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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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.