The role of Epstein-Barr virus and human endogenous retroviruses in the pathogenesis of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS), the development of which is associated with the action of a large number of pathogenetic factors which role can vary significantly at different stages of the disease. Although the etiology of MS still remains unclear, in recent years the hypothesis of the pathogenetic role of Epstein-Barr virus (EBV) and human endogenous retroviruses, such as MSRV / HERV-W, is actively considered. EBV has a unique ability to infect, activate, and latently persist within B lymphocytes during human life. Immune control of EBV infection in healthy organisms is realized through humoral and cellular mechanisms – EBV virions are destroyed by neutralizing antibodies, and proliferating and lytically active EBV-infected B cells are the targets of specific CD8+ T cells. At the same time, EBV remains latent for most of the life of the infected individual, expressing a single gene (EBNA1) within memory B cells. EBNA1 protein is not well recognized by CD8+ T cells, allowing infected memory B cells to avoid detection. In addition to epidemiological data, association of EBV with MS is indicated by a significant increase in IgG titres to EBV antigens, mainly to EBNA1, in serum of patients a few years before the onset of clinical manifestations of the disease. Although the data on the presence of EBV in the CNS remain controversial due to a number of methodological difficulties, a number of studies have shown the presence of EBV-infected B cells in the CNS, as well as effector CD8+ T cells specific for them in meningeal inflammatory infiltrates and white matter lesions in brain samples of MS patients. At the same time, the EBV bystander damage hypothesis which considers CNS damage in multiple sclerosis as a result of EBV-targeted cytotoxic reactions of CD8+ T cells, does not explain the autoimmune nature of MS, although secondary autoimmune responses could develop as a result of sensitization to CNS antigens released after a cytotoxic response directed to EBV elimination causing bystander neuronal damage. It also does not explain why the EBV-targeted T cell immune response sufficient to cause bystander CNS damage does not eliminate EBV-infected B cells from the CNS. It was found that subpopulations of EBV-specific CD8+ T cells in MS patients show signs of depletion, increasing with the duration of the disease, which apparently allows EBV-infected B cells to accumulate in the CNS and leads to the formation of a vicious circle, in which the initially defective T cell response is aggravated by depletion of T cells as a result of a constant high viral load in CNS. M. Pender has proposed a hypothesis of the pathogenesis of MS according to which MS is caused by the accumulation in the CNS of autoreactive EBV-infected B cells that are capable of self-sustaining proliferation, production of pathogenic antibodies in the CNS, and providing costimulatory and survival-promoting signals to autoreactive CD4+ T cells. But it remains unclear what type of CD8+ T cells is dominant in CNS lesions in patients with MS - specific to EBV, specific to myelin proteins, or both types of cells.

However, the delay between seroconversion in the EBV-positive status in late EBV infection and the development of MS may indicate the presence of additional factors in the development of the disease. In recent years, a number of studies indicate a possible pathogenetic role of endogenous human retroviruses (HERV) in MS. In infectious mononucleosis, the increased expression of MSRV/HERV-W in peripheral blood mononuclear cells has been observed, moreover, a direct correlation has been found between levels of IgG to EBNA-1 and levels of MSRV-specific mRNA expression. Binding of the EBV caused activation of MSRV / HERV-W in peripheral blood mononuclear cells and in astrocytes. Activation of MSRV/HERV-W was also revealed in inflammatory context and in neuropathogenic processes in MS. In the peripheral blood mononuclear cells culture of MSRV-positive individuals, expression of MSRV was activated by the action of pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ, and significantly decreased by IFN-β. At the brain level, HERV-Wenv activates Toll-like receptors (TLR4) of oligodendroglial precursor cells, which results in the production of pro-inflammatory cytokines as well as inducible nitric oxide synthase (iNOS), and a decrease in myelin protein expression. Within chronic brain lesions in MS, HERV-Wenv was detected in microglia / macrophages near TLR4-positive oligodendroglial precursor cells. Immunohistochemical detection of HERV-Wenv protein in postmortem brain samples of MS patients showed its elevated levels only in active lesions in astrocytes and microglia, and the intensity of staining correlated with the degree of active demyelination and inflammation. Thus, EBV infection and activation of retroviruses are considered as important elements in the pathogenesis of MS. Within the framework of the "viral hypothesis", the most important tasks are the verification of data indicating the possible etiological role of EBV, the study of the pathogenetic mechanisms associated with MSRV/HERV-W at different stages of MS development, as well as the identification of immunological and genetic factors associated with the defective control of EBV-infected B cells and, as a result, their migration and accumulation in the CNS. Thus, EBV infection and activation of retroviruses are considered as important factors in the pathogenesis of MS. Late EBV infection may be the initiating trigger of the pathological process leading to the development of MS years later, and HERV-W / MSRV affect as active cofactors of the neuropathogenesis of the MS accompanying the course of the disease. The aimof the review was to consider the latest evidence of possible mechanisms of the involvement of EBV and human endogenous retroviruses in the pathogenesis of multiple sclerosis.