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: Khalid Muhammad, Petra Roll, Thomas Seibold, Stefan Kleinert, Hermann Einsele, Thomas Dörner, Hans-Peter Tony
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 70 Issue 8 Pg. 1507-10 (Aug 2011) ISSN: 1468-2060 [Electronic] England
• PMID: 21551509 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• Immunoglobulin G
• Immunoglobulin Variable Region
• Receptors, Interleukin-6
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha
• tocilizumab
• Etanercept

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antirheumatic Agents (pharmacology, therapeutic use)
• Arthritis, Rheumatoid (drug therapy, genetics, immunology)
• B-Lymphocyte Subsets (drug effects, immunology)
• Etanercept
• Female
• Gene Rearrangement, B-Lymphocyte (genetics)
• Humans
• Immunoglobulin G (pharmacology, therapeutic use)
• Immunoglobulin Variable Region (genetics)
• Immunologic Memory (genetics)
• Male
• Middle Aged
• Prospective Studies
• Receptors, Interleukin-6 (antagonists & inhibitors, immunology)
• Receptors, Tumor Necrosis Factor (therapeutic use)
• Somatic Hypermutation, Immunoglobulin (immunology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)