Abstract
Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. The inflammatory process in MS is driven by both T and B cells and current therapies are targeted to each of these cell types. Epigenetic mechanisms may provide a valuable link between genes and environment. DNA methylation is the best studied epigenetic mechanism and is recognized as a potential contributor to MS risk. The objective of this study was to identify DNA methylation changes associated with MS in CD19+ B-cells. We performed an epigenome-wide association analysis of DNA methylation in the CD19+ B-cells from 24 patients with relapsing-remitting MS on various treatments and 24 healthy controls using Illumina 450 K arrays. A large differentially methylated region (DMR) was observed at the lymphotoxin alpha (LTA) locus. This region was hypermethylated and contains 19 differentially methylated positions (DMPs) spanning 860 bp, all of which are located within the transcriptional start site. We also observed smaller DMRs at 4 MS-associated genes: SLC44A2, LTBR, CARD11 and CXCR5. These preliminary findings suggest that B-cell specific DNA-methylation may be associated with MS risk or response to therapy, specifically at the LTA locus. Development of B-cell specific epigenetic therapies is an attractive new avenue of research in MS treatment. Further studies are now required to validate these findings and understand their functional significance.
Highlights
Multiple Sclerosis is an inflammatory and neurogenerative disease leading to demyelination and axonal loss
We are the first to describe changes in the global DNA methylation profile in the cluster of differentiation 19 (CD19)+ B-cells of Multiple Sclerosis (MS) patients compared to healthy controls
We find a slight overall hypomethylation and enrichment of genes involved in innate immunity and B-cell receptor and cytokine signaling pathways
Summary
Multiple Sclerosis is an inflammatory and neurogenerative disease leading to demyelination and axonal loss. Others, have used genome-wide DNA methylation technologies to identify differentially methylated positions (DMPs) in the T-cells of MS patients compared to healthy controls[4,5,6,7,8]. Activated B-cells may contribute to MS pathology as antibody producing cells, antigen presenting cells or as a source of pro-inflammatory cytokines (reviewed in Lehmann-Horn et al.[10]) Evidence for this is in the success of B-cell depleting monoclonal antibodies, such as rituximab[11] and ocrelizumab[12] as MS therapies. In an effort to identify B-cell specific DMPs associated in MS, we performed genome-wide DNA methylation study of CD19+ B-cells from MS patients and healthy controls. We used the same cohort and data analysis techniques as our previous studies so that the results could be compared to those from the CD4+ and CD8+ T-cells
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