Senescent-like activated naive B cells contribute to progression to clinical rheumatoid arthritis

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.