• EBV is established as the definitive environmental trigger for multiple sclerosis, with seroconversion preceding clinical onset by years.
• Molecular mimicry between EBNA1 and GlialCAM drives cross-reactive immune responses that break self-tolerance in the CNS.
• EBV reprograms B cells to establish a persistent CNS reservoir, sustaining chronic neuroinflammation.
• Precision therapies targeting the EBV-MS axis, including CNS-penetrant kinase inhibitors and EBV-specific CAR-T cells, are emerging as promising alternatives to broad immunosuppression.