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Spondyloarthritis
Distinct immune modulatory roles of regulatory T cells in gut versus joint inflammation in TNF-driven spondyloarthritis
  1. Koen Venken1,2,
  2. Matthias Jarlborg1,2,
  3. Tine Decruy1,2,
  4. Céline Mortier1,2,
  5. Carolien Vlieghe1,2,
  6. Elisabeth Gilis1,2,
  7. Ann-Sophie De Craemer1,2,
  8. Julie Coudenys1,2,
  9. Isabelle Cambré1,2,
  10. Devan Fleury3,
  11. Alexander Klimowicz3,
  12. Filip Van den Bosch1,2,
  13. Anne Hoorens4,
  14. Triana Lobaton5,6,
  15. Sytze de Roock7,
  16. Tim Sparwasser8,
  17. Gerald Nabozny3,
  18. Peggy Jacques1,2,
  19. Dirk Elewaut1,2
  1. 1 Molecular Immunology and Inflammation Unit, VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
  2. 2 Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Rheumatology unit), Ghent University, Ghent, Belgium
  3. 3 Immunology and Respiratory Department, Boehringer Ingelheim Corp Pharmaceutical Research and Development Centre Ridgefield, Ridgefield, Connecticut, USA
  4. 4 Department of Pathology, University Hospital Ghent, Gent, Belgium
  5. 5 Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Gastroenterology unit), Ghent University, Ghent, Belgium
  6. 6 Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
  7. 7 Department of Pediatric Immunology, Center for Molecular and Cellular Intervention CMCI, Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
  8. 8 University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  1. Correspondence to Professor Koen Venken, Department of Internal Medicine and Pediatrics (Rheumatology Unit), Ghent University, Gent, Belgium; koen.venken{at}ugent.be

Abstract

Objectives Gut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+ regulatory T (Treg) cells in a model of Crohn’s-like ileitis and concomitant arthritis.

Methods RNA-sequencing and flow cytometry was performed on inflamed gut and joint samples and tissue-derived Tregs from tumour necrosis factor (TNF)∆ARE mice. In situ hybridisation of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble TNFR (sTNFR) levels were measured in serum of mice and patients with SpA and controls. Treg function was explored by in vitro cocultures and in vivo by conditional Treg depletion.

Results Chronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 messenger RNA levels were noted in TNF∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in patients with SpA with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆ARE mice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue-restricted TNFSF receptor and p38MAPK gene expression.

Conclusions These data point to profound differences in immune-regulation between Crohn’s ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.

  • spondyloarthritis
  • T-lymphocyte subsets
  • arthritis, experimental

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/ard-2022-223757

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors The project was designed, conceived and planned by KV (guarantor), GN, PJ and DE. Experiments were performed by KV, TD, MJ, EG, CM, JC, IC, TS, A-SDC, DF, AK, SdR. Patient sample collection and histological evaluations were done by PJ, FvdB, A-SDC, and AH. The data were analysed by KV, TD, A-SDC, DF and CV. The paper was written and edited by KV and DE. All authors revised the paper critically for important intellectual content and gave their final approval for submission. KV is the guarantor.

    • Funding KV is supported by FWO-Vl (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Grant 3E014310), VLAIO (Flanders Innovation & Entrepreneurship, HBC.2016.0622) and a FOREUM research grant. DE is supported by FWO-Vl (3G079911, 3G0C7719, 3G051016), Research Council of Ghent University (01GA3217) and a FWO Excellence of Science (EOS) Grant (EOS 30480119). FvdB is supported by a Special Research Fund (01G03122) from Ghent University. TS was supported by DFG/CRC355 (project A4).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.