scholarly journals Hypermethylation of MIR21 in CD4+ T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes

2017 ◽  
Vol 24 (10) ◽  
pp. 1288-1300 ◽  
Author(s):  
Sabrina Ruhrmann ◽  
Ewoud Ewing ◽  
Eliane Piket ◽  
Lara Kular ◽  
Julio Cesar Cetrulo Lorenzi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dna Methylation ◽  
T Cells ◽  
Cd4 T Cells ◽  
Target Genes ◽  
Significant Negative Correlation ◽  
Chronic Inflammatory Disease ◽  
Epigenetic Mechanism ◽  
Relapsing Remitting ◽  
Genome Activity

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors. Objective: We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC). Methods: We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression. Results: We observed significant methylation differences in the VMP1/MIR21 locus, with RR-MS displaying higher methylation compared to SP-MS and HC. VMP1/MIR21 methylation did not correlate with a known MS risk variant in VMP1 or smoking but displayed a significant negative correlation with age and the levels of mature miR-21 in CD4+ T cells. Accordingly, RR-MS displayed lower levels of miR-21 compared to SP-MS, which might reflect differences in age between the groups, and healthy individuals and a significant enrichment of up-regulated miR-21 target genes. Conclusion: Disease-related changes in epigenetic marking of MIR21 in RR-MS lead to differences in miR-21 expression with a consequence on miR-21 target genes.

scholarly journals Unraveling Natalizumab Effects on Deregulated miR-17 Expression in CD4+T Cells of Patients with Relapsing-Remitting Multiple Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Maria Meira ◽  
Claudia Sievers ◽  
Francine Hoffmann ◽  
Maria Rasenack ◽  
Jens Kuhle ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell Activation ◽  
Posttranscriptional Regulation ◽  
Cell Activation ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Expression Of Genes ◽  
Relapsing Remitting

MicroRNAs (miRNAs) are a family of noncoding RNAs that play critical roles in the posttranscriptional regulation of gene expression. Accumulating evidence supports their involvement in the pathogenesis of multiple sclerosis (MS). Here, we compare miR-17 expressions in CD4+T cells from relapsing-remitting (RR) MS patients treated with natalizumab versus untreated patients. miR-17 was downregulated under natalizumab treatment and upregulated during relapse, therefore supporting a possible role of miR-17 in MS immunopathogenesis. Downregulation of miR-17 was associated with upregulation of PTEN, BIM, E2F1, and p21 target genes.In vitromiR-17 inhibition was associated with upregulation of the same targets and resulted in impaired CD4+T cell activation and proliferation. We further describe deregulated TGFBR2 expression in untreated patients versus healthy volunteers (HVs) and confirmin vitrothe link between miR-17 and TGFBR2 expressions. These findings support an effect of natalizumab on expression of specific miRNA and subsequent expression of genes involved in proliferation and control of the cell cycle.

scholarly journals Immunomodulatory Effects of Calcitriol through DNA Methylation Alteration of FOXP3 in the CD4+ T Cells of Mice

2020 ◽  
Author(s):  
Mona Oraei ◽  
Sama Bitarafan ◽  
Seyed Alireza Mesbah-Namin ◽  
Ali Noori-Zadeh ◽  
Fatemeh Mansouri ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vitamin D ◽  
T Cells ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Epigenetic Mechanism ◽  
Control Group ◽  
Foxp3 Gene ◽  
Tgf Β1

Vitamin D plays a variety of physiological functions, such as regulating mineral homeostasis. More recently, it has emerged as an immunomodulator player, affecting several types of immune cells, such as regulatory T (Treg) cells. It has been reported that vitamin D exerts some mediatory effects through an epigenetic mechanism. In this study, the impacts of calcitriol, the active form of vitamin D, on the methylation of the conserved non-coding sequence 2 (CNS2) region of the forkhead box P3 (FOXP3) gene promoter, were evaluated. Fourteen C57BL/6 mice were recruited in this study and divided into two intervention and control groups. The CD4+ T cells were isolated from mice splenocytes. The expression of FOXP3, IL-10, and transforming growth factor-beta (TGF-β1) genes were relatively quantified by real-time PCR technique, and the DNA methylation percentage of every CpG site in the CNS2 region was measured individually by bisulfite-sequencing PCR. Vitamin D Intervention could significantly (p<0.05) increase the expression of FOXP3, IL-10, and TGF-β1 genes in the CD4+ T cells of mice comparing with the control group. Meanwhile, methylation of the CNS2 region of FOXP3 promoter was significantly decreased in three of ten CpG sites in the vitamin D group compared to the control group. The results of this study showed that vitamin D can engage the methylation process to induce FOXP3 gene expression and probably Treg cytokines profile. Further researches are needed to discover the precise epigenetic mechanisms by which vitamin D modulates the immune system.

scholarly journals Distinct Expression of Inflammatory Features in T Helper 17 Cells from Multiple Sclerosis Patients

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 533 ◽  
Author(s):  
Alessia Capone ◽  
Manuela Bianco ◽  
Gabriella Ruocco ◽  
Marco De Bardi ◽  
Luca Battistini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Chronic Inflammatory Disease ◽  
T Helper ◽  
T Helper 17 ◽  
Inflammatory Status ◽  
Healthy Donors ◽  
Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-β, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-β, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status.

Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis

2013 ◽  
Vol 20 (8) ◽  
pp. 1033-1041 ◽  
Author(s):  
MC Graves ◽  
M Benton ◽  
RA Lea ◽  
M Boyle ◽  
L Tajouri ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dna Methylation ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cpg Island ◽  
Major Effect ◽  
Differential Methylation ◽  
Genome Wide ◽  
A Genome ◽  
Drb1 Locus

Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk of developing MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation are recognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure and inherited genetic systems. Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNA methylation analysis of CD4+ T cells from 30 patients with relapsing–remitting MS and 28 healthy controls using Illumina 450K methylation arrays. Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. After prioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of a major effect CpG island in DRB1 in MS cases ( pFDR < 3 × 10−3). In addition, we found 55 non-HLA CpGs that exhibited differential methylation, many of which localise to genes previously linked to MS. Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation to MS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.

scholarly journals Altered Expression of miR-326 in T Cell-derived Exosomes of Patients with Relapsing-remitting Multiple Sclerosis

2019 ◽  
Author(s):  
Maryam Azimi ◽  
Mojdeh Ghabaee ◽  
Abdorreza Naser Moghadasi ◽  
Maryam Izad
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Pathological Condition ◽  
Healthy Controls ◽  
Altered Expression ◽  
Expression Levels ◽  
Relapsing Remitting ◽  
Th17 Differentiation ◽  
Relapsing Remitting Multiple Sclerosis

Invasion of auto-reactive CD4+ T cells especially Th17 into central nervous system (CNS) is an underlying pathogenic mechanism in multiple sclerosis (MS). CD4+ T cells release exosomes which are enriched in microRNAs, reflective of cell’s physiological or pathological condition. Thus exosomes could be potent agents to provide quantitative and qualitative information about involved cells in MS. We investigated the expression of pathogenic microRNAs in T cells-derived exosomes of MS patients or healthy controls. Conventional T cells (Tconv) derived from relapsing-remitting (RR) MS patients (n=10) and healthy controls (n=10) were purified and cultured for 3 days by soluble anti-CD3/CD28. Exosomes were purified from cultured-T cells supernatants. The expression levels of exosomal miR-146a, miR-29a, miR-155, and miR-326 were quantified by real-time PCR. A statistically significant increased expression of miR-326 in Tconv-derived exosomes was observed in RRMS patients as compared with controls (7.5±1.88vs 2.51±0.9 p=0.03), On the contrary, no differences were found in the expression levels of miR-155, miR-146a, and miR-29a, in Tconv-derived exosomes of  patients as compared with controls (p>0.05).  Our results point to altered expression in exosome-derived microRNAs. MiR-326 was previously shown to play a role in the immunopathogenesis of MS by inducing TH17 differentiation and maturation. Therefore, miR-326 containing exosomes might also be a potential clinical target in course of MS. Moreover, the deregulation of this miRNA in exosomes may serve as a diagnostic and prognostic biomarker.  

scholarly journals Epigenetic differences at the HTR2A locus in progressive multiple sclerosis patients

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vicki E. Maltby ◽  
Rodney A. Lea ◽  
Sean Burnard ◽  
Alexandre Xavier ◽  
Thao Van Cao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dna Methylation ◽  
T Cells ◽  
Progressive Multiple Sclerosis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Potential Biomarker ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
Chip Analysis

AbstractThe pathology of progressive multiple sclerosis (MS) is poorly understood. We have previously assessed DNA methylation in the CD4+ T cells of relapsing–remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39. This study aimed to investigate the DNA methylation profiles of the CD4+ T cells of progressive MS patients. DNA methylation was measured in two separate case/control cohorts using the Illumina 450K/EPIC arrays and data was analysed with the Chip Analysis Methylation Pipeline (ChAMP). Single nucleotide polymorphisms (SNPs) were assessed using the Illumina Human OmniExpress24 arrays and analysed using PLINK. Expression was assessed using the Illumina HT12 array and analysed in R using a combination of Limma and Illuminaio. We identified three DMRs at HTR2A, SLC17A9 and HDAC4 that were consistent across both cohorts. The DMR at HTR2A is located within the bounds of a haplotype block; however, the DMR remained significant after accounting for SNPs in the region. No expression changes were detected in any DMRs. HTR2A is differentially methylated in progressive MS independent of genotype. This differential methylation is not evident in RRMS, making it a potential biomarker of progressive disease.

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