Abstract
Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease [1, 2] associated with aggressive synovitis that over time causes bone, tendon, and cartilage damage
Memory B cells had a greater propensity to produce pro-inflammatory cytokines TNF, and B cell TNF production was reduced after depletion and reconstitution. These results suggest that the outcome of B cell depletion therapy depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and upon B cell repopulation
Data is expressed as the median +/- interquartile range
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease [1, 2] associated with aggressive synovitis that over time causes bone, tendon, and cartilage damage. The dissociation between changes in autoantibodies and clinical efficacy points to the autoantibody independent roles of B cells in the disease. These may include antigen-presentation, T-cell activation/polarization, dendritic cell modulation, and formation of ectopic lymphoid structures [9,10,11] [12] and are mediated at least in part by the ability of B cells to produce cytokines [13]. B cells can contribute to autoimmunity via the secretion of pro-inflammatory cytokines such as TNF-α and IL-6 [14, 15], and may play a protective or regulatory role in the immune system likely depending on the particular subset and inflammatory milieu [16,17,18]. Which B cell subsets produce pro-inflammatory cytokines in RA, the contribution of B cell protective functions, and the potential plasticity of B cell function depending on environmental context remains unknown
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