Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis.
Rui LiAyman RezkMathab GhadiriFelix LuessiFrauke ZippHulun LiPaul S GiacominiJack AntelAmit Bar-OrPublished in: Journal of immunology (Baltimore, Md. : 1950) (2016)
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.
Keyphrases
- multiple sclerosis
- disease activity
- anti inflammatory
- rheumatoid arthritis
- systemic lupus erythematosus
- cell death
- mass spectrometry
- rheumatoid arthritis patients
- ms ms
- combination therapy
- machine learning
- juvenile idiopathic arthritis
- immune response
- cell proliferation
- inflammatory response
- end stage renal disease
- hiv infected
- working memory
- smoking cessation