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01.02 In rheumatoid arthritis synovitis is not dominated by polymorphic local, but rather by uniform systemic t-cell responses
  1. Anne Musters1,
  2. Paul Klarenbeek1,2,
  3. Marieke Doorenspleet1,2,
  4. Rebecca Esveldt1,2,
  5. Barbera van Schaik3,
  6. Aldo Jongejan3,
  7. Sander Tas1,2,
  8. Antoine van Kampen3,
  9. Frank Baas4,
  10. Niek de Vries1,2
  1. 1Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Centre
  2. 2Laboratory of Experimental Immunology
  3. 3Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics
  4. 4Laboratory for Genome Analysis, all at the Academic Medical Centre, University of Amsterdam, The Netherlands

Abstract

Background Previously we found a strong enrichment of highly expanded T-cell clones in rheumatoid arthritis (RA) synovial tissue (ST) of inflamed joints. To gain more insight into the potential role of these expanded clones in the inflammatory polyarthritis in this disease, we studied the distribution of these T-cell clones.1

Methods In nine RA-patients we simultaneously obtained ST biopsies from two inflamed joints via mini-arthroscopy together with paired peripheral blood (PB) and synovial fluid samples (SF). Biopsies were obtained from ankle (n=1) or from the infrapatellar region of the knee (n=8). In 7 patients we took additional independent suprapatellar biopsies within the same knee joint. Samples were processed for RNA-based next-generation sequencing. T-cell clones were identified by their unique T-cell receptor β-chain sequence. To test for dissimilarity the Chao-modified Sørensen index was used.2

Results Only a small proportion of the clones present in ST were retrieved in the same proportion in PB (Chao-modified Sørensen index 0.14, SD 0.07). In contrast, considerable overlap was seen if we analysed cellular infiltrate in ST biopsies from different regions of the same joint and when comparing different joints: 0.51 (SD 0.11) and 0.38 (SD 0.11) respectively. These overlaps were significantly different from that between ST and PB (p<0.0001 and p<0.01 resp.). Interestingly, the overlap between ST and SF was similarly high: 0.42 (SD 0.13). However, of the top-25 most expanded clones in ST only a limited number was retrieved as top-25 clones in SF (30%, SD 14.8). This was significantly different from top-25 overlap in ‘intra- and interjointal’ comparisons (both 56%, p<0.001 and p<0.01 resp.).

Conclusions SF and PB T-cells do not fully reflect the repertoire of dominant clones in ST, suggesting that analysis of biopsies is preferred. Biopsies taken from different locations within the same joint show substantial overlap suggesting that single biopsies, eg, taken by ultrasound, show a representative snapshot of the ST T-cell infiltrate. Interestingly, biopsies from different joints also show substantial overlap. This indicates that in individual active RA-patients a limited number of T-cell clones dominate the adaptive immune response in the ST. Detailed cellular characterisation of these clones seems warranted, and may help to devise more selective strategies for therapeutic targeting.

Acknowledgements This work was supported in part by BTCURE, a research project from the Innovative Medicines Initiative Joint Undertaking (grant No 115142–2).

References

  1. Klarenbeek, P. L. et al. Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease. Ann. Rheum. Dis. 2012;71:1088–93.

  2. Chao, A., Chazdon, R. L. & Shen, T. J. A new statistical approach for assessing similarity of species composition with incidence and abundance data. Ecol. Lett. 2005;8:148–159.

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