Abstract
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance. In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology. Three miRNAs resulted >2 folds up-regulated in MS vs controls, whereas none resulted down-regulated. Interestingly, the most up-regulated miRNA (mir-155; fold change = 3.30; P = 0.013) was previously reported to be up-regulated also in MS brain lesions. Mir-155 up-regulation was confirmed by qPCR experiments. The role of mir-155 in MS susceptibility was also investigated by genotyping four single nucleotide polymorphisms (SNPs) mapping in the mir-155 genomic region. A haplotype of three SNPs, corresponding to a 12-kb region encompassing the last exon of BIC (the B-cell Integration Cluster non-coding RNA, from which mir-155 is processed), resulted associated with the disease status (P = 0.035; OR = 1.36, 95% CI = 1.05–1.77), suggesting that this locus strongly deserves further investigations.
Highlights
Multiple sclerosis (MS) (OMIM #126200) is a common autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, myelin loss, varying degrees of axonal pathology, and progressive neurological dysfunction [1,2,3]
To be relevant for the molecular pathogenesis of MS, candidate miRNAs would be expected either to be pivotal players in activation/function of immune responses, or to be expressed in tissues affected by the disease process, or to map within regions that have been linked/associated with MS
We selected 22 immunity-related miRNAs (Table 1) based on the following criteria: (i) human miRNAs expressed in the immune system and showing immune-related functions were retrieved from the literature [30,31,32,33,34,35,36,37,38,39,40,41,42,43]; (ii) human miRNA genes mapping within loci previously associated with MS or EAE
Summary
Multiple sclerosis (MS) (OMIM #126200) is a common autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, myelin loss, varying degrees of axonal pathology, and progressive neurological dysfunction [1,2,3]. As for non-HLA loci, GWAS have substantially contributed to identify a number of MS susceptibility genes: so far, approximately 50 genes conferring a mild-to-modest effect on risk (odds ratio, OR < 1.3) have been robustly associated with MS, many of which display primarily immunologic functions [9,12,14]. Despite these extensive studies, identification of MS-specific genes still remains challenging and mainly focused on protein-coding loci. Genetic association with MS was explored for the most up-regulated miRNA gene, mir-155
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