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Epstein–Barr virus and multiple sclerosis

Nature Reviews Microbiology volume 21, pages 51–64 (2023)Cite this article

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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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Fig. 1: The maturation of the immune system, EBV infection and the development of MS.
Fig. 2: EBNA1 sequences and their potential role in molecular mimicry and autoreactivity.
Fig. 3: EBV latency drives B cell survival of inflammatory B cells.
Fig. 4: Mechanisms of EBV-mediated inflammatory cascades in periphery and CNS.

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    Samantha S. Soldan & Paul M. Lieberman

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Glossary

Burkitt lymphoma

An aggressive form of non-Hodgkin lymphoma endemic to sub-Saharan Africa, where it is associated with Epstein–Barr virus infection.

Relapsing–remitting MS

(RRMS). A form of multiple sclerosis (MS) where disease exacerbations are interspersed with periods of disease inactivity.

Secondary progressive MS

(SPMS). A form of multiple sclerosis (MS) that follows relapsing–remitting MS where progressive disability accumulates with or without discernible relapse.

Primary progressive MS

(PPMS). A form of multiple sclerosis (MS) that lacks distinct periods of disease exacerbations.

Clinically isolated syndrome

An initial episode of neurological symptoms associated with inflammation and demyelination with symptoms characteristic of multiple sclerosis that frequently, although not always, progresses to multiple sclerosis.

Waldeyer’s tonsillar ring

A ring of lymphoid tissue surrounding the nasopharynx and oropharynx that includes the tonsils and adenoids.

Germinal centre

(GC). An area within lymph nodes and other secondary lymphoid organs, including the spleen, where T cell-dependent B cell activation, differentiation and proliferation occur. Germinal centres are concentrated areas of B cell somatic mutation and selection.

Chronic active EBV infection

A rare condition marked by poor control of Epstein–Barr virus (EBV) infection, resulting in high EBV plasma viral loads and systemic infiltration by EBV-positive B cells or EBV-positive T cells.

Oral hairy leukoplakia

A white lesion on the tongue with a ‘hairy’ appearance that is caused by Epstein–Barr virus lytic infection and that can occur in immunocompromised individuals, especially those with HIV/AIDS.

Infectious mononucleosis

A self-limiting disorder characterized by fever, extreme fatigue, sore throat and highly swollen lymph nodes; most frequently caused by immune response to primary Epstein–Barr virus infection, although milder forms are associated with cytomegalovirus infection.

Graft-versus-host disease

A condition in which the donor’s immune system (the graft) rejects the recipient (the host) as non-self.

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Soldan, S.S., Lieberman, P.M. Epstein–Barr virus and multiple sclerosis. Nat Rev Microbiol 21, 51–64 (2023). https://doi.org/10.1038/s41579-022-00770-5

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