The Relationship Between Epstein-Barr Virus and Multiple Sclerosis

NeurologyLiveNovember 2022
Volume 5
Issue 6

The paradigm-shifting evidence of the link between MS and EBV does not exist in isolation. In fact, the relationship has been suspected for more than 40 years, and evidence therein has been accumulating over the past 2 decades.

Bridget A. Bagert, MD, MPH, Director, Ochsner Multiple Sclerosis Center, Ochsner Health

Bridget A. Bagert, MD, MPH

IN JANUARY 2022, Bjornevik and colleagues published the results of a 20-year prospective seroepidemiologic study on the relationship between Epstein-Barr virus (EBV) and multiple sclerosis (MS) in which investigators observed an enormous increase in the risk of MS after EBV infection. They concluded that EBV is the leading cause of MS.1 The study included clinical and serologic data collected from a large cohort of military personnel within the US Department of Defense, and its novel design explored and refuted possible alternative explanations of the association, including reverse causation and confounding. The magnitude of the observed effect, a 32-fold increase in MS risk after EBV infection, is so large to be comparable with that of lung cancer and smoking.

Published in Science, the study garnered significant press and captured the attention and imagination of patients with MS and providers alike who were fascinated by the possibility that MS may result from a viral infection after all—and by what this fact might mean for future MS therapies and even the possibility of a cure. In its scale and scope, the Bjornevik study is in fact a profoundly comprehensive and convincing investigation cementing the fact that EBV infection is a necessary but not sufficient step for MS to develop. Yet this paradigm-shifting evidence does not exist in isolation. In fact, the idea of an association between EBV and MS is not at all new. The relationship has been suspected for more than 40 years, and evidence therein has been accumulating over the past 2 decades in various fields of medical science, including pathology, epidemiology, immunology, and clinical trials.

In 1980, Sumaya and colleagues were among the first of several groups to report a differential EBV antibody response in patients with MS compared with controls.2 In 2001, Ascherio and colleagues reported on the first prospective seroepidemiologic study addressing this question; the results identified a significantly increased risk of MS after EBV infection.3 Similar prospective seroepidemiologic studies were then conducted in both the United States and Europe in the ensuing decade. In 2013, Pakpoor and colleagues published a meta-analysis of this body of prospective seroepidemiology and concluded that, for an EBV seronegative individual, the odds of developing MS are null.4 Meanwhile, in the field of neuropathology, Serafini and colleagues described in 2004 the surprising discovery of abnormal lymphoid follicles composed predominantly of B cells in the meninges of patients with progressive MS,5 and in 2007 that same group reported that EBV RNA and protein were present within these B-cell follicles in the MS brain.6

This discovery of EBV in the MS brain was not successfully replicated for more than a decade, which led to skepticism about the possible link between EBV and MS. Then, in 2018, 2 separate groups finally confirmed that EBV was, in fact, present in the MS brain,7,8 after which the idea of an association was revitalized, only to be strengthened further by the landmark Bjornevik study earlier this year.1

As we consider these threads of evidence, the biology and tropism of this virus are important to remember. EBV infects B lymphocytes. A herpesvirus with which humans have coevolved for 30 million years,7 EBV literally infects a cell in the human immune system that we know to be integral to the pathology of MS. In healthy carriers, EBV’s viral genome programs B cells to differentiate into memory B cells, immortalizing them and establishing a latent infection that persists for a lifetime.8,9 In 2003, Michael P. Pender, MD, PhD, proposed his “Pender hypothesis” to describe how EBV might cause MS in genetically susceptible individuals, the crux of which centered on B-cell pathology driven by EBV.10 The hypothesis held that the EBV-infected B cells accumulate abnormally in the MS brain,11 and that these virally cloned B cells then attract autoreactive T cells into the brain, leading to chronic autoimmunity and central nervous system damage.12-14 The preponderance of pathology evidence that both EBV protein and RNA exist within meningeal B-cell follicles in the MS brain6-8 has served to prove part of the Pender hypothesis, as has evidence from Burrows and colleagues published in 2017 suggesting that the abnormal accumulation of B-cell follicles in the MS brain results from defective T-cell control of EBV-infected B cells.15

Furthermore, Pender’s idea that B-cell pathology is central to MS pathophysiology has been validated by a series of clinical trials and real-world experience over the past 14 years. In 2008, Hauser and colleagues reported the robust and surprising effectiveness of the anti-CD20 drug rituximab (Rituxan; Genentech/Biogen) in a phase 2 trial in relapsing-remitting MS.16 This observation ultimately led to the development and 2017 approval of ocrelizumab (Ocrevus; Genentech), a humanized anti-CD20 agent that has proven to be among the most highly effective disease-modifying therapies for MS available. Anti-CD20 agents are likely eliminating an abnormal population of EBV-infected B cells in the peripheral immune system of patients with MS before they enter the brain and establish entrenched inflammation in the meninges. However, several important unresolved questions surrounding the mechanism of EBV pathophysiology in MS remain, such as why exactly the brain is targeted by EBV-infected B cells in MS, and whether the B-cell pathology is directed by the EBV viral genome13 or by alternative mechanisms such as molecular mimicry.14,15

The fact that 90% to 95% of the general population have EBV antibodies, yet only a small fraction of them develop MS, adds to the complexity of this story. The most likely explanation is that genetic factors confer a differential ability to successfully manage EBV infection between those who do and do not develop MS, and evidence has accumulated to support this idea.16-18 Yet environmental factors likely play a role as well, specifically the timing of primary EBV infection. It is established that mononucleosis, a late primary EBV infection that occurs in adolescence, is associated with a higher risk of MS.19-21 Primary EBV infection in infants, by contrast, is usually asymptomatic.22 It is interesting to speculate how a late primary EBV infection may lead to the cascade of immunological events that result in MS. The immune response of adolescents to primary EBV infection is fundamentally different from that of infants. Specifically, in cases of mononucleosis in adolescents, there is a massive expansion of CD8+ T cells in that is not seen in infant infections.23 Perhaps this normal age-related difference in the immune response to primary EBV infection leads to a consequential dysregulation of the virus, and ultimately to MS, in individuals who are genetically at higher risk for MS.

