title: Differential effects of fingolimod on B-cell populations in multiple sclerosis.
abstract: BACKGROUND
  Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells.
  
  
  OBJECTIVE
  To clarify the effects of fingolimod on B-cell populations in patients with MS.
  
  
  METHODS
  We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts.
  
  
  RESULTS
  The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells (CD38(int-high)), particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138(+)) among whole plasmablasts, in the patients treated with fingolimod.
  
  
  CONCLUSIONS
  The marked reduction of Ki-67(+) memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138(+) plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual patients.
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Masakazu
authors: M
authors: Nakamura
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan.
authors: Takako
authors: T
authors: Matsuoka
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan.
authors: Norio
authors: N
authors: Chihara
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Sachiko
authors: S
authors: Miyake
authors: Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan Department of Neurology, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Wakiro
authors: W
authors: Sato
authors: Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Manabu
authors: M
authors: Araki
authors: Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan Department of Neurology, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Tomoko
authors: T
authors: Okamoto
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan Department of Neurology, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Youwei
authors: Y
authors: Lin
authors: Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan Department of Neurology, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Masafumi
authors: M
authors: Ogawa
authors: Department of Neurology, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Miho
authors: M
authors: Murata
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan.
authors: Toshimasa
authors: T
authors: Aranami
authors: Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan yamamura@ncnp.go.jp.
authors: Takashi
authors: T
authors: Yamamura
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D004351:Drug Resistance; D005260:Female; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D011409:Propylene Glycols / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000081025:Sphingosine-1-Phosphate Receptors; D053668:Syndecan-1 / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D011409:Propylene Glycols; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C508241:SDC1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D053668:Syndecan-1; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: B cells; CD138; CD38; fingolimod; memory B cell; multiple sclerosis; plasmablast; proliferation; resistance; sphingosine 1-phosphate receptor 1