Identification of Novel MicroRNA Signatures Linked to Experimental Autoimmune Myasthenia Gravis Pathogenesis: Down-Regulated miR-145 Promotes Pathogenetic Th17 Cell Response

Abstract

Emerging evidence demonstrates that miRNAs, a new family of key mRNA regulatory molecules, have crucial roles in controlling and modulating immunity. Their contribution to myasthenia gravis (MG), a T cell-dependent, antibody-mediated nervous system autoimmune disease, has not been thoroughly investigated. In the present study, using a highly sensitive microarray-based approach, we identified 11 miRNAs with differential expression between Peripheral Blood Mononuclear Cells (PBMC) from experimental autoimmune MG (EAMG) rats and control rats. miR-145 is one of the most significantly down-regulated miRNAs in PBMC from EAMG rats. Down-regulation of miR-145 expression was confirmed in PBMC and CD4+CD25- T cells (T effector cells) from both EAMG rats and MG patients by real-time PCR. Bioinformatics target prediction identified two crucial immune-related molecules-CD28 and NFATc1, as putative targets of miR-145. Furthermore, miR-145 inhibited CD28 and NFATc1 expression by directly targeting their 3'-UTRs, which was abolished by mutation of the miR-145 and CD28/NFATc1 binding sites. In vitro up-regulation of miR-145 in CD4+ T cells can significantly reduce CD28 protein levels accompanied by decreased proliferative response. In a dendritic cell (DC)-T cell coculture system, overexpression of miR-145 in AChR-specific CD4+ T cells suppresses NFATc1 expression and T Helper 17 cells level. Finally, we observed that administration of lentiviral-miR-145 decreased the severity of ongoing, established EAMG with decreased IL-17 production, and also decreased serum anti-AChR IgG levels. Our studies provide an important new insight into the pathogenesis of EAMG and MG, which may open a new perspective for the development of effective gene therapy for EAMG/MG.

A plasma microRNA signature as a biomarker for acquired aplastic anemia

“…Indeed, miRNA expression profiles are cell-type specific. Of note, regardless of discrepancies between cellular and circulating miRNA profiles, we could observe some common miRNA signatures in both AA and MG, such as decreased miR-145-5p in T cells 14,64 and increased miR-150-5p in plasma specimens. 21 In conclusion, we demonstrate that expression levels of 3 dysregulated miRNAs in AA plasma associate with clinical parameters and normalize after IST, suggesting their use as potential biomarkers in AA.…”

Identifying a Polymorphic ‘Switch’ That Influences miRNAs' Regulation of a Myasthenia Gravis Risk Pathway

“…Compared with one recent miRNA microarray analysis [6], which had found 44 miRNAs to be significantly dysregulated in MG, 16 miRNAs were simultaneously predicted in our potential miRNA profile, including 11 down-regulated miRNAs and 5 up-regulated miRNAs. A microarray-based study had previously validated that miR-145, one of the functionally associated miRNAs we predicted, was one of the most significantly down-regulated miRNAs in experimental autoimmune MG rat models and its down-regulation could promote pathogenic Th17 cell responses in MG [54].…”

“…The inhibition of the miR-181 family in thymocytes could decrease TCR sensitivity and impair positive and negative T cell selection in the thymus, which are essential for the immunotolerance process and autoimmune disease [52], [53]. Moreover, the expression of miR-181c has been demonstrated to be significantly down-regulated in a recent microarray study of an experimental autoimmune MG rat model [54]. miR-181c downregulation might influence the pathogenesis of MG by causing the over-expression of KRAS [47] and by disturbing immunotolerance in the thymus.…”

Identification of novel microRNA signatures linked to acquired aplastic anemia

“…However, there is some commonality in miRNA dysregulation in other autoimmune diseases. For example, decreased expression of miR-145-5p was detected in T cells from patients with myasthenia gravis 46 and systemic lupus erythematosus. 47 MiR-223-3p is overexpressed in T cells from patients with rheumatoid arthritis, 48 indicating the similarity and difference of miRNA expression in different type of diseases.…”