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

Graves, Moira C.; Benton, Miles C.; Lea, Rodney Arthur; Boyle, Michael; Tajouri, Lotti; Macartney-Coxson, Donia; Scott, Rodney J.; Lechner‐Scott, Jeannette

doi:10.1177/1352458513516529

Cited by 119 publications

(125 citation statements)

References 27 publications

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“…In this study, we chose to focus on CD4+ T cells as they are thought to be the main cell infiltrates. Our previous studies also show that CD4+ T cells exhibit significant changes in methylation profiles in RRMS [33, 34]. …”

Section: Discussionmentioning

confidence: 66%

Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells

Sanders

Benton²,

Lea

et al. 2016

Clin Epigenet

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BackgroundImmunoactivation is less evident in secondary progressive MS (SPMS) compared to relapsing-remitting disease. MicroRNA (miRNA) expression is integral to the regulation of gene expression; determining their impact on immune-related cell functions, especially CD4+ T cells, during disease progression will advance our understanding of MS pathophysiology. This study aimed to compare miRNA profiles of CD4+ T cells from SPMS patients to healthy controls (HC) using whole miRNA transcriptome next-generation sequencing (NGS). Total RNA was extracted from CD4+ T cells and miRNA expression patterns analyzed using Illumina-based small-RNA NGS in 12 SPMS and 12 HC samples. Results were validated in a further cohort of 12 SPMS and 10 HC by reverse transcription quantitative polymerase chain reaction (RT-qPCR).ResultsThe ten most dysregulated miRNAs identified by NGS were selected for qPCR confirmation; five (miR-21-5p, miR-26b-5p, miR-29b-3p, miR-142-3p, and miR-155-5p) were confirmed to be down-regulated in SPMS (p < 0.05). SOCS6 is targeted by eight of these ten miRNAs. Consistent with this, SOCS6 expression is up-regulated in SPMS CD4+ T cells (p < 0.05). This is of particular interest as SOCS6 has previously been shown to act as a negative regulator of T cell activation.ConclusionsNinety-seven percent of miRNA candidates identified by NGS were down-regulated in SPMS. The down-regulation of miRNAs and increased expression of SOCS6 in SPMS CD4+ T cells may contribute to reduced immune system activity in progressive MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0253-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 66%

Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells

Sanders

Benton²,

Lea

et al. 2016

Clin Epigenet

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“…In patients with multiple sclerosis, HLA transmission was distorted by the parent of origin and by gender of the affected offspring [7]. A differential methylation signal with a peak at HLA-DRB1 was observed in CD4 + T cells of multiple sclerosis patients compared with controls in another study, suggesting a potential explanation for this observation [14]. …”

Section: Discussionmentioning

confidence: 99%

Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence according to charge and parental inheritance in systemic sclerosis

et al. 2017

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BackgroundSpecific HLA class II alleles are associated with systemic sclerosis (SSc) risk, clinical characteristics, and autoantibodies. HLA nomenclature initially developed with antibodies as typing reagents defining DRB1 allele groups. However, alleles from different DRB1 allele groups encode the same third hypervariable region (3rd HVR) sequence, the primary T-cell recognition site, and 3rd HVR charge differences can affect interactions with T cells. We considered 3rd HVR sequences (amino acids 67–74) irrespective of the allele group and analyzed parental inheritance considered according to the 3rd HVR charge, comparing SSc patients with controls.MethodsIn total, 306 families (121 SSc and 185 controls) were HLA genotyped and parental HLA-haplotype origin was determined. Analysis was conducted according to DRβ1 3rd HVR sequence, charge, and parental inheritance.ResultsThe distribution of 3rd HVR sequences differed in SSc patients versus controls (p = 0.007), primarily due to an increase of specific DRB1*11 alleles, in accord with previous observations. The 3rd HVR sequences were next analyzed according to charge and parental inheritance. Paternal transmission of DRB1 alleles encoding a +2 charge 3rd HVR was significantly reduced in SSc patients compared with maternal transmission (p = 0.0003, corrected for analysis of four charge categories p = 0.001). To a lesser extent, paternal transmission was increased when charge was 0 (p = 0.021, corrected for multiple comparisons p = 0.084). In contrast, paternal versus maternal inheritance was similar in controls.ConclusionsSSc patients differed from controls when DRB1 alleles were categorized according to 3rd HVR sequences. Skewed parental inheritance was observed in SSc patients but not in controls when the DRβ1 3rd HVR was considered according to charge. These observations suggest that epigenetic modulation of HLA merits investigation in SSc.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1253-9) contains supplementary material, which is available to authorized users.

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“…Methylation pattern analysis of a CpG island located in the PAD2 promoter showed that over-expression is due to promoter demethylation in PBMCs from patients with MS (Calabrese et al, 2012). Graves and colleagues first reported that differential DNA methylation at HLA-DRB1 is related to MS risk (Graves et al, 2013). In addition, DNA methylation/demethylation also has been identified in PBMCs of MS patients.…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 96%

Epigenetic dynamics in immunity and autoimmunity

Zhao

Wang

Yung

et al. 2015

The International Journal of Biochemistry & Cell Biology

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

Abstract: 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.

Cited by 119 publications

References 27 publications

Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells

Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells

Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence according to charge and parental inheritance in systemic sclerosis

Epigenetic dynamics in immunity and autoimmunity

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