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Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis
  1. Izumi Kurata1,
  2. Isao Matsumoto1,
  3. Ayako Ohyama1,
  4. Atsumu Osada1,
  5. Hiroshi Ebe1,
  6. Hoshimi Kawaguchi1,
  7. Shunta Kaneko1,
  8. Yuya Kondo1,
  9. Hiroto Tsuboi1,
  10. Azusa Tomioka2,
  11. Hiroyuki Kaji2,
  12. Takayuki Sumida1
  1. 1Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  2. 2Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
  1. Correspondence to Dr Isao Matsumoto, Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8577, Japan; ismatsu{at}md.tsukuba.ac.jp

Abstract

Objective An increased proportion of circulating follicular helper T (Tfh) cells was reported in rheumatoid arthritis (RA), but it remains uncertain how Tfh cells affect antibody hyposialylation. We investigated the regulation of autoantibody hyposialylation by Tfh cells in RA using murine model.

Methods Behaviours of Tfh cells and their function on B cell promotion were analysed. Change of arthritogenicity and sialylation of autoantibodies during the course of arthritis was examined by mass spectrometry. Tfh-mediated regulation of hyposialylation was investigated, and the responsible cell surface molecule was specified both in vitro and in vivo. The relation between circulating Tfh cells and hyposialylation was analysed in patients with RA.

Results An increase in Tfh, particularly interleukin-17 producing Tfh (Tfh17) cells, at the onset of arthritis and their enhancement of autoantibody production were found. Autoantibodies at the onset phase demonstrated stronger inflammatory properties than those at the resolution phase, and mass spectrometric analysis revealed their difference in sialylation. In vitro coculture showed enhanced hyposialylation by the Tfh cells via OX40, which was highly expressed in the Tfh and Tfh17 cells. Blockade of OX40 prevented the development of arthritis with reduction in Tfh17 cells and recovery of autoantibody sialylation. Analysis of patients with RA showed abundance of OX40-overexpressing Tfh17 cells, and their proportion correlated negatively with the expression of α2,6-sialyltransferase 1, an enzyme responsible for sialylation.

Conclusions OX40 expressed on Tfh cells can regulate autoantibody sialylation and play a crucial role in the development of autoimmune arthritis.

  • rheumatoid arthritis
  • t cells
  • autoantibodies
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Footnotes

  • Handling editor Josef S Smolen

  • Contributors IK, IM and TS designed the study. IK, AOs and SK performed the experiments and collected the data. YK supervised the tissue analysis. AT and HKaj performed the mass spectrometric analysis. IK, AOh, AOs, HE, HKaw, YK and HT participated in the discussion. IK, IM and TS analysed the data and wrote the manuscript. All authors have read and approved the manuscript for publication.

  • Funding This work was supported by a Grant-in-Aid for Scientific Research (grant number 18K08403) from the Ministry of Education, Culture, Sports, Science and Technology and by the Japan Society for the Promotion of Science.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Institutional Animal Care and Use Committee of the University of Tsukuba.

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

  • Data availability statement Data are available upon reasonable request.

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