Gene expression profiling of epithelium-associated FcRL4+ B cells in primary Sjögren's syndrome reveals a pathogenic signature

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 lymphoma...

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Veröffentlicht in:Journal of autoimmunity 2020-05, Vol.109, p.102439-102439, Article 102439
Hauptverfasser: Verstappen, Gwenny M., Ice, John A., Bootsma, Hendrika, Pringle, Sarah, Haacke, Erlin A., de Lange, Kim, van der Vries, Gerben B., Hickey, Peter, Vissink, Arjan, Spijkervet, Frederik K.L., Lessard, Christopher J., Kroese, Frans G.M.
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Sprache:eng
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Zusammenfassung: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. •Epithelium-associated B cells in parotid glands of pSS patients are highly activated.•Glandular FcRL4+ B cells express the pro-inflammatory markers CD11c and T-bet.•NF-κB activation and IL-6 secretion are pathogenic features of FcRL4+ cells in pSS.•The activation profile of FcRL4+ B cells suggests increased risk of lymphomagenesis.
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2020.102439