Enhanced Expression of CCL25 to Facilitate Increased Numbers of CCR9-Expressing Tfh-like Cells in Salivary Glands of Primary Sjögren’s Syndrome Patients

S.L.M. Blokland^1,2, M.R. Hillen^1,2, A.a. Kruize², A. Kislat³, S. Meller³, B. Homey³, G.M. Smithson⁴, J. Zalevsky⁵, T.R.D.J. Radstake² and J.a.G. van Roon², ¹Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ²Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ³Department of Dermatology, University of Düsseldorf, Medical Faculty, Düsseldorf, Germany, ⁴Takeda Pharmaceuticals International, Chicago, IL, ⁵Takeda California, San Diego, CA

Meeting: 2014 ACR/ARHP Annual Meeting

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

Session Information

Title: T cell Biology in Lupus, Vasculitis, Myositis and Other Autoimmunity

Session Type: Abstract Submissions (ACR)

Background/Purpose
In primary Sjögren’s syndrome (pSS) B cell activation and autoantibody secretion are hallmark immunopathological features. Specific lymphoid organization (including germinal centers) is associated with increased risk for development of extraglandular manifestations and lymphoma. Thus better understanding of the cellular and molecular pathways that underlie formation of ectopic lymphoid structures is of pivotal importance. Tfh cells, expressing ICOS and cytokines like IL-21 play a critical role in the formation of such structures and in activation of B cells. Recently, a novel subset of CD4+ T cells found to have Tfh-like characteristics was found to be specifically attracted to mucosal sites by CCL25, the ligand for CCR9.

Objective
To investigate the presence of CCL25 and CCR9-expressing Tfh-like cells in pSS patients.

Methods
Levels of CCL25 were measured in the serum of patients with pSS (n=13), non-Sjögren’s sicca (nSS, n=15) and healthy controls (HC, n=6). Also, the correlation of CCL25 with other inflammatory mediators as assessed by Luminex was determined. Secretion of CCL25 by labial salivary gland (LSG) biopsy samples from pSS (n=14) and nSS (n=14) patients was assessed and CCL25 mRNA was quantified (n=9 vs n=9). CCR9-expressing cells were assessed in the circulation of HC and pSS patients and expression of Tfh markers including CXCR5, ICOS and PD-1 was analyzed.

Results
Increased CCL25 levels were observed in serum of pSS and nSS patients as compared to HC (pSS 2984 ± 286, nSS 2692 ± 177, HC 2140 ± 154, p = 0.02 and p = 0.03 resp). CCL25 serum levels in pSS correlated with the presence of chemokines involved in formation of ectopic lymphoid structures CXCL13 and CCL19 (r=0.594, p=0.04) and proinflammatory cytokines IL-12 (r=0.615, p=0.03) and TWEAK (r=0.621, p=0.03). In addition, pSS patients displayed a 10 fold increase in CCL25 mRNA levels in LSG (p<0.05) and an increase in CCL25 protein levels in LSG washouts compared to nSS patients (2029 ± 2986 vs 974 ± 188 pg/mL, p=0.03), correlating with CXCL13 (r=0.832, p<0.001). pSS patients had enhanced numbers of CCR9-expressing T cells in the circulation as compared to HC (14.1% vs 7.9%, p=0.05). Interestingly, comparable to Tfh a substantial proportion of CCR9+ cells expressed CXCR5, PD-1 and ICOS.

Conclusion
Our results suggest that enhanced expression of CCL25 in the labial salivary gland might promote elevation of CCR9-expressing Tfh-like cells at the site of inflammation. Considering the expression of ICOS and the capacity of CCL25 to induce proinflammatory cytokine secretion this suggests that the CCL25/CCR9-axis might play a role in the immunopathology of pSS, representing a novel therapeutic target in this disease.

Disclosure:

S. L. M. Blokland,