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Vasculitis
Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis
  1. Ignatius Ryan Adriawan1,2,
  2. Faranaz Atschekzei1,2,
  3. Oliver Dittrich-Breiholz3,
  4. Panagiotis Garantziotis1,
  5. Stefanie Hirsch1,
  6. Linus Maximillian Risser1,
  7. Maike Kosanke3,
  8. Reinhold Ernst Schmidt1,2,
  9. Torsten Witte1,2,
  10. Georgios Sogkas1,2
  1. 1Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
  2. 2Cluster of Excellence RESIST, Hannover Medical School, Hannover, Germany
  3. 3Research Core Unit Genomics, Hannover Medical School, Hannover, Germany
  1. Correspondence to Dr Georgios Sogkas, Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; sogkas.georgios{at}mh-hannover.de

Abstract

Objectives Giant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens.

Methods A total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients’ and healthy blood donors’ (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis.

Results Transcriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission.

Conclusions Our findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.

  • giant cell arteritis
  • autoimmunity
  • inflammation
  • T-lymphocyte subsets

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/annrheumdis-2021-220955

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors Conception and design of the works: GS, IRA. Data acquisition, analysis, interpretation: IRA, GS, OD-B, PG, MK. Patient recruitment: SH, LMR, PG, TW, GS. First manuscript draft: IRA, GS. Funding: GS, FA, IRA, TW, RES. All authors revised and approved the manuscript.

    • Funding This project was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2155 'RESIST'—Project ID 39087428, the German Federal Ministry of Education and Research (BMBF) through a grant to the German Auto-Immunity Network (GAIN), grant code 01GM1910E Hannover and the Rosemarie-Germscheid Foundation. IRA was supported by the German Academic Exchange Service (DAAD, personal reference number 91720367) and the Hannover Biomedical Research School (HBRS)—Center for Infection Biology (ZIB).

    • Competing interests None declared.

    • 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.