Primary Sjögren disease (SjD) is a systemic autoimmune disease characterized by exocrine gland dysfunction, most prominently the salivary and lacrimal glands. B cell overactivation is a hallmark of SjD. However, the role of age-associated B cells (ABCs) in SjD remains largely unknown. This study aims to investigate the potential role of ABCs in SjD.

Peripheral blood mononuclear cells (PBMCs) and salivary gland (SG) single-cell RNA-seq datasets of SjD were analyzed. Peripheral and salivary gland ABCs were examined using flow cytometry (FC) and immunofluorescence in an independent SjD and control cohort, respectively. ABC differentiation stimulated by SjD-related cytokines was assessed using FC. The humanized model was established by transferring SjD or healthy control (HC) PBMCs with or without ABC depletion into NOG mice, salivary flow rate and SG histopathology were analyzed. Naïve CD4⁺ T cell differentiation stimulated with ABCs or non-ABCs were analyzed using FC. Differentially expressed genes in SjD ABCs versus non-ABCs were screened by Smart-seq, validated by FC, and confirmed by blockade.

scRNA-seq analysis indicated the ABCs were expanded in SjD . Circulating CD19⁺CD11c⁺T-bet⁺ and CD19⁺IgD^-CD27^-CD11c⁺CXCR5^- ABCs were expanded in SjD, and ABCs infiltrated in SG of SjD. IL-21 promoted ABC differentiation from naïve B cells, which was suppressed by tofacitinib and STAT5 inhibitor STAT5-IN-1. Transfer of SjD but not HC PBMCs induced saliva reduction, lymphocytic infiltrates and glandular destruction in NOG mice, which were partially attenuated in mice transferred with ABC-depleted SjD PBMCs. ABCs promoted follicular T helper cell (Tfh) differentiation in vitro. Smart-seq and FC identified ABCs overexpressed PD-L1, and PD-1 blockade reversed Tfh differentiation mediated by ABCs.

ABCs are expanded in SjD by IL-21 through JAK/STAT5 pathway, and promote Tfh differentiation by overexpressing PD-L1, which contributes to SG dysfunction in SjD. This finding suggests the IL-21/ABCs/Tfh axis is a key immunopathology mechanism of SjD, which might be targeted by tofacitinib.