Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Abstract

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

Keywords: Epstein–Barr virus; cell-based therapies; immune evasion; multiple sclerosis; ocrelizumab; vaccination.

Figure 1

The Autoreactive B Cell Hypothesis (A) Tonsil to germinal center (GC): naïve B cells (white) are infected by Epstein–Barr Virus (EBV, orange) and proliferate in GCs. B cell receptor (BCR) and EBV proteins are expressed on latently infected autoreactive memory B cells. (B) Circulation: EBV-infected memory B cells exit the tonsil into the circulation (orange). EBV-specific cytotoxic CD8⁺ T cells normally control the number of EBV-infected B cells but, in the case of multiple sclerosis (MS), there is a defect in this mechanism. (C) EBV-infected B cells enter the MS brain residing for long periods of time where they produce oligoclonal IgG bands and pathogenic autoantibodies which attack and damage neurons. EBV-infected B cells provide co-stimulatory survival signals (B7) to CD28 receptors expressed on autoreactive T cells (green) that normally undergo apoptosis. Autoreactive T cells entering the brain are reactivated by EBV-infected B cells presenting CNS antigens (Cp) bound to MHC molecules. Autoreactive T cells produce cytokines [e.g., IL2, interferon (IFN)-γ, tumor necrosis factor (TNF)-β] and recruit other inflammatory cells (effector and cytotoxic T cells) that damage oligodendrocytes (yellow), myelin, and neurons. Adapted, with permission, from [18]. Abbreviations: B7, co-stimulatory molecule; CD28, T cell surface receptor; CNS, central nervous system; Cp–MHC, CNS peptides bound to MHC molecules; TCR, T cell receptor.