Delayed acquisition of somatic hypermutations in repopulated IGD+CD27+ memory B cell receptors after rituximab treatment.

Abstract

OBJECTIVE:

Transient B cell depletion by rituximab has been used with clinical efficacy in the treatment of patients with rheumatoid arthritis (RA). Previous studies of B cell repopulation have shown long-term numerical reduction in memory B cells. Non-class-switched IgD+CD27+ memory B cells, in particular, repopulate slowly. This study was undertaken to determine whether mutational acquisition in individual B cell receptors in repopulating class-switched and non-class-switched memory B cells is affected by rituximab.

METHODS:

Cells obtained from 16 RA patients, 4 healthy donors, and 3 patients who underwent allogeneic stem cell transplantation (ASCT) were analyzed using single B cell sorting followed by nested polymerase chain reaction and Ig V(H)3 sequencing.

RESULTS:

There was a delayed acquisition of mutations in Ig receptors of IgD+ memory B cells over a period of 6 years after a single course of rituximab. One year after rituximab treatment, 84% of single repopulating IgD+CD27+ B cells were unmutated, and no highly mutated Ig receptors were found (compared with 52% before therapy). Over time, increasing numbers of mutations were detected. Even 6 years after rituximab treatment, however, mutations in IgD+ memory B cells were still significantly reduced. In contrast, class-switched memory B cells repopulated with quantitatively normal mutations. In comparison, in patients undergoing ASCT, IgD+ memory cells repopulated earlier with higher mutations in Ig receptors.

CONCLUSION:

Our data suggest that IgD+ memory B cells are particularly susceptible to the effects of rituximab, with delayed acquisition of mutations in their Ig receptors still evident 6 years after a single course of rituximab. Our findings indicate that these cells have different requirements for mutational acquisition compared with class-switched memory B cells.

• Authors: Khalid Muhammad, Petra Roll, Hermann Einsele, Thomas Dörner, Hans-Peter Tony
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 8 Pg. 2284-93 (Aug 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19644860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antirheumatic Agents
• Receptors, Fc
• Tumor Necrosis Factor Receptor Superfamily, Member 7
• immunoglobulin D receptor
• Rituximab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects)
• Antibodies, Monoclonal, Murine-Derived
• Antirheumatic Agents (therapeutic use)
• B-Lymphocytes (drug effects, immunology)
• Gene Rearrangement, B-Lymphocyte (drug effects, immunology)
• Humans
• Immunologic Memory (drug effects, immunology)
• Middle Aged
• Receptors, Fc (drug effects, immunology)
• Rituximab
• Somatic Hypermutation, Immunoglobulin (drug effects)
• Tumor Necrosis Factor Receptor Superfamily, Member 7 (immunology, metabolism)