The EBV-MS paradigm: beyond molecular mimicry toward new therapeutic strategies

Epstein-Barr virus (EBV) is now recognized as the definitive environmental driver of multiple sclerosis (MS), shifting the conceptual landscape of this autoimmune disorder to an infection-triggered model. In this review, we systematically evaluate the multidimensional evidence linking EBV to MS. This evidence ranges from epidemiological associations and the identification of mimotopes to emerging therapeutic strategies. We also discuss the broader implications of infection-driven immune dysregulation for autoimmune research. This pathogenic link is underpinned by molecular mimicry, where immune responses against the viral protein EBNA1 cross-react with the central nervous system (CNS) protein GlialCAM. Beyond this initial insult, EBV reprograms B cells to survive and proliferate abnormally, creating a compartmentalized viral reservoir within the CNS that sustains chronic neuroinflammation. These mechanistic insights catalyze a transition from broad immunosuppression to precision therapies targeting the EBV-MS axis, including CNS-penetrant kinase inhibitors and EBV-specific CAR-T cells. By integrating etiological discovery with mechanism-based intervention, the EBV-MS paradigm serves as a blueprint for transforming idiopathic autoimmune diseases into mechanistically tractable conditions with actionable therapeutic targets. Epstein-Barr virus (EBV) is established as a key environmental driver of multiple sclerosis (MS), repositioning it as an infection-triggered disease. This review synthesizes evidence linking EBV to MS, providing a framework for redefining idiopathic autoimmunity in mechanistic terms. • Mechanisms of EBV pathogenesis are detailed, including molecular mimicry between EBNA1 and CNS proteins and viral reprogramming of B cells. • The role of compartmentalized CNS viral reservoirs, stage-dependent immune responses, and advances in mimotope discovery are examined. • Progress in precision therapies targeting the EBV-MS axis are summarized, alongside proposed treatment strategies.