Decreased Circulating CXCR3+CCR9+ Th Cells Coincides with Elevated Levels of Their Ligands CXCL10 and CCL25 in the Salivary Gland of Sjögren’s Syndrome Patients Which Synergistically Facilitate Th Cell Migration

Sofie L.M. Blokland^1,2, Maarten R. Hillen^3,4, Stephan Meller⁵, Bernhard Homey⁵, Glennda Smithson⁶, Aike A. Kruize², Timothy R.D.J. Radstake^2,7 and Joel A.G. van Roon^2,3, ¹Rheumatology & Clinical Immunology/ Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ²Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ³Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands, ⁴Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ⁵Department of Dermatology, University of Düsseldorf, Düsseldorf, Germany, ⁶Takeda Global Research & Development Center, Inc, Chicago, IL, ⁷Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: ACR/ARHP Annual Meeting 2017

Date of first publication: September 18, 2017

Keywords: Chemokine Receptors, Sjogren's syndrome, T cells and chemokines

Session Information

Date: Sunday, November 5, 2017

Title: Sjögren's Syndrome Poster I: Translational Research

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Primary Sjögren’s syndrome (pSS) is characterized by dryness and lymphocytic infiltration in the salivary glands. CXCR3+ T cells and ligands CXCL9/10/11 are known to be abundantly present in the salivary glands of pSS patients. In addition, 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 CXCL9/10/11 and CXCR3 are abundantly expressed in the salivary glands of pSS and CCR9+ Th cells have Th1 characteristics, the potential role in lymphocytic infiltration of the combination of the CXCL10-CXCR3 and CCL25-CCR9 interactions was studied in comparison with other chemokine receptors.

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=24 vs n=33, 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=6 HC, n=10 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 in salivary gland supernatants (all p<0.05). 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 correlated with CXCL10 (p=0.01) 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 (both p<0.01 as compared to CCL25 or CXCL10 only).

Conclusion:

The decreased frequency of CXCR3+CCR9+ Th cells in blood of pSS patients may be facilitated by 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: S. L. M. Blokland, None; M. R. Hillen, None; S. Meller, None; B. Homey, None; G. Smithson, Takeda, 3; A. A. Kruize, None; T. R. D. J. Radstake, Takeda, 5; J. A. G. van Roon, None.

To cite this abstract in AMA style:

Blokland SLM, Hillen MR, Meller S, Homey B, Smithson G, Kruize AA, Radstake TRDJ, van Roon JAG. Decreased Circulating CXCR3+CCR9+ Th Cells Coincides with Elevated Levels of Their Ligands CXCL10 and CCL25 in the Salivary Gland of Sjögren’s Syndrome Patients Which Synergistically Facilitate Th Cell Migration [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/decreased-circulating-cxcr3ccr9-th-cells-coincides-with-elevated-levels-of-their-ligands-cxcl10-and-ccl25-in-the-salivary-gland-of-sjogrens-syndrome-patients-which-synergistically-faci/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/decreased-circulating-cxcr3ccr9-th-cells-coincides-with-elevated-levels-of-their-ligands-cxcl10-and-ccl25-in-the-salivary-gland-of-sjogrens-syndrome-patients-which-synergistically-faci/