Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets

Abstract

Objective:To test the hypothesis that dimethyl fumarate (Tecfidera, BG-12) affects B-cell subsets in patients with relapsing-remitting multiple sclerosis (RRMS).Methods:Peripheral blood B cells were compared for surface marker expression in patients with RRMS prior to initiation of treatment, after 4–6 months, and at more than 1 year of treatment with BG-12. Production of interleukin (IL)–10 by RRMS patient B cells was also analyzed.Results:Total numbers of peripheral blood B lymphocytes declined after 4–6 months of BG-12 treatment, due to losses in both the CD27+ memory B cells and CD27neg B-cell subsets. Some interpatient variability was observed. In contrast, circulating CD24highCD38high (T2-MZP) B cells increased in percentage in the majority of patients with RRMS after 4–6 months and were present in higher numbers in all of the patients after 12 months of treatment. The CD43+CD27+ B-1 B cells also increased at the later time point in most patients but were unchanged at 4–6 months compared to pretreatment levels. Purified B cells from 7 of the 9 patients with RRMS tested after 4–6 months of treatment were able to produce IL-10 following CD40 ligand stimulation, and the amount corresponded with the combined levels of T2-MZP and B-1 B cells in the sample. None of the patients with RRMS in this study have had a relapse while taking BG-12.Conclusions:These data suggest that BG-12 differentially affects B-cell subsets in patients with RRMS, resulting in increased numbers of circulating B lymphocytes with regulatory capacity.

B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate

“…This cross-sectional study demonstrates that while DMF-treatment causes a time-dependent reduction in CD19 + CD27 + CD38memory B cells in blood, it leads to a depletion of CD19 + CD27 + CD38 + plasmablasts in the CSF. Our findings in blood are in agreement with recent publications [13][14][15][16] , and the present work demonstrates how the peripheral effects of DMF translate into the CSF. These data point to a possible B-cell mediated mechanism of action for DMF, in addition to the previously discussed pluripotent immunomodulatory effects 12 .…”

“…Previous studies have shown that DMF reduces the number of memory B cells in blood [13][14][15][16] , typically identified as CD19 + CD27 + cells. To identify these cells in blood and CSF, a gating strategy based on available data was devised ( Figure 1).…”

“…Dimethyl fumarate (DMF) is an oral disease-modifying treatment (DMT) approved for treating relapsing-remitting MS (RRMS). The mechanism of action is not fully clarified 12 , but includes a reduction of peripheral blood CD19 + CD27 + memory B cells [13][14][15][16] . Upon intake, DMF is rapidly metabolized to monomethyl fumarate (MMF), which crosses the blood-brain barrier in animal models and in humans, however only at 15% of plasma concentration 17,18 .…”

Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients

“…Moreover, NK-like T cells (NKT), identified as FSC low CD14 - TCRαβ + CD56 + , were progressively decreased and the differences were significant between the long term >18M treatment group and the untreated group ( P =0.0007). B cell counts were significantly decreased after >18 months of treatment and the detailed B cell subtype changes were described in our recent paper (14). Total NK cell counts showed no significant differences among the three groups.…”

“…The effectiveness of DMF in psoriasis also suggests an immune regulatory role, which prompted us to study the effects of DMF treatment on human peripheral lymphocytes in DMF-treated RRMS patients. We recently reported that RRMS patients treated with DMF had reduced levels of naïve and memory B cells, while there was an increase in B cells with phenotypes reported to produce IL-10 and to have regulatory capacity (14). Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported to be associated with long-term DMF treatment of psoriasis and MS patients (15-18), which make it important to understand the immunological changes induced by DMF treatment in order to find reliable biomarker(s) that can predict JC virus activation and prevent PML.…”