Epstein-Barr virus activity may foreshadow MS relapses

Clinical takeaway: Emerging evidence suggests that Epstein-Barr virus (EBV) reactivation may contribute to multiple sclerosis (MS) relapses, raising the possibility that future blood-based biomarkers of EBV activity could help identify patients at heightened risk of an impending attack.

EBV infection has long been associated with MS risk, but exactly how the virus contributes to disease activity has remained unclear. This study provides some of the strongest evidence to date that episodic EBV reactivation, together with underlying genetic susceptibility, may help trigger relapses rather than simply increase the risk of developing MS.

In this longitudinal analysis, investigators examined blood samples from 114 patients with MS and 21 healthy controls, including samples collected up to 90 days before confirmed relapses. Using single-cell RNA sequencing, flow cytometry, bulk RNA sequencing, and viral transcript analyses, the researchers identified distinct immune changes that emerged weeks to months before clinical attacks.

B cells, which can harbor dormant EBV, showed some of the strongest pre-relapse changes. Researchers found evidence of increased EBV activity, including elevated expression of the viral transcript LMP-1, along with activation of antiviral and inflammatory pathways. Atypical B cells associated with viral infection and autoimmunity expanded before relapse, increasing by a median 60% in paired patient samples. EBV gp350-positive B cells also increased by roughly 40% during the pre-relapse period compared with remission.

The immune signature appeared as early as 3 months before symptom onset and was enriched for genes previously linked to MS susceptibility, suggesting that viral reactivation and inherited risk factors may converge to trigger disease activity. The authors note that larger prospective studies are needed, but these findings raise the possibility that EBV-related biomarkers could eventually complement MRI and existing blood tests, which typically detect disease activity after inflammation is already underway.

“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,” said senior author Tanuja Chitnis.

Source: King DA, et al. (2026 Sep 16). Nat Med. EBV reactivation priming of the peripheral immune system in multiple sclerosis relapse