Detailed characterization of the immune response to Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment

Aim : To define the viral load and immune response to Epstein-Barr virus (EBV) in multiple sclerosis (MS) and the effect of B cell depleting therapy (BCDT). Methods : The study included healthy controls (HC) and persons with MS (pwMS). EBV viral load was quantified from whole blood DNA. Humoral immune responses were assessed in plasma, and cellular immune responses in peripheral blood mononuclear cells. T cell receptor Vβ (TCRVβ) analysis was performed on sorted blood and cerebrospinal fluid (CSF) cells. Results : EBV viral load did not differ between pwMS and HC. In contrast, distinct differences were found in both humoral and cellular EBV-specific immunity in MS. Antibodies against EBV were increased in pwMS, whereas CD8+ T cell reactivity against lytic antigens, including BZLF1, was reduced. Notably, during periods of disease activity, both CD4+ and CD8+ T cell responses to lytic antigens increased. In addition, BZLF1-specific T cell clones recognizing the peptide RAKFKQLL were the most clonally expanded population in the intrathecal compartment of a pwMS with high CSF T cell counts. BCDT reduced EBV viral load and was coupled to a pronounced reduction in CD8+ T cell responses to all lytic EBV antigens. Conclusion : These findings delineate distinct alterations in EBV-specific immunity in MS and demonstrate that BCDT modulates both viral load and T cell responses. The data support a potential role for CD8+ T cell clones targeting lytic EBV proteins in MS pathogenesis.