THU0241 Decreased circulating CXCR3+CCR9+ th cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with SJÖGREN'S syndrome to potentially facilitate concerted migration. (15th June 2017)

• Record Type: Journal Article
• Authors: Blokland, SL; Hillen, MR; Meller, S; Homey, B; Smithson, GM; Kruize, AA; Radstake, TR; Roon, JA van
• Is Part Of: Annals of the rheumatic diseases. Volume 76(2017)Supplement 2
• Page Start: 295
• Page End: 295
• Publication Date: 2017-06-15
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2017-eular.2830
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Primary Sjögren's syndrome (pSS) is characterized by dryness and lymphocytic infiltration in the salivary glands. Both CXCR5+ T follicular helper (Tfh) cells and CCR9+ Tfh-like cells and their specific chemotactic ligands CXCL13 and CCL25 are present at increased levels in the salivary glands of pSS patients. Recently, we and others found that CCR9+ Th cells are elevated in pSS peripheral blood and co-express CXCR3 and other chemokine receptors, known to be differentially expressed by Th cell subsets. CCR9+ Th cells play an important role in mucosal immunity and have been shown to produce high levels of IFN-γ, like CXCR3+ Th1 cells. Since ligands of CXCR3 (CXCL9/10/11) are abundantly expressed in the salivary glands of pSS patients the potential role of this receptor in conjunction with CCL25 was studied in comparison with other chemokine receptors. Objectives: To study potential chemokine interactions causing enhanced migration of CCR9+ T cells into the salivary glands in pSS. Methods: CXCL10, CCL25, CXCL13, CCL17 and CCL20 mRNA and protein expression in the salivary gland of pSS and non-Sjögren's sicca (nSS) patients was assessed (mRNA: n=9 vs n=9 and protein: n=26 vs n=34, respectively). Frequencies of CXCR3, CCR9, CXCR5, CCR4 and CCR6 expressing Th cells in blood of pSS patients and healthy controls were assessed by flow cytometry (n=11 vs n=11). Chemotaxis assays (n=3 HC, n=5 pSS) were performed to study migration induced by CXCL10 and CCL25. Results: CCL25, CXCL10 and CXCL13 expression were increased in pSS compared to nSS patients, both at mRNA and protein level (all p≤0.02). CCL17 and CCL20 expression were low and detectable in only few patients. Protein levels of CXCL10 and CXCL13 correlated with lymphocytic focus scores and all 3 chemokines correlated with serum IgG levels in pSS (all p<0.05). CCL25 protein levels strongly correlated with CXCL10 (r=0.545, p=0.004) but not with CXCL13. A relative decrease of CXCR3+ cells was found in the CCR9+ Th subset in the peripheral blood of pSS patients (p=0.04), which was most pronounced in the effector and effector memory subsets (64% vs 26%, p=0.03 and 51% vs 27% p=0.01, respectively). CCR4 or CCR6-expressing CCR9+ Th cells and CXCR3 or CCR6-expressing CXCR5+ Th cells were not decreased. To test the hypothesis that CXCR3 ligands and CCL25 facilitate migration, co-migration of lymphocytes in response to CXCL10 and CCL25 was studied. CXCL10 and CCL25 induced synergistic Th cell chemotaxis in vitro (p=0.02 and p<0.01 as compared to CCL25 or CXCL10 only, respectively). Conclusions: The decreased frequency of CXCR3+CCR9+ Th cells in blood of pSS patients may be due to a concerted action of overexpressed ligands at the site of inflammation. Elevated expression of ligands CXCL10 and CCL25 in the salivary gland and the synergistic effect on chemotaxis in vitro indicate a potential role for these chemokines in formation of lymphocytic infiltrates in exocrine glands of pSS patients. Disclosure of Interest: None declared