title: Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.
abstract: Fingolimod, an oral therapeutic agent approved for patients with relapsing-remitting Multiple Sclerosis (MS), has been shown to prevent lymphocyte egress from secondary lymphoid tissues; however the specific drug effect on B cells in fingolimod-treated patients remains to be fully elucidated. We present here a comprehensive analysis on the proportions of B cell subsets in the periphery, and the levels of activation, functional surface markers and cytokine profile of B cells in MS patients, following initiation of fingolimod therapy, using flow cytometry and cytokine bead array. Fingolimod therapy increased the ratio of naïve to memory cells, elevated the percentage of plasma cells and highly increased the proportion of transitional B cells as well as additional regulatory subsets, including: IL10(+), CD25(+) and CD5(+) B cells. The percentage of activated CD69(+) cells was highly elevated in the remaining circulating B cells, which produced increased levels of IL10, TGFβ, IL6, IL4, LTα, TNFα and IFNγ cytokines, with an overall increased ratio of TGFβ to pro-inflammatory cytokines. Furthermore, fingolimod therapy reduced ICAM-1(+) cells, suggesting a possible reduction in antigen-presenting capacity. Phosphorylated-fingolimod was shown in vitro to reduce S1PR1 RNA and protein, to slightly increase viability and to activate anti-apoptotic Bcl2 in transformed B cells of patients with MS. In conclusion, fingolimod therapy modulates significantly the composition of circulating B cells, promoting regulatory subsets and an anti-inflammatory cytokine repertoire.
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Blumenfeld
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Elsebeth
authors.initials: E
authors.lastname: Staun-Ram
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Neuroimmunology Unit & Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel. Electronic address: milleras@netvision.net.il.
authors.forename: Ariel
authors.initials: A
authors.lastname: Miller
mesh_terms: D000328:Adult; D017951:Antigen Presentation / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis*; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000068876:Fingolimod Hydrochloride
keywords: Autoimmunity; B cell subsets; Cytokine; Fingolimod; Multiple sclerosis; Regulatory cells