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
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