Proinflammatory Epstein–Barr Virus Antibody Functions Track with Disease Activity in Multiple Sclerosis

OBJECTIVE: Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Elevated immunoglobulin G (IgG) titers against EBV nuclear antigen 1 (EBNA1) represent the most consistent serological marker of MS risk, with levels remaining persistently elevated following disease onset. METHODS: We conducted high-dimensional profiling of virus-specific antibody-associated immune features in 60 individuals with relapsing-onset MS followed over time and in 54 age- and sex-matched EBV-seropositive healthy controls. RESULTS: EBNA1-specific IgG in MS patients exhibited a distinct proinflammatory Fc signature, characterized by increased affinity for Fc γ receptors (FcγRs) and enhanced Fc-mediated effector functions, including antibody-dependent phagocytosis, complement activation, and natural killer cell engagement. This signature was not observed for antibodies against other common viral antigens and showed a strong association with MS. Increased FcγR binding by IgG, specific for both EBNA1 and the lytic EBV glycoprotein 350 (EBV-gp350) correlated with disease activity, defined as clinical relapse and/or presence of contrast-enhancing brain lesions (CELs). INTERPRETATION: Both fragment antigen-binding and pro-inflammatory functional Fc-mediated features contribute to the association between EBNA1-specific antibody responses and MS. Fc effector functions of EBV-specific antibodies may actively participate in promoting focal disease activity in MS. ANN NEUROL 2026.