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.

在原发性干燥综合征 (pSS) 中，FcRL4 ⁺ B 细胞存在于发炎的唾液腺组织中，位于导管上皮内或附近。FcRL4 也由几乎所有 pSS 相关的粘膜相关淋巴组织 (MALT) B 细胞淋巴瘤表达，将 FcRL4 表达与淋巴瘤发生联系起来。腺性 FcRL4 ⁺ B 细胞是否具有致病性、这些细胞如何起源以及它们在 pSS 中与 FcRL4 ^- B 细胞有何不同尚不清楚。本研究旨在探讨pSS 患者外周和腮腺组织中FcRL4 ⁺ B 细胞的表型和功能。一、循环FcRL4 ⁺通过流式细胞术分析来自 44 pSS 和 54 非 SS-sicca 患者的 B 细胞。此外，还对从 6 名 pSS 患者的腮腺细胞悬液中分选的 FcRL4 ⁺ B 细胞进行了RNA 测序。根据以下定义，从细胞悬液中将 B 细胞分选为小批量（5 个细胞/孔）：CD19 ⁺ CD27 ^- FcRL4 ^-（“初始”）、CD19 ⁺ CD27 ⁺ FcRL4 ^-（“记忆”）和 CD19 ⁺ FcRL4 ⁺ B 细胞。我们发现，虽然 FcRL4 ⁺与非 SS 干燥症患者相比，pSS 中的 B 细胞在血液中没有富集，这些细胞通常表现出促炎表型。编码 CD11c ( ITGAX )、T-bet ( TBX21 )、TACI ( TNFRSF13B )、Src 酪氨酸激酶和 NF-κB 通路相关基因的基因在腺 FcRL4 ⁺ B 细胞中与 FcRL4 ^- B 细胞相比显着上调。通路分析显示 B 细胞活化、细胞周期和代谢通路上调。因此，FcRL4 ⁺pSS 中的 B 细胞表现出许多慢性活化、促炎性 B 细胞的特征，它们的基因表达谱表明淋巴瘤发生的风险增加。我们假设这些细胞对腺组织中观察到的上皮损伤有显着影响，并且 FcRL4 ⁺ B 细胞是 pSS 中的重要治疗靶点。