Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy

Abstract

Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8(+) T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8(+) T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4(+) T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8(+) T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8(+) T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production.

Figure 1

Proposed role of EBV infection in the development of MS. During primary infection, EBV infects autoreactive naïve B cells in the tonsil, driving them to enter germinal centres where they proliferate intensely and differentiate into latently infected autoreactive memory B cells (Step 1), which then exit from the tonsil and circulate in the blood (Step 2). The number of EBV-infected B cells is normally controlled by EBV-specific cytotoxic CD8⁺ T cells, which kill proliferating and lytically infected B cells, but not if there is a defect in this defence mechanism. Surviving EBV-infected autoreactive memory B cells enter the CNS where they take up residence and produce oligoclonal IgG and pathogenic autoantibodies, which attack myelin and other components of the CNS (Step 3). Autoreactive T cells that have been activated in peripheral lymphoid organs by common systemic infections circulate in the blood and enter the CNS where they are reactivated by EBV-infected autoreactive B cells presenting CNS peptides (Cp) bound to major histocompatibility complex (MHC) molecules (Step 4). These EBV-infected B cells provide costimulatory survival signals (B7) to the CD28 receptor on the autoreactive T cells and thereby inhibit the activation-induced T-cell apoptosis, which normally occurs when autoreactive T cells enter the CNS and interact with non-professional antigen-presenting cells such as astrocytes and microglia, which do not express B7 costimulatory molecules^{, ,} (Step 6). After the autoreactive T cells have been reactivated by EBV-infected autoreactive B cells, they produce cytokines such as interleukin-2 (IL2), interferon-γ (IFNγ) and tumour necrosis factor (TNFβ) and orchestrate an autoimmune attack on the CNS with resultant oligodendrocyte and myelin destruction (Step 5). Reproduced from Pender, with permission.