Abstract
IntroductionEnhanced B cell activity, particularly memory B cells have gained interest in evaluating response during therapies with biologics. CD27-IgD- double-negative (DN) B cells lacking the conventional memory marker CD27 are reported to be part of the memory compartment, however, only scarce data is available for rheumatoid arthritis (RA). We therefore focused on DN B cells in RA, studied their isotypes and modulation during interleukin-6 receptor (IL-6R) inhibition by tocilizumab (TCZ).MethodsDN B cells were phenotypically analyzed from 40 RA patients during TCZ at baseline week 12, week 24 and 1 year. A single B cell polymerase chain reaction (PCR) approach was used to study Ig receptors, VH gene rearrangements and specific isotypes.ResultsPhenotypic analysis showed a significantly expanded population of DN B cells in RA which contain a heterogeneous mixture of IgG-, IgA- and IgM-expressing cells with a clear dominance of IgG+ cells. DN B cells carry rearranged heavy chain gene sequences with a diversified mutational pattern consistent with memory B cells. In contrast to tumor necrosis factor alpha (TNF-α) inhibition, a significant reduction in mutational frequency of BCR gene rearrangements at week 12, 24 and 1 year (P <0.0001) was observed by in vivo IL-6R inhibition. These changes were observed for all BCR isotypes IgG, IgA and IgM at week 12, 24 and 1 year (P <0.0001). IgA-RF, IgA serum level and IgA+ DN B cells decreased significantly (P <0.05) at week 12 and week 24 during TCZ. Patients with a good European League Against Rheumatism (EULAR) response to TCZ had less DN B cells at baseline as compared to moderate responders (P = 0.006). Univariate logistic regression analysis revealed that the frequency of DN B cells at baseline is inversely correlated to a subsequent good EULAR response (P = 0.024) with an odds ratio of 1.48 (95% confidence interval as 1.05 to 2.06).ConclusionsIn RA, the heterogeneous DN B cell compartment is expanded and dominated by IgG isotype. TCZ can modulate the mutational status of DN Ig isotype receptors over 1 year. Interestingly, the frequency of DN B cells in RA may serve as a baseline predictor of subsequent EULAR response to TCZ.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0580-y) contains supplementary material, which is available to authorized users.
Highlights
Enhanced B cell activity, memory B cells have gained interest in evaluating response during therapies with biologics
Double-negative (CD19 + immunoglobulin D (IgD)-CD27-) B cells are expanded in rheumatoid arthritis (RA) Based on surface expression of IgD and CD27 (Figure 1A), human peripheral CD19 + B cells were divided into four subsets: mature naïve B cells (IgD + CD27-), pre-switch memory B cells (IgD + CD27+), post-switch memory B cells (IgD-CD27+) and DN B cells (IgD-CD27-)
We found significantly enhanced frequencies of DN B cells in RA patients compared to healthy age-matched donors (HD) (Figure 1B)
Summary
Enhanced B cell activity, memory B cells have gained interest in evaluating response during therapies with biologics. IL-6 is a multifunctional pleiotropic cytokine acting as stimulator of both B and T cell functions. It is produced by various cells of the innate immune system (for example macrophages, dendritic cells, mast cells, neutrophils), B cells, and to some extent by CD4 effector T helper (Th) cells [7]. IL-6 influences various cell types and has multiple biological activities through its unique receptor system [8]. It has been described as a late-acting B cell differentiation factor that is involved in in vitro differentiation of B cells into antibody-forming cells and germinal center reactions. TCZ has shown convincing clinical efficacy by reduction of signs/symptoms and a marked inhibition of radiological progression [11]
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