It is also interesting to consider differences in modern hygiene practices that may account for observed differences in the prevalence of primary EBV infection, and whether these changes may influence MS risk. EBV infection is more prevalent in infants than in adolescents in communities with lower socioeconomic status and poor hygiene standards,24,25 and it is well established that the prevalence of MS is lower in countries with lower socioeconomic status than in developed countries.10 In other words, in countries where primary EBV infection typically occurs in infancy, MS prevalence is lower, and in countries where primary EBV infection commonly occurs in adolescence, MS prevalence is higher, suggesting that the timing of EBV infection may be an important factor in MS risk. Considering that humans have coevolved with EBV over millions of years,26 perhaps the human immune system has evolved in turn to manage EBV more successfully in infancy than in adolescence. Speculating further on the relationship between the timing of EBV infection and MS risk, the mode of viral transmission may be another key. EBV is transmitted via oral secretions. Throughout human history infants would have been exposed to EBV reliably through the premastication of food passed from mother to child.27-31 The practice of premastication has all but disappeared in modern developed societies, and perhaps with it the opportunity to inoculate young children with EBV at the time in their lives when their immune systems are best able to manage it. Could these relatively recent changes in human hygiene practices explain, in part, the modern increase in the incidence of MS?

In my clinical practice and teachings, I now feel comfortable stating simply that MS results from the failure to manage EBV infection. And while it is true that the relationship between EBV and MS is more complex than this, I think it important at this moment that we in the MS scientific community do not get bogged down in the complexity, but rather acknowledge the evidence that MS is caused by a virus after all. The totality of the past 40 years of evidence of this relationship is both irrefutable and convincing, and the future of MS research and the possibility of a cure hinges on our willingness to acknowledge it as such. Excitingly, several EBV-directed therapies for MS are already being explored in early clinical trials, including direct antiviral therapies, adoptive T-cell immunotherapies targeting EBV-infected B cells, and potential EBV vaccine therapies. Another interesting idea is whether MS itself might be prevented with a safe and effective EBV vaccine, and several early clinical trials are underway in healthy adults exploring this question.

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2. Sumaya CV, Myers LW, Ellison GW. Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol. 1980;37(2):94-96. doi:10.1001/archneur.1980.00500510052009
3. Ascherio A, Munger KL, Lennette ET, et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA. 2001;286(24):3083-3088. doi:10.1001/jama.286.24.3083
4. Pakpoor J, Disanto G, Gerber JE, et al. The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. Mult Scler. 2013;19(2):162-166. doi:10.1177/1352458512449682
5. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14(2):164-174. doi:10.1111/j.1750-3639.2004.tb00049.x
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7. Moreno MA, Or-Geva N, Aftab BT, et al. Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e466. doi:10.1212/NXI.0000000000000466
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9. McGeoch DJ, Cook S, Dolan A, Jamieson FE, Telford EA. Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. J Mol Biol. 1995;247(3):443-458. doi:10.1006/jmbi.1995.0152
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12. Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 2003;24(11):584-588. doi:10.1016/
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18. Lünemann JD, Jelcić I, Roberts S, et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J Exp Med. 2008;205(8):1763-1773. doi:10.1084/jem.20072397
19. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7
20. Zdimerova H, Murer A, Engelmann C, et al. Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15. Eur J Immunol. 2021;51(1):64-75. doi:10.1002/eji.202048655
21. Afrasiabi A, Parnell GP, Fewings N, et al. Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility. Genome Med. 2019;11(1):26. doi:10.1186/s13073-019-0640-z
22. Keane JT, Afrasiabi A, Schibeci SD, Swaminathan S, Parnell GP, Booth DR. The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype.EBioMedicine. 2021;71:103572. doi:10.1016/j.ebiom.2021.103572
23. Warner HB, Carp RI. Multiple sclerosis etiology—an Epstein-Barr virus hypothesis. Med Hypotheses. 1988;25(2):93-97. doi:10.1016/0306-9877(88)90024-2
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27. Dowd JB, Palermo T, Brite J, McDade TW, Aiello A. Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6-19, 2003-2010. PLoS One. 2013;8(5):e64921. doi:10.1371/journal.pone.0064921
28. Smatti MK, Al-Sadeq DW, Ali NH, Pintus G, Abou-Saleh H, Nasrallah GK. Epstein-Barr virus epidemiology, serology, and genetic variability of LMP-1 oncogene among healthy population: an update. Front Oncol. 2018;8:211. doi:10.3389/fonc.2018.00211
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30. McGeoch DJ, Cook S, Dolan A, Jamieson FE, Telford EA. Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. J Mol Biol. 1995;247(3):443-458. doi:10.1006/jmbi.1995.0152
31. Van Esterik P, Williams A, Fewtrell MS, Tolboom JJM, Lack G, Penagos M. Commentaries on Premastication: the second arm of infant and young child feeding for health and survival? By Gretel Pelto, Yuanyuan Zhang & Jean-Pierre Habicht. Matern Child Nutr. 2010;6(1):19-26. doi:10.1111/j.1740-8709.2009.00227.x
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