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.

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

“…As such, these miRNAs may be differentially expressed in other immunemediated diseases and have broader implications on CD4 T cell development and differentiation. It is well established that miRNAs play key roles in the development and function of Tregs (Gao et al, 2012;Josefowicz et al, 2012;Dooley et al, 2013), and differential expression of miRNAs have been found in patients with multiple sclerosis (Du et al, 2009;Keller et al, 2009;Otaegui et al, 2009;De Santis et al, 2010;Guerau-de-Arellano et al, 2011;Noorbakhsh et al, 2011;Jr OeF et al, 2012;Smith et al, 2012;Gandhi et al, 2013;Ridolfi et al, 2013;Søndergaard et al, 2013). To our knowledge none of the miRNAs identified in this study had been previously defined to play a role in Tregs.…”

“…Information on patients with multiple sclerosis and control subjects used in the miRNA profiling study, as well as the methods and data from this miRNA profiling study can be found in Guerau-de-Arellano et al (2011). The data shown in Fig.…”

“…While genetic studies have identified genes critical to the immune system as being potential risk factors (Baranzini et al, 2009b;De Jager et al, 2009;Beecham et al, 2013), many of the genetic contributors to this disease are unknown. An emerging area of interest in multiple sclerosis has been genetic regulation at the microRNA (miRNA) level (Du et al, 2009;Keller et al, 2009;Otaegui et al, 2009;De Santis et al, 2010;Guerau-de-Arellano et al, 2011;Noorbakhsh et al, 2011;Jr OeF et al, 2012;Smith et al, 2012;Gandhi et al, 2013;Ridolfi et al, 2013;Søndergaard et al, 2013). MiRNAs are small, non-coding RNA that regulate gene expression and, thus, modify cellular pathways and disease processes (Ambros, 2004;Bartel, 2004).…”

“…Our lab previously performed a miRNA profiling study on naïve CD4 T cells of untreated patients with multiple sclerosis and healthy individuals, identifying 85 miRNAs as being differentially expressed in patients with multiple sclerosis (Guerau-de-Arellano et al, 2011). Pathway analysis predicted that the transforming growth factor-beta (TGFb) signalling pathway was potentially altered by the differential expression of miRNAs in the naïve T cells of patients with multiple sclerosis.…”

Assessment of microRNA-related SNP effects in the 3′ untranslated region of the IL22RA2 risk locus in multiple sclerosis

“…Given the emerging evidence for a pathogenic role of IL-22 in autoimmune processes as well as the importance of small non-coding microRNAs (miRNAs) for the regulation of gene expression in MS (e.g. [8][9][10]), we set out to explore whether the MS association signal at the 3′ end of IL22RA2 may be owing to one or more functional sequence variants in or near miRNA binding sites located in the IL22RA2 3′ untranslated region (UTR). Such variants may alter the binding of certain miRNA(s) to the mRNA 3′UTR and, as a result, the expression levels of IL22RA2.…”