Elevated CCL25 and CCR9-Expressing T Helper Cells in Salivary Glands of Primary Sjögren's Syndrome Patients: Potential New Axis in Lymphoid Neogenesis

Introduction T follicular helper (Tfh)-cells play a critical role in germinal center formation and B-cell activation, both hallmarks of primary Sjogren's syndrome (pSS). CCR9-expressing Th-cells have “Tfh-like” characteristics and are increased at mucosa-associated sites in several inflammatory conditions. Because of their unique characteristics and limited evaluation we investigated the local and systemic CCL25/CCR9-axis in pSS. Methods CCL25 protein and mRNA levels and CCR9+ Th-cells were assessed in labial salivary glands (LSG) of pSS and non-Sjogren's sicca (nSS) patients and their correlation with inflammatory and clinical parameters was evaluated. Circulating CCR9+ and CXCR5+ Th-cells were compared based on phenotypic and functional properties. Results CCL25 protein and mRNA levels were elevated in LSG from pSS versus nSS patients and associated with B-cell hyperactivity, autoimmunity and levels of IL-21 and soluble IL-7Rα. The frequency of CCR9-expressing cells was increased in the LSG of pSS patients. Circulating CCR9+ Th-cells expressing PD-1 and ICOS were elevated in pSS patients. CCR9+ Th-cells displayed higher expression of IL-7Rα and secreted higher levels of IFN-γ, IL-17, IL-4 and IL-21 as compared to CXCR5+ Th-cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ Th-cells induced IgG production by B-cells more potently than CCR9-CXCR5- Th-cells. Conclusion Enhanced CCL25 expression in pSS LSG can facilitate attraction of CCR9+ Th-cells, secreting high levels of pro-inflammatory cytokines when triggered with antigen or IL-7. Associations with B-cell hyperactivity, autoimmunity and markers of lymphoid neogenesis indicate the CCL25/CCR9-axis plays a significant role in pSS immunopathology, representing a novel therapeutic target. This article is protected by copyright. All rights reserved.