Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing

Clin Exp Immunol. 2018 Jun;192(3):259-270. doi: 10.1111/cei.13118. Epub 2018 Mar 24.


Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C-X-C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C-X-C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5+ and CXCL13+ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS-associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5+ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19+ CD27+ immunoglobulin (Ig)D+ marginal zone (P < 0·001), CD19+ CD27+ IgD- memory (P < 0·05) and CD27-IgD double-negative (P < 0·01) B cells and CD4+ CXCR3- CCR6+ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5+ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5+ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.

Keywords: B cells; CXCR5; Sjögren's syndrome; T cells; eQTL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • B-Lymphocyte Subsets / immunology*
  • Chemokine CXCL13 / blood*
  • Chemokine CXCL13 / metabolism
  • Chromosomes, Human, Pair 11 / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Inflammation / immunology
  • Male
  • Middle Aged
  • Polymorphism, Genetic / genetics
  • Receptors, CXCR5 / biosynthesis
  • Receptors, CXCR5 / blood*
  • Sjogren's Syndrome / blood*
  • Sjogren's Syndrome / genetics
  • Sjogren's Syndrome / immunology
  • T-Lymphocyte Subsets / immunology*
  • Young Adult


  • CXCL13 protein, human
  • CXCR5 protein, human
  • Chemokine CXCL13
  • Receptors, CXCR5