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Review
. 2023 Jan;21(1):51-64.
doi: 10.1038/s41579-022-00770-5. Epub 2022 Aug 5.

Epstein-Barr virus and multiple sclerosis

Samantha S Soldan  1 , Paul M Lieberman  2
Affiliations
Review

Epstein-Barr virus and multiple sclerosis

Samantha S Soldan et al. Nat Rev Microbiol. 2023 Jan.

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus with a well-established causal role in several cancers. Recent studies have provided compelling epidemiological and mechanistic evidence for a causal role of EBV in multiple sclerosis (MS). MS is the most prevalent chronic inflammatory and neurodegenerative disease of the central nervous system and is thought to be triggered in genetically predisposed individuals by an infectious agent, with EBV as the lead candidate. How a ubiquitous virus that typically leads to benign latent infections can promote cancer and autoimmune disease in at-risk populations is not fully understood. Here we review the evidence that EBV is a causal agent for MS and how various risk factors may affect EBV infection and immune control. We focus on EBV contributing to MS through reprogramming of latently infected B lymphocytes and the chronic presentation of viral antigens as a potential source of autoreactivity through molecular mimicry. We consider how knowledge of EBV-associated cancers may be instructive for understanding the role of EBV in MS and discuss the potential for therapies that target EBV to treat MS.

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Conflict of interest statement

P.M.L. founded and is an adviser to Vironika LLC. P.M.L. is named on a patent for inhibitors of EBNA1. S.S.S. declares no competing interests.

Figures

Fig. 1
Fig. 1. The maturation of the immune system, EBV infection and the development of MS.
The consequences of Epstein–Barr virus (EBV) infection are influenced by the age and genetic background of an individual. The risk of both infectious mononucleosis and multiple sclerosis (MS) increases when primary EBV infection occurs after the age of 10 years, when thymic negative selection of autoreactive T cells slows and T helper 1 (TH1) cell-mediated responses approach their peak. Most individuals receive a diagnosis of MS between the ages of 20 years and 50 years, years after EBV exposure. EBV infection increases the survival of memory B cells and causes lasting changes in the host cytokine response. There are many gaps in our understanding of how the maturation of the immune system triggers an evolving process of EBV-driven autoimmune reactivity leading to the development of MS. CMV, cytomegalovirus.
Fig. 2
Fig. 2. EBNA1 sequences and their potential role in molecular mimicry and autoreactivity.
Computational model of EBNA1 full-length protein indicating the most frequent peptide epitopes associated with multiple sclerosis autoimmunity. DNA is shown as solid, protein as ribbon. Epitopes are highlighted in magenta and boxed. A partial list of EBNA1 peptides and their autoimmune properties, including immune response type and cellular protein mimic. aa, amino acids; ANO2, anoctamin 2; β-SYN, β-synuclein; CRYAB, α-crystallin B chain; DBD, DNA-binding domain; (GA)n, glycine-alanine repeats; glialCAM, glial cell adhesion molecule; MBP, myelin basic protein; NTD, amino-terminal domain.
Fig. 3
Fig. 3. EBV latency drives B cell survival of inflammatory B cells.
Epstein–Barr virus (EBV) infection promotes the proliferation and survival of memory B cells that may alter T cell control of EBV infection and autoimmune reactive B cells and T cells. EBV LMP1 and LMP2 function as CD40-like and B cell receptor (BCR)-like mimics to bypass T cell-dependent germinal centre reactions. EBNA1 and EBNA2 drive gene regulatory changes that may affect preferentially multiple sclerosis (MS)-risk alleles. EBV-induced viral and cellular factors may promote inflammation, driving autoreactivity through direct interaction with T cells or natural killer (NK) cells, as well as through soluble factors, including exosomes. EBNA1 is frequently processed as an antigenic epitope that can stimulate autoreactive B cell and T cell development. Although EBV-positive cells are shown as antigen-presenting cells, it is not known whether they actually present EBNA1 peptides or whether these are presented by uninfected antigen-presenting cells, including uninfected dendritic cells and macrophages that captured infected cell debris. OPN, osteopontin; TNF, tumour necrosis factor.
Fig. 4
Fig. 4. Mechanisms of EBV-mediated inflammatory cascades in periphery and CNS.
Epstein–Barr virus (EBV) may drive inflammatory events in both the periphery and the central nervous system (CNS), leading to the development of the multiple sclerosis lesion in the CNS. EBV immune-evasive features and risk-associated immune deficiencies promote EBV inflammatory cascades in the periphery. CNS pathogenesis may be initiated through multiple mechanisms, including natural and EBV-driven CNS trafficking of autoreactive B cells and T cells, molecular mimicry driven by chronic EBV infection, EBV-driven inflammatory cytokines and exosomes, and aberrant EBV lytic infection and tropisms owing to deficient immune control. CTL, cytotoxic T lymphocyte; glialCAM, glial cell adhesion molecule; MBP, myelin basic protein; OPN, osteopontin.
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