A SIGNIFICANT proportion of multiple sclerosis (MS) cases are driven by antibodies targeting the Epstein-Barr virus (EBV) that mistakenly attack the brain protein GlialCAM, with genetic risk factors amplifying this autoimmune response. This breakthrough clarifies the long-suspected link between EBV and MS, offering pathways for improved diagnostics and therapies.
Multiple sclerosis, an autoimmune disorder damaging the central nervous system’s myelin sheath, has been epidemiologically tied to prior EBV infection. Nearly all MS patients are EBV carriers, but the mechanisms connecting the virus to neurodegeneration remained unclear until recent studies identified molecular mimicry between EBV proteins and neuronal components. Research now demonstrates that antibodies against EBV’s EBNA1 protein cross-react with GlialCAM, a protein critical for maintaining myelin, providing a direct biological explanation for this association.
Researchers analysed blood samples from 650 MS patients and 661 healthy controls, measuring antibodies against EBNA1 and three CNS proteins (GlialCAM, ANO2, CRYAB). Elevated anti-EBNA1 antibodies were present in 20–25% of MS patients, with cross-reactivity to GlialCAM confirmed through structural and blocking experiments149. Patients carrying the HLA-DRB115:01* genetic variant faced a 9.4-fold higher MS risk when combined with anti-EBNA1 and anti-GlialCAM antibodies, compared to a 2.7-fold increase from the gene alone9. Conversely, the absence of the protective HLA-A02:01* allele doubled risk when paired with these antibodies9. Antibody levels against GlialCAM, ANO2, and CRYAB were consistently higher in MS patients, with epitope spreading observed in GlialCAM-targeting immune responses59.
These findings underscore the clinical potential of anti-EBNA1 and anti-GlialCAM antibodies as biomarkers for early MS detection and risk stratification. The additive effect of genetic and immunological factors highlights opportunities for personalised medicine, particularly in individuals with high-risk HLA profiles. Future research should prioritise longitudinal studies to determine when cross-reactive antibodies emerge relative to disease onset, which could inform preemptive therapies. Clinically, interventions targeting EBV—such as vaccines or antiviral drugs—and therapies dampening cross-reactive immune responses, like B-cell depletion, warrant exploration. Additionally, monitoring antibody levels in high-risk populations could enable earlier, more effective treatment, potentially slowing disease progression. By unravelling the interplay between viral triggers, genetic susceptibility, and autoimmune pathology, this work marks a pivotal step toward transforming MS management.
Katrina Thornber, EMJ
Reference
Sattarnezhad N et al. Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls. PNAS. 2025;122(11):e2424986122.
