Does EBV Reactivation Warn of Coming MS Relapse?

New research helps explain how a common virus and genetic susceptibility may work in concert to trigger multiple sclerosis (MS) attacks.An analysis of longitudinal blood samples from patients with relapsing-remitting MS revealed evidence of Epstein-Barr virus (EBV) reactivation and broad immune activation beginning weeks to months before a clinical relapse. The pre-relapse changes were particularly prominent in B-cell populations enriched for MS-associated genetic risk signals.If validated in larger, prospective studies, blood biomarkers of EBV activity could complement MRI scans and existing blood biomarkers to identify relapse risk before overt inflammatory damage is detected, researchers noted.“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,” senior author Tanuja Chitnis, MD, chief of the Division of Neuroimmunology at the Neurosciences Institute, Mass General Brigham in Boston, said in a statement.Tanuja Chitnis, MDThe findings could also open a new avenue for targeted therapeutics, Chitnis noted.“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,” she said.The study was published online on September 16 in Nature Medicine.Predictive Pre-Relapse Immune ChangesThe researchers analyzed blood samples from 114 patients with MS and 21 healthy participants in a long-running study of patients with MS at Brigham and Women’s Hospital.Samples were collected up to 90 days before some patients experienced a relapse, which allowed investigators to compare pre-relapse immune activity with periods of remission in the same patients. Single-cell RNA sequencing and other molecular techniques were used to pinpoint which immune cells changed most before relapse.A “reproducible” pre-relapse signature in monocytes and B cells emerged up to 3 months before clinical onset. This included activation of genes involved in antiviral responses, inflammation, and EBV activity, along with an increase in atypical memory B cells-like B cells, a subset associated with viral infections and autoimmune disease, they reported.Notably, the pre-relapse transcriptional changes overlapped with MS genetic risk loci and regulatory elements bound by the EBV protein EBNA-2, suggesting that viral activity and inherited susceptibility may converge within the same immune pathways.The findings point to a model in which episodic EBV activity in latently infected B cells may help prime the peripheral immune system for relapse in genetically susceptible patients, the researchers said.Researchers are now working on validation studies, which could pave the way for more clinical applications. “I think we are about 1-2 years from an EBV-based biomarker that could be used in the clinic,” Chitnis told Medscape Medical News.The study also points toward more targeted therapeutic strategies. Potential treatment strategies include targeting pathways linking EBV activation with B-cell immune responses. Ultimately, therapies directed against EBV itself could potentially reduce the latent viral reservoir, the researchers suggested.Important Questions RemainThis observational study cannot establish that EBV reactivation causes attacks, researchers cautioned. It remains possible that early, clinically silent MS activity triggers peripheral immune activation and secondary EBV reactivation, or that EBV transcription increases as a consequence of more general B-cell activation.The study was also limited to peripheral blood, leaving unanswered whether similar virus-driven immune states occur within the central nervous system and how the peripheral changes relate directly to lesion formation, they said.The “biggest unknown” is exactly what factors trigger EBV reactivation in B cells, Chitnis noted. “These could be endogenous, environmental, or pharmacological. We are working on this question with large-scale screens,” she said.“The other questions relate to whether there are specific antigens that are presented by B cells to T cells, and what signals cause these cells to migrate to the brain specifically. In the literature, there are multiple candidate EBV-related antigens that can activate T cells, and this will be an interesting question to further explore,” she added.Reached for comment, Dalia Rotstein, MD, PhD, associate professor of medicine in the Division of Neurology at the University of Toronto in Toronto, Ontario, Canada, called the study “exciting,” noting that the pathophysiology of MS relapses remains poorly understood and that studies examining the period before relapse were needed.She cautioned that the relatively small number of patients with pre-relapse samples and the observational design make it impossible to determine whether EBV activity drives relapse or is merely a bystander.“However, these results, if replicated, suggest that EBV markers could be useful in monitoring individuals with MS who are at risk for relapse and allow for earlier intervention to prevent disability,” Rotstein said. She added that the findings support a possible role for EBV beyond MS initiation and bolster the rationale for exploring EBV-targeted therapies in established disease.The study received no commercial funding. Author disclosures are available with the original study publication. Rotstein reported receiving consulting and/or speaking honoraria from Alexion, Amgen, EMD Serono, Novartis, Roche, and Sanofi.