Investigating the Genetic Link Between EBV and MS Risk: David A. Hafler, MD, FANA; Yoshiaki Yasumizu, MD, PhD

Epstein-Barr virus (EBV), a widespread herpesvirus that establishes lifelong latency after primary infection, has emerged as a strong and consistent risk factor for multiple sclerosis (MS).¹ Some of the most compelling support came from a longitudinal analysis of more than 10 million young adults on active duty in the US military, in which MS risk increased 32-fold after EBV infection but not after infection with other viruses. In that cohort, serum neurofilament light chain increased only after EBV seroconversion.² Still, the genetic and cellular mechanisms linking EBV activity to MS susceptibility have remained unclear.³

Emerging evidence suggests EBV may interact with MS susceptibility loci to reshape B-cell transcriptional programs and differentiation, including expansion of atypical B cells that can stimulate autoreactive T cells.¹ Building on this work, Yale investigators presented data at the 10th Joint ACTRIMS-ECTRIMS Meeting (MSToronto 2026), held October 21-23, 2026, in Toronto, Ontario, Canada, from a cross-ancestry genome-wide association study (GWAS) of EBV DNA positivity in 617,186 individuals, using a whole-genome sequencing–based pipeline to quantify EBV DNA.³

The analysis identified 39 independent loci, with the strongest signal in the HLA region and significant overlap with MS risk genes (P = 1.3 × 10⁻¹²), and Mendelian randomization analyses supported a causal contribution of EBV activity to MS risk.⁴ Single-cell profiling across 38 individuals further identified 1069 EBV-infected B cells, predominantly latent and enriched among memory, atypical, and antibody-secreting cells, which upregulated MS risk genes and costimulatory programs influencing T-cell activation.

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“We think the virus makes the B cells into the adjuvant, which juices up the immune system, which breaks tolerance.” —David A. Hafler, MD, FANA

To discuss these findings, NeurologyLive^® spoke with David A. Hafler, MD, FANA, the William S. and Lois Stiles Edgerly Professor of Neurology, and Yoshiaki Yasumizu, MD, PhD, associate research scientist, both of Yale School of Medicine. In the conversation, Hafler framed the work against the long-standing epidemiologic link between EBV and MS. Yasumizu then described the pipeline the team developed with collaborators to detect and quantify EBV DNA from whole-genome sequencing data.

From there, the researchers discussed how their findings may contribute to a broader understanding of EBV's role in MS, including its potential influence on immune function and disease development. They also highlighted the need for further research to better characterize this relationship and explore its implications for future MS prevention and treatment strategies.

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REFERENCES
1. Lünemann JD, Münz C. Epstein-Barr virus and multiple sclerosis: from associations to mechanisms to potential therapies. Lancet Neurol. 2026;25(8):755-763. doi:10.1016/S1474-4422(26)00177-8
2. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
3. Yasumizu Y, Kim N, Rivier C, et al. A genetically driven immunologic mechanism underlying the link between EBV and multiple sclerosis. Presented at: MSToronto2026; October 21-23; Toronto, Canada. Abstract 564.
4. Yasumizu Y, Kim N, Rivier CA, et al. Host Genetic Architecture between Epstein-Barr Virus Activity and Multiple Sclerosis Reveals Shared Pathways. Preprint. medRxiv. 2025;2025.12.11.25342083. Published 2025 Dec 15. doi:10.64898/2025.12.11.25342083