Aaron Bennett

Background: Multiple Sclerosis (MS) is an inflammatory autoimmune-driven demyelinating disease of the central nervous system with a relatively unknown etiology and lack of a cure. ^1-3 Symptoms of MS include optic neuritis, vision loss, neuralgia, fatigue, and ataxia. ^1-3 Epstein-Barr Virus (EBV) is a herpesvirus that has infected over 90% of the human population due to its highly infectious nature. ³ EBV is typically asymptomatic but can occasionally manifest as infectious mononucleosis. ³ EBV remains in the body for the remainder of life as latent B-cells. There is currently no cure or vaccine for EBV. ³ Previously, there has been suspicion that latent EBV cells are linked to the onset of multiple sclerosis due to elevated serum antibody titers against EBV Nuclear Antigens (EBNAs) in MS patients. ^1-3

Objective: In this narrative review, we examine the evidence of the correlation between MS and EBV in humans, a molecular mechanism that links them together, and the potential for irradicating EBV latent B-cells as a treatment for MS patients.

Search Methods: An online search on PubMed was conducted from 2018 to 2023 using the following keywords: “multiple sclerosis”, “Epstein Barr virus”, “molecular mimicry”, “EBV T-cell therapy”

Results: A 20-year collaboration with the US military providing 10 million serum samples taken from service members were analyzed to determine if there was a relationship between the onset of MS and EBV infection using ELISA and Western Blotting. ³ The hazard rate for MS comparing EBV serum positive samples to EBV serum negative samples concluded that being EBV positive increased the risk of developing MS by 32.4-fold (95% CI, P < 0.001). ³ ANO2 is a calcium-activated chloride channel protein found throughout the human body but in especially high concentrations in the cerebellum. ⁴ ANO2 has a similar epitope to EBNA1 (ANO2 aa 140-149 and EBNA1 aa 431-440). ⁴ IgG production against EBNA1 during an EBV infection can lead to an autoimmune molecular mimicry-based attack on healthy ANO2 proteins. ⁴ It was concluded that having anti-EBNA1 and anti-ANO2 increased the risk of developing MS by 5.3-fold, further linking MS to EBV. ⁴ 11 MS-positive patients were treated with AdE1-LMPpoly adenoviral vector encoded  CD8+ T-cells that attacked EBNA1-tagged cells. ⁵ All 6 patients that had strong EBV-reactivity, showed drastic clinical improvements using the Expanded Disability Status Scale. ⁵ Only 1 patient with weak EBV-reactivity showed improvement. ⁵

Conclusion: Studies are published every year that continue to show how MS and EBV are related. Considering the evidence of a relation between the two diseases, further research is warranted in discovering treatments, cures, and vaccines for EBV to prevent and treat MS.

Works Cited:

1. Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019;26(1):27-40. doi:10.1111/ene.13819
2. Tarlinton RE, Martynova E, Rizvanov AA, Khaiboullina S, Verma S. Role of Viruses in the Pathogenesis of Multiple Sclerosis. Viruses. 2020;12(6):643. Published 2020 Jun 13. doi:10.3390/v12060643
3. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
4. Tengvall K, Huang J, Hellström C, et al. Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc Natl Acad Sci U S A. 2019;116(34):16955-16960. doi:10.1073/pnas.1902623116
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