Christina Garcia

Background: Multiple Sclerosis (MS) is the most common neurodegenerative disease to affect young adults, affecting females more commonly than males.¹ MS is characterized by perivascular inflammatory lesions which lead to oligodendrocyte damage and demyelinating plaques.¹ There is no cure for MS and the available treatments are limited and expensive, posing an issue for those affected with low socioeconomic status.² The etiology of MS is complex and the overall risk for developing MS is a combination of genetics, environmental and epigenetic factors.³ Known risk factors include low vitamin D, genetics, such as being HLA-DR15⁺, and Epstein Barr virus (EBV) infection.^1,2 The current proposed pathogenesis is due to failed central tolerance within the thymus, creating impaired T cells that become reactive to myelin leading to oligodendrocyte damage and MS pathology.² Establishing a prognosis is difficult due to heterogeneity of the disease, but MRI is useful for analysis of lesion accumulation over time.¹ Poor prognosis factors include male gender, late onset and short interattack intervals.³ Common signs and symptoms include optic neuritis, numbness/tingling, muscle spasms and mobility issues.¹ MS can be diagnosed using clinical history, neurological exam, MRI and ruling out similar presenting conditions such as Lupus, Meningitis and Lyme disease.³ Lumbar puncture and CSF analysis are also an option, but are typically unnecessary.³ The goal of current treatment methods include reducing inflammation and stabilizing the blood brain barrier (BBB) in order to prevent entry of autoreactive T cells and delay disease progression.³ High dose corticosteroids are used for acute MS relapses and concurrent or consecutive plasma exchanges are used for resistant MS patients.³ Interferon-beta (INF) was the first injectable disease modifying therapy (DMT) to treat MS and acts to stabilize the blood brain barrier and promote a shift from pro-inflammatory to an anti-inflammatory environment in the CNS.³ Despite current treatment options and knowledge, significant knowledge gaps remain including understanding of mechanisms behind MS pathogenesis.⁴ The complex combination of genetics and environment make pinpointing a cause for MS difficult, however, infection with EBV has become a compelling area of research for understanding these pathogenic mechanisms.⁴

Overview: In this narrative review, the mechanisms behind the viral etiology of Multiple Sclerosis, specifically the concept of molecular mimicry, were explored and the proposition of future research needed to develop more specific and effective treatment therapy was addressed.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using “MeSH” and the following keywords: “multiple sclerosis”, “Epstein Barr virus”, “GlialCAM”, “EBNA1”, “etiology”, “diagnosis”, “drug therapy”, “epidemiology” and “pathology”.

Results: Bjornevik et al. successfully established an epidemiological link between EBV and MS over a 20 year period studying a cohort of 10 million young adults on active duty.⁵ Neurofilament Light Chain (NfL), a biomarker for ongoing neuroaxonal degeneration, was analyzed in the serum of participants before, during and after infection with EBV.⁵ The study concluded that NfL levels in individuals who were EBV negative at baseline and then developed MS were similar to those of non-MS controls prior to EBV infection.⁵ However, NfL levels were increased after EBV infection in individuals who developed MS compared to those who did not.⁵ Despite this link, a mechanistic link between EBV and MS is limited. B cells are known to play a central role in the pathogenesis of MS by triggering proliferation and autoreactivity of Th1 cells which leads to pathology.⁶ Therefore, it is proposed that EBV infection can mediate B cell activity in order to cause MS pathology.⁶ van Langelaar et al. and Wieland et al have provided evidence that increased protein expression in MS patients of certain proteins, such as CXCR3 and Human Endogenous Retrovirus (HERV), are mediated by B cells and may cause autoimmune reactions that lead to its pathogenesis.^7,8 This research paved the way for the most recent study conducted by Lanz et al. demonstrating that the concept of molecular mimicry may play a critical role in MS pathogenesis after infection with EBV.⁹ The study concluded that EBV immortalized B cells, that secrete anti-EBNA1 antibodies, travel to the CNS, encounter and recognize GlialCAM (via molecular mimicry) and undergo somatic hypermutation in order to create high affinity anti-GlialCAM antibodies.⁹ These antibodies attack myelin, resulting in inflammation and demyelination.⁹

Conclusions: Studies have found that molecular mimicry between EBNA1, an EBV protein, and GlialCAM, an immunoglobulin-like adhesion molecule expressed in glial cells, can trigger autoimmunity in the CNS, leading to inflammation and demyelination, hallmark characteristics of MS.⁹ Despite this recent and promising mechanistic link between EBV infection, B cell mediation and MS pathogenesis, further research is needed in order to gain a deeper understanding of MS. Doing so will provide more specific and efficient therapy methods that may be able treat, or possibly cure, MS.⁹

Works Cited:

1. Dobson, R., & Giovannoni, G. (2019). Multiple sclerosis – a review. Eur J Neurol, 26, 27-40. https://doi.org/10.1111/ene.13819
2. Ward, M., & Goldman, M. D. (2022). Epidemiology and Pathophysiology of Multiple Sclerosis. Continuum (Minneapolis, Minn.), 28(4), 988-1005. https://doi.org/https://doi.org/10.1212/CON.0000000000001136
3. Perez, C. A., Cuascut, F. X., & Hutton, G. J. (2022). Immunopathogenesis, Diagnosis, and Treatment of Multiple Sclerosis: A Clinical Update. Neurologic Clinics, 41(1), 87-106. https://doi.org/10.1016/j.ncl.2022.05.004
4. Wekerle, H. (2022). Epstein-Barr virus sparks brain autoimmunity in multiple sclerosis. Nature, 603(7900), 230-232. doi:https://doi.org/10.1038/d41586-022-00382-2
5. Bjornevik, K. et al. (2021). Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 375(6578), 296-301. https://doi.org/10.1126/science.abj8222
6. Jelcic, I. et al. (2018). Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis. Cell, 175(1), 85-100. https://doi.org/10.1016/j.cell.2018.08.011
7. van Langelaar, J. et al. (2021). The association of Epstein-Barr virus infection with CXCR3(+) B-cell development in multiple sclerosis: impact of immunotherapies. Eur J Immunol, 51(3), 626-633. https://doi.org/10.1002/eji.202048739
8. Wieland, L. et al (2022). Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis. Cells, 11(22), 3619. https://doi.org/10.3390/cells11223619
9. Lanz, T. V. et al. (2022). Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature, 603(7900), 321-327. https://doi.org/10.1038/s41586-022-04432-7