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- W4313359834 abstract "Abstract Background Dimethylfumarate (DMF) is known to be converted to monomethylfumarate (MMF) by esterases and then metabolized to fumarate and citric acid via the Krebs cycle. In cancer cells, accumulation of fumarate has been shown to inhibit DNA demethylation and that prompted us to investigate whether the immunomodulatory effects of fumaric acid esters (FAEs) in MS patients could also be related to changes of DNA methylation in CD4 T cells. Methods PBMCs were collected for immunophenotyping and CD4 T cell isolation from 54 Naive and 36 DMF treated RRMS patients. In addition, CD4 T cells were also isolated from 7 patients before and after DMF treatment. DNA methylation was analyzed using the Infinium Methylation EPIC BeadChip array. Methylation changes were validated in naïve and memory CD4 T cell cultures in vitro using MassArray EpiTYPER. qPCR was performed to assess the effect of DNA methylation on transcript levels in CD4 T cells. Results DMF treatment was associated with a significant reduction of CCR6+ CD4 T cells and a strong DNA hypermethylation signature in CD4 T cells. The highest levels of DNA methylation in DMF treated patients compared to controls were detected in a DNA region that was spanning the promoter of microRNA-21 (miR21) in both the cross-sectional and longitudinal cohorts. This region was also found to be hypermethylated in naïve CD4 T cells after treatment with MMF in vitro. Naïve CD4 T cells that were treated with MMF also exhibited reduced miR21 and CCR6 transcript levels. Conclusions Our results suggest that by modulating DNA methylation in CD4 T cells, FAEs reduce the expression of miR21 and prevent the production of CCR6+ CD4 T cells, which in recent studies were identified as potentially encephalitogenic in MS patients." @default.
- W4313359834 created "2023-01-06" @default.
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- W4313359834 date "2018-05-01" @default.
- W4313359834 modified "2023-09-27" @default.
- W4313359834 title "Fumaric acid esters hypermethylate the miR21 locus and prevent the formation of CCR6+ CD4 T cells in multiple sclerosis." @default.
- W4313359834 doi "https://doi.org/10.4049/jimmunol.200.supp.54.4" @default.
- W4313359834 hasPublicationYear "2018" @default.
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