In primary Sjögren's syndrome (pSS), FcRL4⁺ B cells are present in inflamed salivary gland tissue, within or in close proximity to ductal epithelium. FcRL4 is also expressed by nearly all pSS-related mucosa-associated lymphoid tissue (MALT) B cell lymphomas, linking FcRL4 expression to lymphomagenesis. Whether glandular FcRL4⁺ B cells are pathogenic, how these cells originate, and how they functionally differ from FcRL4^- B cells in pSS is unclear. This study aimed to investigate the phenotype and function of FcRL4⁺ B cells in the periphery and parotid gland tissue of patients with pSS. First, circulating FcRL4⁺ B cells from 44 pSS and 54 non-SS-sicca patients were analyzed by flow cytometry. Additionally, RNA sequencing of FcRL4⁺ B cells sorted from parotid gland cell suspensions of 6 pSS patients was performed. B cells were sorted from cell suspensions as mini bulk (5 cells/well) based on the following definitions: CD19⁺CD27^-FcRL4^- ('naive'), CD19⁺CD27⁺FcRL4^- ('memory'), and CD19⁺FcRL4⁺ B cells. We found that, although FcRL4⁺ B cells were not enriched in blood in pSS compared with non-SS sicca patients, these cells generally exhibited a pro-inflammatory phenotype. Genes coding for CD11c (ITGAX), T-bet (TBX21), TACI (TNFRSF13B), Src tyrosine kinases and NF-κB pathway-related genes were, among others, significantly upregulated in glandular FcRL4⁺ B cells versus FcRL4^- B cells. Pathway analysis showed upregulation of B cell activation, cell cycle and metabolic pathways. Thus, FcRL4⁺ B cells in pSS exhibit many characteristics of chronically activated, pro-inflammatory B cells and their gene expression profile suggests increased risk of lymphomagenesis. We postulate that these cells contribute significantly to the epithelial damage seen in the glandular tissue and that FcRL4⁺ B cells are an important treatment target in pSS.

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