Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity

M Guerau-de-Arellano, KM Smith, J Godlewski, Y Liu… - Brain, 2011 - academic.oup.com
M Guerau-de-Arellano, KM Smith, J Godlewski, Y Liu, R Winger, SE Lawler, CC Whitacre
Brain, 2011academic.oup.com
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 naļve and miR-340 in memory CD4+ T
cells from patients with multiple sclerosis, inhibiting Th2 cell development and favouring pro …
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 naļve 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.
Oxford University Press