How Dimethyl Fumarate May Rewire the Epigenetics of Immune Cells in Multiple Sclerosis
Multiple sclerosis (MS) is a complex immune-mediated disease where the body’s immune system mistakenly attacks the central nervous system, damaging the protective myelin sheath around nerve fibers. While there are now many treatment options for MS, one of the ongoing mysteries in medicine is how these therapies actually work at the molecular level.
A study led by Vicki Maltby and colleagues in Multiple Sclerosis Journal—Experimental, Translational and Clinical (2018) took a closer look at one of these therapies: dimethyl fumarate (DMF). Best known under the trade name Tecfidera, DMF is widely prescribed as a first-line oral treatment for relapsing–remitting MS. Patients taking DMF often show reduced relapse rates and lower inflammatory activity—but the underlying biology has remained murky.
This research suggests that DMF doesn’t just dampen inflammation—it may also act as an epigenetic modifier, changing the way immune cells regulate their genes through DNA methylation.
DNA Methylation: The Epigenetic Switchboard
DNA methylation is a chemical modification where a methyl group is added to DNA, often at CpG sites (regions rich in cytosine and guanine bases). This process doesn’t alter the DNA sequence itself but can “switch off” genes by making them less accessible for transcription.
In immune-mediated diseases like MS, changes in methylation patterns can contribute to the misfiring of the immune system. Previous studies showed differences in methylation between MS patients and healthy individuals, particularly in CD4+ T cells, a type of immune cell that plays a central role in driving MS-related inflammation.
What the Researchers Did
The study followed seven MS patients who were about to start DMF treatment. Blood samples were collected before treatment and again six months later.
The team isolated CD4+ T cells and used Illumina EPIC arrays—a technology that scans hundreds of thousands of methylation sites across the genome—to compare DNA methylation patterns before and after treatment.
Their goal was simple but powerful: to see if DMF leaves an “epigenetic fingerprint” in these immune cells.
The Key Findings
Widespread Hypermethylation: After six months on DMF, 97% of the differentially methylated positions (DMPs) were hypermethylated (gained methyl groups). This points to a general trend of gene silencing.
Four Genes of Interest: The study identified SNORD1A, SHTN1, MZB1, and TNF as having differentially methylated regions (DMRs) located right at their transcriptional start sites—the critical “on/off” switches of genes.
Why These Genes Matter:
MZB1: Linked to calcium regulation in immune cells. Reduced expression may contribute to fewer active CD4+ T cells, aligning with DMF’s anti-inflammatory role.
TNF (Tumor Necrosis Factor): A well-known pro-inflammatory cytokine. Hypermethylation at its start site could mean less TNF production, and therefore less activation of the NF-κB pathway, which drives inflammation.
SNORD1A & SHTN1: Less is known about their role in MS, but their epigenetic shifts may hint at broader immune and neuronal regulation.
Why This Matters
This was the first longitudinal study to directly show that DMF can reshape the DNA methylation landscape of CD4+ T cells in MS patients. The results suggest DMF doesn’t just reduce inflammation through known mechanisms like oxidative stress protection—it might also silence pro-inflammatory genes at the epigenetic level.
This opens up a new way of thinking about MS treatments: perhaps part of their effectiveness comes from reprogramming the immune system’s “memory” at the molecular level.
Caveats and Next Steps
The study was small (7 patients) and lacked direct transcriptional data (we don’t yet know which genes actually changed their expression as a result of methylation).
Some patients had recent relapses, making it hard to fully disentangle treatment effects from natural disease fluctuations.
Future research will need larger cohorts, comparisons with other MS therapies, and integrated analysis of both methylation and gene expression.
Final Thoughts
This study adds an exciting piece to the MS puzzle: dimethyl fumarate may act not just as a drug but as an epigenetic sculptor, dialing down the genes that keep inflammation alive. If confirmed in larger studies, this could pave the way for new treatments that harness epigenetic reprogramming to calm autoimmune diseases.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Maltby, V. E., Lea, R. A., Ribbons, K. A., Sanders, K. A., Kennedy, D., Min, M., ... & Lechner-Scott, J. (2018). DNA methylation changes in CD4+ T cells isolated from multiple sclerosis patients on dimethyl fumarate. Multiple Sclerosis Journal–Experimental, Translational and Clinical, 4(3), 2055217318787826.
