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Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell
  1. Masaru Takeshita1,
  2. Katsuya Suzuki1,
  3. Yasushi Kondo1,
  4. Rimpei Morita2,
  5. Yuumi Okuzono3,
  6. Keiko Koga3,
  7. Yoshiaki Kassai3,
  8. Kanae Gamo3,
  9. Maiko Takiguchi3,
  10. Rina Kurisu3,
  11. Hideyuki Mototani3,
  12. Yukihiko Ebisuno3,
  13. Akihiko Yoshimura2,
  14. Tsutomu Takeuchi1
  1. 1 Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
  2. 2 Department of Microbiology and Immunology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
  3. 3 Research, Immunology Unit, Takeda Pharmaceutical Co Ltd, Fujisawa-Shi, Kanagawa, Japan
  1. Correspondence to Professor Tsutomu Takeuchi, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku 160-8582, Tokyo, Japan; tsutake{at}z5.keio.jp

Abstract

Objectives Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively.

Methods We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other.

Results We identified that ‘effector memory-Tfh’ subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment.

Conclusion Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.

  • rheumatoid arthritis
  • T cell
  • synovial fluid

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors Study design: MT, KS, RM, KK, Y.Ka., KG, HM, YE, AY and TT. Data acquisition: MT, YK, KK, YK, MT and RK. Data analysis and interpretation: MT, KS, RM, YO, KK and YK. Manuscript drafting: MT, KS, YO and TT.

  • Funding This work was partly supported by Takeda Pharmaceutical Company Limited, Kanagawa, Japan (grant number 04-078-0067).

  • Competing interests YO, KK, YK, KG, MT, RK, HM and YE are employees of Takeda Pharmaceutical Company Limited. KS has received research grants from Eisai, Bristol-Myers Squibb, Kissei Pharmaceutical, and Daiichi Sankyo, and speaking fees from Abbie Japan, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Fuji Film Limited, Janssen Pharmaceutical, Kissei Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Pfizer Japan, Shionogi, Takeda Pharmaceutical, and UCB Japan, consulting fees from Abbie, and Pfizer Japan. AY has received speaking fees from Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, Maruho, and Novartis, and consulting fees from GSK Japan. TT has received research grants from Astellas Pharma Inc, Bristol-Myers KK, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd, Takeda Pharmaceutical Co. Ltd, Teijin Pharma Ltd, AbbVie GK, Asahikasei Pharma Corp, Mitsubishi Tanabe Pharma Co, Pfizer Japan Inc, and Taisho Toyama Pharmaceutical Co. Ltd, Eisai Co. Ltd, AYUMI Pharmaceutical Corporation, and Nipponkayaku Co. Ltd, and speaking fees from AbbVie GK, Bristol-Myers KK, Chugai Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Co, Pfizer Japan Inc, and Astellas Pharma Inc, and Diaichi Sankyo Co. Ltd, and consultant fees from Astra Zeneca KK, Eli Lilly Japan KK, Novartis Pharma KK, Mitsubishi Tanabe Pharma Co, Abbivie GK, Nipponkayaku Co. Ltd, Janssen Pharmaceutical KK, Astellas Pharma Inc, and Taiho Pharmaceutical Co. Ltd.

  • Patient consent for publication Not required.

  • Ethics approval Ethics approval was obtained from the Institutional Review Board of Keio University School of Medicine.

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

  • Data availability statement Thetranscriptome data are available at the GEO database. The accession codes are GSE113156 and GSE118829. All custom computer codes in the generation or processing of the described data are available upon reasonable request.

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