title: Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis.
abstract: The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-α, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-κB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses.
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Ayman
authors.initials: A
authors.lastname: Rezk
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Mathab
authors.identifier: 0000-0003-3594-4880
authors.initials: M
authors.lastname: Ghadiri
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.|Department of Neurology, Focus Program Translational Neuroscience and Immunotherapy, Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany; and.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience and Immunotherapy, Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany; and.
authors.forename: Frauke
authors.identifier: 0000-0002-1231-1928
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Department of Neurobiology, Harbin Medical University, NanGang District, Harbin 150086, Heilongjiang, China.
authors.forename: Hulun
authors.initials: H
authors.lastname: Li
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Paul S
authors.identifier: 0000-0002-1346-3042
authors.initials: PS
authors.lastname: Giacomini
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; amit.bar-or@mcgill.ca.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
mesh_terms: D000328:Adult; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000276:immunology*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate