Epstein Barr Virus and Multiple Sclerosis: Is a Cure Possible?

Viral ImmunologyVol. 36, No. 7 EditorialFree AccessEpstein Barr Virus and Multiple Sclerosis: Is a Cure Possible?Rochelle Y. Benoit and Craig S. MooreRochelle Y. BenoitDivision of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.Search for more papers by this author and Craig S. MooreAddress correspondence to: Prof. Craig S. Moore, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, NL, Canada A1B 3V6 E-mail Address: [email protected]Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.Search for more papers by this authorPublished Online:15 Sep 2023https://doi.org/10.1089/vim.2023.0109AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Acquiring autoimmunity requires combinatorial factors that arise from both genetic influences and specific triggering events associated with the environment (Getts et al., 2013; Olsson et al., 2017). In this process, an individual's immune system develops antibodies that incidentally recognize self-antigen and elicit damage, thereby resulting in the development of certain diseases, including rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (MS) (Szekanecz et al., 2021).MS has long been debated regarding whether it meets the criteria of an autoimmune disease; however, most evidence supports this theory as it has both environmental and genetic predispositions, followed by the development of auto-antibodies targeting myelin antigens within the central nervous system (CNS) (Barkhane et al., 2022).Although the exact cause of MS is unknown, there is strong evidence to support that MS arises through an “Outside-In” theory (Morgan et al., 2020; Titus et al., 2020). This “Outside-In” concept suggests a role for molecular mimicry whereby a stimulus or antigen within the periphery activates the immune system and results in the generation of B cells that produce antibodies against a target/epitope that resembles myelin antigens (Morgan et al., 2020; Titus et al., 2020). The interplay of the periphery and CNS is complex, and although the presumed initial peripheral immune stimulus has yet to be identified in MS, autoreactivity toward CNS myelin epitopes has been well documented (Titus et al., 2020).Despite this mechanism not being clear, a scientific consensus is building, whereby antigen presenting cells such as monocytes, B cells, and dendritic cells target invading viruses in the periphery and present specific viral antigens to T cells. Within the CNS, T cells (both Th1 and Th17) and B cells are activated by recognizing endogenous myelin antigens through molecular mimicry and produce proinflammatory cytokines (tumor necrosis factor [TNF], interleukin (IL)-6, IL-18, and IL-1β, which leads to neuroinflammation, demyelination, and axonal injury (Bhat and Steinman, 2009).Though the immune system recognizes bacteria, parasites, viruses, and protozoans, one virus, in particular, has been given credit for the potential development (or cause) of MS, Epstein Barr Virus (EBV) (Burnard et al., 2017; Soldan and Lieberman, 2023). EBV is a form of herpesvirus (HHV-4) that infects >95% of the world's population. Transmission is primarily through saliva, and the normally asymptomatic infection often occurs in early to late adolescent years (Bu et al., 2022). EBV enters the cell through fusion with the membrane or through endocytosis.Once moved through the cytoplasm into the nucleus, the virus will either undergo lytic replication to produce more virus or enter a latency state during which no viral progeny is produced (Damania et al., 2022). During the various stages of latency, many viral gene products are produced, such as Epstein Barr nuclear antigens (EBNAs) and latent membrane proteins (Damania et al., 2022). The EBNAs are the key players in sharing similar sequence and/or structural homology with myelin proteins (Fanelli et al., 2022; Jog et al., 2020).EBNA1 shares an amino acid sequence with glial cell adhesion molecule (GlialCAM) along residues 386–405, and an amino acid sequence with myelin basic protein including residues 411–426; both capable of eliciting an IgG immune response (Soldan and Lieberman, 2023). The mimicry between the EBNA1 and MS-related proteins provides reason to believe that EBV infection could be a precursor to the development of MS.Owing to speculation that EBV might be the main contributing factor or cause of MS, a longitudinal study following military personnel was conducted to search for a potential correlation between the development of MS and prior EBV infection. A 20-year-long analysis from 1993 to 2013 followed ethnically diverse individuals and availed of serum samples that had been taken for routine HIV testing. There was an 83.1% male to 15.9% female