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

Gwenny M Verstappen*, John A Ice, Hendrika Bootsma, Sarah Pringle, Erlin A Haacke, Kim de Lange, Gerben B van der Vries, Peter Hickey, Arjan Vissink, Frederik K L Spijkervet, Christopher J Lessard, Frans G M Kroese

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number102439
Number of pages9
JournalJournal of Autoimmunity
Volume109
Early online date2020
DOIs
Publication statusPublished - May-2020

Keywords

  • Sjogren's syndrome
  • B lymphocytes
  • Epithelium
  • Salivary gland
  • RNA sequencing
  • MALT lymphoma
  • Autoimmunity
  • TYROSINE KINASE
  • RNA-SEQ
  • RECEPTOR
  • ACTIVATION
  • POPULATION
  • LYMPHOMAS
  • SURVIVAL
  • LESIONS
  • IL-27
  • BAFF

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