Epstein-Barr virus in multiple sclerosis pathogenesis: The path towards mechanistically faithful models

Multiple Sclerosis (MS) is a chronic, disabling autoimmune disease of the central nervous system (CNS). While its aetiology is multifactorial, compelling evidence now implicates Epstein-Barr virus (EBV) as a primary aetiological agent. This review summarises the extensive epidemiological and mechanistic data supporting a causal link between EBV infection and MS. Epidemiological studies demonstrate that EBV infection confers >30-fold increased risk for MS, with seroconversion preceding the onset of neuroaxonal damage. The leading proposed mechanism is molecular mimicry, where antibodies and T cells targeting the EBV nuclear antigen 1 (EBNA1) cross-react with CNS proteins, such as GlialCAM, initiating autoimmune-mediated demyelination. This process is modulated by synergistic interactions with genetic risk factors, and environmental factors like smoking and adolescent obesity. A critical evaluation of the experimental models used to investigate this connection is presented. In vitro systems using patient-derived cells have confirmed dysregulated immune responses to EBV antigens, while in vivo models - ranging from murine experimental autoimmune encephalomyelitis (EAE) and humanised mice to non-human primate models with homologous γ-herpesviruses - have been instrumental in demonstrating the role of EBV in breaking immune tolerance and driving neuroinflammation. Despite their utility, each model possesses limitations, underscoring the need for next-generation model systems that more accurately recapitulate the complex interplay between the virus, host genetics, and the CNS environment. Future research focused on refining these models is crucial for developing targeted EBV-based therapeutics, such as vaccines or antiviral agents, to prevent or treat MS.