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Impact of IL-6 receptor inhibition on human memory B cells in vivo: impaired somatic hypermutation in preswitch memory B cells and modulation of mutational targeting in memory B cells
  1. Khalid Muhammad1,
  2. Petra Roll1,
  3. Thomas Seibold1,
  4. Stefan Kleinert1,
  5. Hermann Einsele1,
  6. Thomas Dörner2,3,
  7. Hans-Peter Tony1
  1. 1Medizinische Klinik und Poliklinik II, Division of Rheumatology/Clinical Immunology, University of Würzburg, Würzburg, Germany
  2. 2CC12, Department of Medicine/Rheumatology and Clinical Immunology, Charite Universitätsmedizin, Berlin, Germany
  3. 3DRFZ Berlin, Berlin, Germany
  1. Correspondence to Dr Hans-Peter Tony, Medizinische Klinik und Poliklinik II, Division of Rheumatology/Clinical Immunology, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany; tony_h{at}medizin.uni-wuerzburg.de

Abstract

Objective Interleukin 6 (IL-6) receptor (IL-6R) inhibition by tocilizumab is a novel anti-inflammatory therapy for rheumatoid arthritis (RA) patients. As IL-6 is a late differentiation factor of B cells the authors asked if IL-6R inhibition impacts on the mutational differentiation of human memory B-cell antigen receptors in vivo.

Methods 1733 immunoglobulin receptors (IgR) of single cell sorted preswitch and postswitch memory B cells were prospectively analysed from 11 RA patients under IL-6R inhibition (7 patients) or tumour necrosis factor (TNF) inhibition (4 patients).

Results The results show a reduced mutational frequency in IgR of preswitch memory B cells (p=0.0001) during week 12, week 24 and 1 year of tocilizumab therapy. Mutational hotspot RGYW/WRCY motifs indicated significantly decreased targeting (p<0.05) in preswitch and postswitch memory B cells. Anti-TNFα therapy had no effect on mutational frequency and mutational hotspot targeting motifs in memory B-cell subsets.

Conclusions These data suggest that preswitch and postswitch memory B cells are susceptible to IL-6R inhibition in vivo. Acquisition of mutations was substantially altered in preswitch memory B cells, while targeting of mutational hotspots affected preswitch and postswitch memory B cells. The results indicate that preswitch and postswitch memory B cells have a differential dependence on the IL-6/IL-6R system for differentiation, which can be influenced by tocilizumab in vivo.

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Footnotes

  • Funding This work was supported by Wilhelm Sanderstiftung 2006.037.2 and project 16, SFB 650.

  • Competing interests Drs. Kleinert and Tony have received consulting fees, speaking fees, and/or honoraria from Roche, Abbott, Chugai and Wyeth (less than $10,000 each). Dr. Dörner has received consulting fees and/or honoraria from Roche, Genentech, Immunomedics, and UCB (less than $10,000 each). All other authors declare no competing interest.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the ethics committee of the University of Würzburg, Germany.

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

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