title: MiR-126: a novel route for natalizumab action?
abstract: BACKGROUND
  MicroRNAs (miRNAs) have emerged as a family of post-transcriptional regulators of gene expression that mediate diverse aspects of immunity. MiRNA dysregulation has been found in multiple sclerosis (MS), reflecting the growing need to identify disease-specific miRNA expression signatures. Our previous low-density array studies reveal differential miR-126 expression in the CD4(+)T cells of untreated relapsing-remitting MS (RRMS) patients. Here, we investigated miR-126 expression in natalizumab-treated patients.
  
  
  METHODS
  We isolated CD4(+) T cells from untreated (n = 12) and natalizumab-treated MS patients (n = 24), and from healthy volunteers (n = 12). We analyzed the expression of miRNAs and potential targets by real time reverse transcription polymerase chain reaction (RT-PCR). We assessed specific inhibition of miR-126, in vitro.
  
  
  RESULTS
  MiR-126 was down-regulated in cells of patients under natalizumab treatment and up-regulated during relapse, supporting a regulatory role in MS immunopathogenesis. MiR-126 expression correlated with the expression of POU2AF1, a regulator of Spi-B that binds to the promoter/enhancer sequences of JC virus (JCV), the pathogen of progressive multifocal leukoencephalopathy (PML), a rare complication of natalizumab treatment. The same trend was found for Spi-B. Strong up-regulation of both genes appeared to be treatment duration-dependent. Specific inhibition experiments supported the link between the expression of miR-126 and POU2AF1/Spi-B.
  
  
  CONCLUSIONS
  Our findings provided deeper insight into the mode of action of natalizumab, with possible implications for understanding both the effects of natalizumab on MS activity and its specific adverse event profile.
authors.affiliation: University Hospital Basel, University of Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Meira
authors.affiliation: University Hospital Basel, University of Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sievers
authors.affiliation: University Hospital Basel, University of Basel, Switzerland.
authors.forename: Francine
authors.initials: F
authors.lastname: Hoffmann
authors.affiliation: University Hospital Basel, University of Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Derfuss
authors.affiliation: University Hospital Basel, University of Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Kuhle
authors.affiliation: University Hospital Basel, University of Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: University Hospital Basel, University of Basel, Switzerland Raija.lindberg@unibas.ch.
authors.forename: Raija L P
authors.initials: RL
authors.lastname: Lindberg
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D000069442:Natalizumab; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D000069442:Natalizumab; C091546:POU2AF1 protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C076877:SPIB protein, human
keywords: Adverse events; CD4+T lymphocytes; mechanism of action; miR-126; miRNA; multiple sclerosis; natalizumab; progressive multifocal leukoencephalopathy