Nature aging · 2026
Senescent-like activated naive B cells contribute to progression to clinical rheumatoid arthritis.
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Wu Xiaohao, Zhang Mengrui, Moon Jae-Seung, Song Eun Kyung, Abrams Joshua C, van Dam Laura S, Sharpe Orr, Wang Zhen, Feser Marie L, Moss Laurakay, Ho Peggy P, Smith Melanie H, Donlin Laura T, Buckner Jane H, James Eddie A, Firestein Gary S, Okamoto Yuko, Lanz Tobias V, Meffre Eric, Lyu Aiping, Holers V Michael, Deane Kevin D, Robinson William H
Аннотация
Rheumatoid arthritis (RA) is an autoimmune disease marked by joint and systemic inflammation. Anticitrullinated protein antibodies identify an at-risk stage that precedes clinical RA, yet the mechanisms driving disease progression remain poorly understood. Here we show that anticitrullinated-protein-antibody-positive individuals who progressed to RA exhibited a marked expansion of CXCR5+CD69+-activated naive B cells (aNAVs) before disease onset. These cells displayed inflammatory and senescent-like transcriptional programs and expressed polyreactive, autoreactive IgM B cell receptors. The expansion, activation and senescent-like phenotype of aNAVs were validated in multiple independent preclinical RA cohorts, and aNAVs were detectable in RA synovium. In vitro, aNAVs stimulated with citrullinated antigens promoted T cell activation in a human-leukocyte-antigen-dependent manner. Chronic exposure to citrullinated antigens and CpG (an innate immune stimulant) synergistically drove activation and senescent-like programming in naive B cells from individuals with RA. These findings identify senescent-like aNAVs as potential contributors and therapeutic targets for RA prevention.