Cross-reactive HERV-W and EBV peptides elicit antibody responses in MS patients and synergistically exacerbate neuroinflammation in EAE

Human endogenous retrovirus W (HERV-W) has been linked to multiple sclerosis (MS), yet its pathogenic role remains unclear. Epstein–Barr virus (EBV), a key MS risk factor, can transactivate HERVs, suggesting a potential interplay. We analyzed immune responses to a HERV-W₁₀₃–₁₁₀ peptide homologous to EBV EBNA1₃₈₆–₄₀₅ in sera from Japanese MS patients (n = 44), neurological controls (n = 28), and healthy controls (n = 48), including an unrelated control antigen (BCG) to assess general humoral activation. MS patients exhibited elevated antibodies to both peptides, indicating cross-reactive immunity. In C57BL/6 J mice, pre-immunization with either peptide modestly modulated experimental autoimmune encephalomyelitis (EAE), whereas combined pre-immunization exacerbated disease, expanding CD4+ and CD8+ T cells and promoting systemic activation. These results support a model in which EBV-driven HERV-W activation elicits cross-reactive humoral and cellular responses that amplify neuroinflammation in MS.