prefix":"10.64898","author":[{"given":"Xiaohao","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengrui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Seung","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Kyung","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C","family":"Abrams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura S","family":"van Dam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orr","family":"Sharpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Feser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy P","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie H","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura H","family":"Donlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane H","family":"Buckner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie A","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary S","family":"Firestein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias V","family":"Lanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Meffre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. Michael","family":"Holers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D","family":"Deane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.14.682430","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:49:09Z","timestamp":1768470549000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.14.682430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,15]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1101\/2025.10.14.682430","relation":{},"subject":[],"published":{"date-parts":[[2025,10,15]]},"subtype":"preprint"}}