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

J Autoimmun. 2020 May;109:102439. doi: 10.1016/j.jaut.2020.102439. Epub 2020 Mar 20.

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.

Keywords: Autoimmunity; B lymphocytes; Epithelium; MALT lymphoma; RNA sequencing; Salivary gland; Sjögren's syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Biomarkers
  • Disease Susceptibility
  • Epithelium / immunology*
  • Epithelium / metabolism*
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation
  • Humans
  • Immunohistochemistry
  • Immunophenotyping
  • Male
  • Middle Aged
  • Receptors, Fc / genetics
  • Receptors, Fc / metabolism*
  • Salivary Glands / immunology
  • Salivary Glands / metabolism
  • Signal Transduction
  • Sjogren's Syndrome / etiology*
  • Sjogren's Syndrome / metabolism
  • Sjogren's Syndrome / pathology
  • Transcriptome*

Substances

  • Biomarkers
  • FCRL4 protein, human
  • Receptors, Fc