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Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease
  1. P L Klarenbeek1,
  2. M J H de Hair1,
  3. M E Doorenspleet1,
  4. B D C van Schaik2,
  5. R E E Esveldt1,
  6. M G H van de Sande1,
  7. T Cantaert1,4,
  8. D M Gerlag1,
  9. D Baeten1,
  10. A H C van Kampen2,5,
  11. F Baas3,
  12. P P Tak1,
  13. N de Vries1,5
  1. 1Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  3. 3Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  4. 4Department of Immunobiology, Yale University, New Haven, Connecticut, USA
  5. 5Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Niek de Vries, Academic Medical Center/University of Amsterdam, Clinical Immunology and Rheumatology, Amsterdam, The Netherlands; niek.devries{at}amc.uva.nl

Abstract

Objective To profile quantitatively the T-cell repertoire in multiple joints and peripheral blood of patients with recent onset (early) or established rheumatoid arthritis (RA) using a novel next-generation sequencing protocol to identify potential autoreactive clones.

Methods Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC).

Results In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2–70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5–24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28–40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0–8%) between synovium and blood (p=0.01).

Conclusions In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.

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Footnotes

  • Contributors All authors fulfilled the International Committee of Medical Journal Editors requirements for authorship/contributorship. All authors made substantial contributions to conception and design, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version to be published.

  • Competing interests None.

  • Funding This work was supported by the IMI JU funded project BeTheCure, contract no 115142-2.

  • Ethics approval The study was performed according to the Declaration of Helsinki and was approved by the local medical ethics committee.

  • Patient consent Obtained.

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

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