Livia George

Background: Multiple Sclerosis (MS) is a chronic, progressive disease of the central nervous system with inflammation and demyelination of nerves. Although the pattern of symptoms can vary, common initial symptoms include visual deficits related to retrobulbar neuritis, paresthesia, and isolated sensory and motor symptoms.¹ Although the exact cause of MS is unclear, many viruses and bacteria have been or are being investigated in connection with MS. A growing number of research findings indicate that previous infection with Epstein-Barr virus (EBV), the virus that causes mononucleosis, contributes to the risk of developing MS.^1,2

Objective: The purpose of this study is to explore the current literature that connects the possible causal link between EBV and MS development, underlying molecular mechanisms and EBV directed therapy aimed at the prevention and treatment of MS.

Search Methods: PubMed was the primary platform for scientific articles, with the search terms including “MS development” and EBV and MS treatment.” The year timeframe searched was 2017-2023.

Results: A longitudinal study including over 10 million young adults on active duty in the US showed that the risk for MS increased 32-fold after infection with EBV but was not increased after infection with other viruses.² Furthermore, serum levels of neurofilament light chain (sNfL), a biomarker for neuroaxonal degeneration, increased only after EBV seroconversion.² These findings could not be explained by any known risk factor for MS and suggest EBV as the leading cause of MS. Lanz et al. provided a mechanistic link for the association between MS and EBV, which could guide the development of new MS therapies. One proposed mechanism of MS development is high-affinity molecular mimicry between EBV transcription factor EBV nuclear antigen 1 (EBNA1) CNS protein glial cell adhesion molecule (GlialCAM); Anti-EBNA1 and Anti-GlialCAM antibodies were distinctly prevalent in patients with MS.³ It was also demonstrated that EBNA1 could cause autoimmunity and exacerbate disease in mouse models.³ In addition to molecular mimicry, increasing evidence indicates EBV-infected autoreactive B cells might accumulate in the CNS due to defective CD8+ cytotoxic T cells.⁴ Pender and his colleagues used EBV-specific T cells to treat progressive MS patients. Although the primary goal was to assess safety and feasibility, there was a modest improvement in symptoms and objective neurological function. Overall, no serious adverse events were recorded, and patients receiving T cells with a stronger EBV reactivity were more likely to show more significant clinical improvement.⁵

Conclusions: Epstein Barr Virus is a causative infectious agent in Multiple Sclerosis, with a 32-fold increased risk of MS after EBV infection. Possible mechanisms include high-affinity molecular mimicry and accumulation of EBV-infected autoreactive B-cells. EBNA1 autoimmunity in the mouse model has important implications for developing a vaccine.³ EBV-specific T-cell therapy shows promising clinical improvement in patients with MS, and further investigation is required to prove efficacy.⁵

Works Cited:

1. 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
2. Kjetil Bjornevik, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.Science375,296-301(2022).DOI:10.1126/science.abj8222
3. Lanz, T.V., Brewer, R.C., Ho, P.P. et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603, 321–327 (2022). https://doi.org/10.1038/s41586-022-04432-7
4. William H. Robinson, Lawrence Steinman. Epstein-Barr virus and multiple sclerosis.Science375,264-265(2022).DOI:10.1126/science.abm7930
5. Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis [published correction appears in JCI Insight. 2020 Oct 15;5(20):]. JCI Insight. 2018;3(22):e124714. Published 2018 Nov 15. doi:10.1172/jci.insight.124714