title: 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.
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.
authors.affiliation: Medizinische Klinik und Poliklinik II, Division of Rheumatology/Clinical Immunology, University of Würzburg, Würzburg, Germany.
authors.forename: Khalid
authors.initials: K
authors.lastname: Muhammad
authors.forename: Petra
authors.initials: P
authors.lastname: Roll
authors.forename: Thomas
authors.initials: T
authors.lastname: Seibold
authors.forename: Stefan
authors.initials: S
authors.lastname: Kleinert
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Tony
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D000068800:Etanercept; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C502936:tocilizumab; D000068800:Etanercept