The Immunosuppression Paradox in Multiple Sclerosis: Are We Fueling the Fire by Suppressing Immunity in an Epstein–Barr Virus–Linked Disease?

Recent studies strongly implicate Epstein-Barr virus (EBV) as a necessary trigger for multiple sclerosis (MS). Longitudinal data show that EBV seroconversion precedes MS onset, while mechanistic studies identify molecular mimicry between EBV antigens and central nervous system proteins. Yet, MS treatments remain largely immunosuppressive, potentially impairing antiviral surveillance required to control EBV latency. Therapies that deplete T cells or impair lymphocyte trafficking have been linked to EBV-driven lymphoproliferative complications, potentially leading to EBV reactivation and exacerbation of MS. In contrast, B-cell-depleting therapies may reduce EBV reservoirs by targeting infected memory B cells and thus be more suited to treating EBV-associated MS. In this Review, we examine the paradox of treating an EBV-associated disease with immunosuppression, highlight data suggesting EBV reactivation under certain MS therapies, and propose that future MS management may require integration of EBV-targeted strategies, including vaccines and virus-directed immunotherapies, to address the underlying viral etiology.