Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis

Frontiers in Immunology

Immunology

Maria Pia Campagna¹  Vilija G. Jokubaitis¹  Helmut Butzkueven²  Trevor Kilpatrick³  Anne-Louise Ponsonby³  Jeannette Lechner-Scott⁴  Vicki E. Maltby⁴  Bruce V. Taylor⁵  Alexandre Xavier⁶  Rodney A. Lea⁷  Rodney J. Scott⁸ 

[1] Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia;Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia;Neuro-Immunology Registry, MSBase Foundation, Melbourne, VIC, Australia;Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia;Hunter Medical Research Institute, Immune Health research program, Newcastle, NSW, Australia;Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia;School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia;Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia;School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia;School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia;Centre of Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, Australia;School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia;New South Wales (NSW) Health Pathology, John Hunter Hospital, Newcastle, NSW, Australia;

关键词: multiple sclerosis;    methylation;    interferon beta (IFN beta);    disease modifying therapy (DMT);    inflammation;    epigenetics (DNA methylation);   

DOI  :  10.3389/fimmu.2023.1162796

 received in 2023-02-10, accepted in 2023-05-12,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionMultiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors.DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFNβ), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNβ reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNβ treatment on methylation.MethodsThe objective of this study was to determine the changes in DNAm associated with INFβ use, using methylation arrays and statistical deconvolutions on two separate datasets (total ntreated = 64, nuntreated = 285).ResultsWe show that IFNβ treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFNβ treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNβ treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNβ induced methylation changes.DiscussionIn conclusion, our study shows that IFNβ treatment is a potent and targeted epigenetic modifier in multiple sclerosis.

【 授权许可】

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Copyright © 2023 Xavier, Campagna, Maltby, Kilpatrick, Taylor, Butzkueven, Ponsonby, Scott, Jokubaitis, Lea and Lechner-Scott