Key result
B-cell EBV reactivation precedes MS relapses by up to 3 months.
Why the study?
The cellular and molecular events preceding multiple sclerosis relapse remain incompletely understood.
Observational
EBV reactivation within a genetically predisposed peripheral immune environment may be a proximal precursor of multiple sclerosis relapse.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We believe this work provides foundational insights into the cause of multiple sclerosis. This study puts all the pieces together, showing a timeline of how the reactivated virus interacts with risk genes to unleash inflammation before relapse occurs.”
“Currently, most MS treatments work by broadly suppressing the immune system. Our results suggest there's an opportunity to be more precise and develop approaches that target EBV or the immune cells involved in relapse.”
Hypothesis-generating for EBV monitoring before MS relapses; extends genetic associations but leaves causal role and interventions unproven.
Despite decades of research, the cellular and molecular events preceding multiple sclerosis (MS) relapse remain incompletely understood. Here, in this observational study of longitudinal blood samples from patients with relapsing-remitting MS, we used single-cell RNA sequencing, bulk transcriptomics, multiparameter flow cytometry and targeted viral reverse transcription quantitative polymerase chain reaction (RT−qPCR) to construct a time-resolved atlas of immune perturbations surrounding relapse. A reproducible pre-relapse signature in monocytes and B cells, emerging up to 3 months before clinical onset, was enriched for host genes responsive to Epstein−Barr virus (EBV) lytic reactivation factors. RT−qPCR confirmed elevated EBV LMP-1 transcripts in pre-relapse B cells, and flow cytometry demonstrated expansion of CD11c+ atypical B cell populations displaying EBV surface protein gp350. Pre-relapse transcriptional modules overlapped with MS genome-wide association study (GWAS) risk loci and EBNA-2-bound enhancers, suggesting that inherited MS susceptibility and EBV-responsive programs operate through shared regulatory elements. How this peripheral activation relates to central nervous system lesion formation remains to be established. These findings nonetheless suggest that EBV reactivation, when occurring within a genetically predisposed peripheral immune environment, is a proximal precursor of MS relapse. Increased expression of EBV reactivation genes in B cells and MS risk genes targeted by the EBV protein EBNA-2 precedes MS attacks, linking EBV reactivation and genetic risk to the development of MS relapses.
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King et al. (2026) conducted an observational in Relapsing-remitting multiple sclerosis. Epstein-Barr virus (EBV) reactivation was evaluated on Pre-relapse immune signature and EBV reactivation markers. Epstein-Barr virus reactivation in B cells precedes multiple sclerosis attacks by up to 3 months, linking EBV reactivation and genetic risk to the development of MS relapses.
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