Epstein-Barr virus and the HLA-DR15 genotype act in concert to drive multiple sclerosis through B cell survival, altered self-presentation, and T cell cross-reactivity.
ABSTRACT This commentary integrates findings from three recent Cell reports to establish a unified mechanistic model of multiple sclerosis (MS) driven by the interplay between Epstein‐Barr virus (EBV) and the HLA‐DR15 genotype. EBV promotes CNS autoimmunity through three distinct but intersecting mechanisms. First, viral LMP1 provides anti‐apoptotic signals that sustain autoreactive B cells within the CNS. Second, EBV alters the B cell immunopeptidome, enabling the HLA‐DR15‐restricted presentation of myelin basic protein (MBP)‐derived self‐peptides to initiate autoreactive CD4 + T cell responses. Third, the virus triggers a B cell–independent attack via molecular mimicry, wherein EBNA1‐specific CD4 + T cells cross‐recognize the CNS autoantigen ANO2, providing a B cell–independent attack mechanism. By framing MS as an EBV‐driven autoimmune disease in which EBV and HLA‐DR15 act in concert to dysregulate both B cell and T cell compartments, this model identifies precise therapeutic vulnerabilities. Targeting LMP1 survival signals, disrupting the presentation of EBV‐altered self‐peptides, or depleting cross‐reactive T cell clones could shift MS management from generalized immunosuppression toward etiology‐specific interventions, although evaluating their impact on basal antiviral immunity remains a critical next step.
Zhu et al. (Fri,) conducted a review in Multiple sclerosis. Epstein-Barr virus and the HLA-DR15 genotype act in concert to drive multiple sclerosis through B cell survival, altered self-presentation, and T cell cross-reactivity.