Gene expression profiling of epithelium-associated FcRL4(+) B cells in primary Sjogren's syndrome reveals a pathogenic signature
- Author(s)
- Verstappen, GM; Ice, JA; Bootsma, H; Pringle, S; Haacke, EA; de Lange, K; van der Vries, GB; Hickey, P; Vissink, A; Spijkervet, FKL; Lessard, CJ; Kroese, FGM;
- Journal Title
- Journal of Autoimmunity
- Publication Type
- Journal Article
- Abstract
- In primary Sjogren'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-kappaB 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.
- Publisher
- Elsevier
- Research Division(s)
- Advanced Technology And Biology
- PubMed ID
- 32201227
- Publisher's Version
- https://doi.org/10.1016/j.jaut.2020.102439
- Open Access at Publisher's Site
https://doi.org/10.1016/j.jaut.2020.102439- Terms of Use/Rights Notice
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Creation Date: 2020-03-26 01:51:55
Last Modified: 2020-04-07 01:22:19