Targeting Glandular IL-21-Production in Primary Sjogren′s Syndrome Patients By Immunomodulatory Treatment

Gwenny M. Verstappen¹, Hendrik L.F. Broekman¹, Erlin A. Haacke², Petra M. Meiners³, Fred K.L. Spijkervet³, Arjan Vissink⁴, Hendrika Bootsma⁵ and Frans G.M. Kroese¹, ¹Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, ²Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, ³Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, ⁴Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, ⁵Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, The Netherlands, Groningen, Netherlands

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: biopsies, salivary gland and treatment, Sjogren's syndrome, T cells

Session Information

Date: Sunday, November 13, 2016

Title: Sjögren's Syndrome - Poster I: Translational Science

Session Type: ACR Poster Session A

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

Background/Purpose: Interleukin-21 plays a central role in plasma cell differentiation and germinal center (GC) formation and is likely involved in the pathogenesis of primary Sjögren’s syndrome (pSS). T follicular helper (Tfh)-cells are the main producers of this cytokine. Interleukin-21 protein and mRNA are present in minor salivary glands of pSS patients. Also serum levels of IL-21 are increased, compared with healthy controls. However, effects of immunomodulatory treatment on local IL-21 levels in pSS patients remain unknown. Treatment of pSS with rituximab or abatacept modulates B-T cell interaction and reduces numbers of circulating Tfh-cells. The objective of this study is to investigate if IL-21-producing cells in parotid gland tissue of pSS patients are also targeted by immunomodulatory treatment with rituximab or abatacept.

Methods: Ten pSS patients treated with rituximab (n=5) or abatacept (n=5) were included. Paraffin-embedded parotid gland tissue sections were available before and after treatment (16 weeks after the first dose of rituximab, 25 weeks after the first dose of abatacept). Sections were deparaffinized, heat-induced antigen retrieval was performed and slides were incubated with rabbit anti-human IL-21 and goat anti-rabbit IgG-AF594. Slides were analyzed by immunofluorescence. Serum levels of rheumatoid factor (RF), anti-SSA, anti-SSB, IL-21 and numbers of circulating Tfh (cTfh)-cells were available before and after treatment.

Results: Interleukin-21-positive cells were found in parotid glands of nine out of ten patients at baseline. Baseline numbers of glandular IL-21-positive cells/mm²correlated strongly with serum IL-21 levels (ρ=0.83, P=0.008) and moderately with RF levels (ρ=0.60, P=0.073). Numbers of IL-21-positive cells/mm²were significantly higher (P=0.032) in patients with GC(s) in their biopsies (n=5), compared with GC-negative patients (n=5). No difference in age, disease duration or ESSDAI score was observed between GC-positive and GC-negative patients. After treatment with rituximab or abatacept, a decrease in IL-21-positive cells/mm²was observed in all GC-positive patients, but this was not evident for GC-negative patients, possibly due to low numbers of IL-21-positive cells in GC-negative biopsies at baseline. In the whole study population a trend towards lower serum levels of IL-21 and a significant decrease in cTfh-cell numbers (P=0.023) was observed after treatment. Furthermore, treatment resulted in reduced titers of RF, anti-SSA and –SSB in all patients.

Conclusion: This pilot study shows that pSS patients with GC-positive biopsies have high numbers IL-21-positive cells in their glands. Numbers of IL-21-positive cells/mm²correlate strongly with serum levels of IL-21 in all patients. This study further indicates that interference with T-B-cell interaction, either by B-cell depletion or inhibition of T cell co-stimulation in pSS can abrogate the pathogenic IL-21-pathway, with a concomitant decrease in systemic autoantibody levels.

Disclosure: G. M. Verstappen, None; H. L. F. Broekman, None; E. A. Haacke, None; P. M. Meiners, None; F. K. L. Spijkervet, None; A. Vissink, None; H. Bootsma, None; F. G. M. Kroese, None.

To cite this abstract in AMA style:

Verstappen GM, Broekman HLF, Haacke EA, Meiners PM, Spijkervet FKL, Vissink A, Bootsma H, Kroese FGM. Targeting Glandular IL-21-Production in Primary Sjogren′s Syndrome Patients By Immunomodulatory Treatment [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/targeting-glandular-il-21-production-in-primary-sjogren%e2%80%b2s-syndrome-patients-by-immunomodulatory-treatment/. Accessed .

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