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

ABSTRACT

Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. CXCR5 is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand CXCL13. We here 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⁺IgD⁺ 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. This article is protected by copyright. All rights reserved.