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

Background: B cells are key pathogenic effectors in multiple sclerosis (MS) and several therapies have been designed to restrain B cell abnormalities by directly targeting this lymphocyte population. Objectives: Moving from our data showing a Toll-like receptor (TLR)7-driven dysregulation of B cell response in relapsing–remitting multiple sclerosis (RRMS) and having found a low serum level of Thymosin-α1 (Tα1) in patients, we investigated whether the addition of this molecule to peripheral blood mononuclear cells (PBMCs) would influence the expansion of regulatory B cell subsets, known to dampen autoimmune inflammation. Methods: Serum Tα1 level was measured by enzyme immunoassay. Cytokine expression was evaluated by Cytometric Bead Array (CBA), enzyme-linked immunosorbent assay (ELISA), and real-time reverse transcription polymerase chain reaction (RT-PCR). B cell subsets were analyzed by flow cytometry. Results: Tα1 pre-treatment induces an anti-inflammatory status in TLR7-stimulated RRMS PBMC cultures, reducing the secretion of pro-inflammatory interleukin (IL)-6, IL-8, and IL-1β while significantly increasing the regulatory IL-10 and IL-35. Indeed, Tα1 treatment enhanced expansion of CD19+CD24+CD38hi transitional-immature and CD24low/negCD38hi plasmablast-like regulatory B cell subsets, which likely inhibit both interferon (IFN)-γ and IL-17 production. Conclusion:: Our study reveals a deficient ability of B cells from MS patients to differentiate into regulatory subsets and unveils a novel anti-inflammatory and repurposing potential for Tα1 in MS targeting B cell response.

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IFNbeta-1b Treatment Alters the Composition of Circulating B Cell Subsets, in Particular Reducing the Number of Autoantibody Secreting B1 Cells in Patients with Relapsing-Remitting Multiple Sclerosis (P02.086)

Neurology ◽

10.1212/wnl.78.1_meetingabstracts.p02.086 ◽

2012 ◽

Vol 78 (Meeting Abstracts 1) ◽

pp. P02.086-P02.086

Author(s):

D. Mielcarz ◽

A. Bergeron ◽

J. DeLong ◽

K. Smith ◽

A. Heyn ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cell ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

B Cell Subsets ◽

B1 Cells ◽

Relapsing Remitting Multiple Sclerosis

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Lymphocyte subtypes in relapsing–remitting multiple sclerosis patients treated with dimethyl fumarate

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217317702933 ◽

2017 ◽

Vol 3 (2) ◽

pp. 205521731770293 ◽

Cited By ~ 6

Author(s):

C Chaves ◽

R Ganguly ◽

C Ceresia ◽

A Camac

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

B Cell ◽

Dimethyl Fumarate ◽

Normal Lymphocyte ◽

Cell Counts ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

Background Recent data suggest that lymphopenia is more prevalent than reported in relapsing–remitting multiple sclerosis (RRMS) patients taking dimethyl fumarate (DMF). Objective The objective of this study was to investigate the effect of DMF on lymphocyte subtypes in RRMS patients with and without lymphopenia. Method A retrospective study compared lymphocyte subtypes in DMF-treated RRMS patients with low (G1, n = 35) and normal lymphocyte counts (G2, n = 24). Results Fifty-nine patients were identified, with mean age 49, 71.2% females, and average DMF duration 20 months. Age, sex, baseline white blood count, disease and treatment durations were similar between groups. Prior interferon therapy and baseline lower normal lymphocyte counts were more frequent in G1. Mean lymphocyte counts were 0.8 ± 0.2 × 109/L in G1 and 1.6 ± 0.3 × 109/L in G2. CD3+, CD4+, and CD8+ T cell mean counts were lower ( p < 0.0001), while CD4/CD8 ratio higher ( p = 0.03) in G1 than G2. Mean CD19 + B cell counts were normal; however, values were lower in G1 ( p = 0.04). After adjusting for confounders, significantly positive correlations were noted between lymphocyte counts and CD3 + , CD4+, CD8+ T, and B cell counts. Negative correlation was observed between lymphocyte counts and CD4/CD8 ratio driven by low CD8+ T cell counts. Conclusion DMF treatment predominantly impacts T cells, in particular CD8+ subtype. This finding may have implications in this population’s immunocompetence.

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Dimethyl fumarate therapy suppresses B cell responses and follicular helper T cells in relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458518790417 ◽

2018 ◽

Vol 25 (9) ◽

pp. 1289-1297 ◽

Cited By ~ 6

Author(s):

Rikke Holm Hansen ◽

Helene Højsgaard Chow ◽

Finn Sellebjerg ◽

Marina Rode von Essen

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Dimethyl Fumarate ◽

Follicular Helper ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Cell Subpopulations ◽

Relapsing Remitting Multiple Sclerosis ◽

The Impact

Background: Dimethyl fumarate (DMF) is a disease-modifying therapy used for patients with relapsing-remitting multiple sclerosis (RRMS). B cells are important contributors to the pathogenesis of RRMS, where they regulate the inflammatory immune responses and participate in development of lesions in the central nervous system (CNS). The impact of DMF on B cell subpopulations remains incompletely understood. Objectives: In this study, we evaluated the effects of DMF on B cell subpopulations and their effector functions. Methods: Blood from 21 DMF-treated and 18 untreated patients with RRMS was analyzed by flow cytometry. Results: We found that DMF reduces the frequency of circulating antigen–experienced B cells, a reduction likely related to a reduced frequency of follicular helper T (TFH) cells and an increased frequency of follicular regulatory T (TFR) cells. Studying the impact of monomethyl fumarate (MMF), the primary metabolite of DMF, on B cell effector function in vitro showed that MMF increased the frequency of transforming growth factor (TGF)-β-producing B cells and decreased the frequency of B cells secreting lymphotoxin (LT)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and to a lesser extent IL-10. Conclusion: In summary, these data suggest an anti-inflammatory role of DMF and its metabolite MMF on the B cell compartment.

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