title: 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.
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, 99 West Huai-hai Rd, Xuzhou, China, 221002.
authors.forename: Jiao
authors.initials: J
authors.lastname: Wang
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Zheng
authors.forename: Ning
authors.initials: N
authors.lastname: Xin
authors.forename: Changxin
authors.initials: C
authors.lastname: Dou
authors.forename: Linlin
authors.initials: L
authors.lastname: Fu
authors.forename: Xiuying
authors.initials: X
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Deqin
authors.initials: D
authors.lastname: Geng
authors.forename: Chenghua
authors.initials: C
authors.lastname: Xiao
authors.forename: Guiyun
authors.initials: G
authors.lastname: Cui
authors.forename: Xia
authors.initials: X
authors.lastname: Shen
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Ruiguo
authors.initials: R
authors.lastname: Dong
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Qiao
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D059467:Transcriptome; D014162:Transfection
chemical_list: D018106:CD28 Antigens; C542511:MIRN145 microRNA, rat; D035683:MicroRNAs; D050778:NFATC Transcription Factors
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