title: Natalizumab restores aberrant miRNA expression profile in multiple sclerosis and reveals a critical role for miR-20b.
abstract: OBJECTIVE
  To identify microRNAs (miRNAs) regulated by anti-α4 integrin monoclonal antibody therapy (natalizumab) in the peripheral blood of patients with relapsing-remitting (RR) multiple sclerosis (MS) and to confirm their role in experimental settings in vivo.
  
  
  METHODS
  In a longitudinal study of 17 RR-MS patients, we investigated blood miRNA expression profiles at baseline and after 1 year of natalizumab therapy by microarray technique and quantitative PCR validation. We compared the baseline expression profiles of these patients to those of 18 age- and sex-matched healthy controls. We confirmed the contribution of resulting candidate miRNAs in an animal model of MS, experimental autoimmune encephalomyelitis (EAE) induced by adoptive transfer of proteolipid protein (PLP)139-151-activated lymphocytes in SJL/J mice or by active immunization of miR-106a∼363-deficient C57BL/6 mice (or wildtype litter mates) with myelin oligodendrocyte glycoprotein (MOG)35-55.
  
  
  RESULTS
  Our longitudinal analysis revealed that miR-18a, miR-20b, miR-29a, and miR-103 were upregulated and predominantly expressed by CD4(+) T cells, whereas miR-326 was downregulated upon natalizumab treatment. A comparison of untreated RR-MS patients at baseline with healthy controls revealed that the four natalizumab-upregulated targets were initially downregulated in MS. All confirmed targets showed disease-dependent expression in splenocytes of mice suffering from EAE. Genetic deletion of the miRNA cluster miR-106a∼363 (containing natalizumab-regulated miR-20b) resulted in a more severe EAE course and an in vivo upregulation of the miR-20b target genes rorgt, stat3, and vegfa.
  
  
  CONCLUSIONS
  Our study indicates that natalizumab restores dysregulated miRNA patterns in MS and reveals the contribution of miR-20b in autoimmune demyelination in vivo.
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Jens
authors: J
authors: Ingwersen
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Til
authors: T
authors: Menge
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Britta
authors: B
authors: Wingerath
authors: Department of Neurology, Medical School, Dokuz Eylül University Izmir, Turkey.
authors: Derya
authors: D
authors: Kaya
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Jonas
authors: J
authors: Graf
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Tim
authors: T
authors: Prozorovski
authors: CBC Comprehensive Biomarker Center GmbH Heidelberg, Germany ; Clinical Bioinformatics, Saarland University Saarbrücken, Germany.
authors: Andreas
authors: A
authors: Keller
authors: Clinical Bioinformatics, Saarland University Saarbrücken, Germany.
authors: Christina
authors: C
authors: Backes
authors: CBC Comprehensive Biomarker Center GmbH Heidelberg, Germany.
authors: Markus
authors: M
authors: Beier
authors: CBC Comprehensive Biomarker Center GmbH Heidelberg, Germany.
authors: Matthias
authors: M
authors: Scheffler
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Thomas
authors: T
authors: Dehmel
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Bernd C
authors: BC
authors: Kieseier
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Hans-Peter
authors: HP
authors: Hartung
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Patrick
authors: P
authors: Küry
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany.
authors: Orhan
authors: O
authors: Aktas
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