title: Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity.
abstract: Pro-inflammatory T cells mediate autoimmune demyelination in multiple sclerosis. However, the factors driving their development and multiple sclerosis susceptibility are incompletely understood. We investigated how micro-RNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T-cell differentiation in multiple sclerosis. miR-128 and miR-27b were increased in naïve and miR-340 in memory CD4(+) T cells from patients with multiple sclerosis, inhibiting Th2 cell development and favouring pro-inflammatory Th1 responses. These effects were mediated by direct suppression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and interleukin-4 (IL4) expression, resulting in decreased GATA3 levels, and a Th2 to Th1 cytokine shift. Gain-of-function experiments with these micro-RNAs enhanced the encephalitogenic potential of myelin-specific T cells in experimental autoimmune encephalomyelitis. In addition, treatment of multiple sclerosis patient T cells with oligonucleotide micro-RNA inhibitors led to the restoration of Th2 responses. These data illustrate the biological significance and therapeutic potential of these micro-RNAs in regulating T-cell phenotypes in multiple sclerosis.
authors.affiliation: Department of Neurology, The Ohio State University, 395 West 12th Avenue Columbus, OH 43210, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Guerau-de-Arellano
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Smith
authors.forename: Jakub
authors.initials: J
authors.lastname: Godlewski
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Ryan
authors.initials: R
authors.lastname: Winger
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Whitacre
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
mesh_terms: D000328:Adult; D000818:Animals; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D035683:MicroRNAs
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