division within the cohort (Bjornevik et al., 2022), which could be a potential limitation as this is not an accurate representation of the epidemiology of MS in the real world, given women are typically three times more likely to develop MS than men (Harbo et al., 2013).The study identified 955 MS diagnoses out of the 10 million young adults sampled. The authors reported a 32-fold increase in the risk of MS after EBV infection (Bjornevik et al., 2022). Not only was there a marked increase in the incidence of MS, but the levels of neurofilament light chain (NfL), a marker of axonal damage in the CNS, were also significantly elevated (Kouchaki et al., 2021). NfL levels remained similar between MS patients and controls before EBV infection; however, serum tests post-EBV infection showed a significant increase in this axonal injury marker (Bjornevik et al., 2022).Although the exact mechanistic role of EBV in MS development is unclear, there is evidence of molecular mimicry between the CNS GlialCAM and EBNA1, which was discovered using an in vivo model of MS, experimental autoimmune encephalomyelitis (Lanz et al., 2022). Using this model, it was demonstrated that EBNA1 immunization increased disease incidence. Furthermore, an EBNA1–GLialCAM cross-reactive antibody was discovered through sequence analysis, whereby CSF-derived mAb targeting revealed the molecular mimicry of EBNA1 to GlialCAM, thus demonstrating a mechanistic link between EBV and MS pathology (Lanz et al., 2022).Beyond the cross-reactive antibody interaction, a potential role for T cells is also an important factor to consider due to their involvement in the pathogenesis of MS (Bhat and Steinman, 2009). In a study involving 1,395 MS patients (including 35 monozygotic MS twin pairs) and 887 controls, the authors investigated the peripheral blood T cells and their exposure to EBV. In healthy controls, EBV-specific T cells were of effector phenotype in both the periphery and CNS, whereas individuals with MS had EBV-specific T cells in the CNS that were of a memory phenotype. The authors, therefore, suggested that T cells were already primed for the virus, providing a rationale for the involvement of EBV inducing autoreactivity in an MS patient CNS environment (Schneider-Hohendorf et al., 2022).Given the precedence of EBV infection, a therapy or preventative method against EBV may be an appropriate goal to eliminate MS. There are currently no vaccines available to combat the effects of EBV, however, given that the major cells involved in EBV replication are B cells and epithelial cells, there are targetable proteins that mediate entry into replicating cells (Wei et al., 2022). The glycolytic protein target gH/gL/gp42 was assembled into a nanoparticle through the addition of bacterial ferritin.Mice, ferrets, and nonhumanized primates receiving the vaccine generated neutralizing antibodies capable of blocking EBV entry into both the B cells and epithelial cells (Wei et al., 2022). A humanized version of the vaccine was created after a passive transfer of IgG from mice vaccinated with the glycolytic protein nanoparticle. Data showed that all control animals were infected, but there was no evidence of EBV in immunized animals, thus supporting a potential vaccine prevention strategy (Wei et al., 2022).There is strong evidence that EBV has a causative connection to MS, yet it still may be premature to conclude that EBV is the true cause. The high rates of self-mimicry by EBV antigens such as EBNA1 still need to be further investigated. Owing to the conserved amino acid regions of EBV antigens and myelin proteins, there is potential for therapy development targeting the immune-associated memory of EBV. One thing to consider is the timeline of developing an EBV vaccine to prevent MS. There is an ongoing phase 1 clinical trial in which the primary outcome is to evaluate the safety of the vaccine in youth aged 12–18 years who are EBV seronegative (Moderna Clinical Trials Support Center, 2023).Beyond determining whether the vaccine is preventative against EBV progression, additional steps will be required to assess the development of MS in the future. Longitudinal studies would have to follow the vaccinated youth over their lifetime to monitor whether they were to ever develop the autoimmune condition. The rationale to use the vaccine in all youth to prevent MS development will take extensive research, as we know there are many other factors, including comorbidities, that contribute to the development of MS.Author Disclosure StatementNo competing financial interests exist.Funding InformationNo funding was received for this article.ReferencesBarkhane Z, Elmadi J, Satish Kumar L, et al., Multiple sclerosis and autoimmunity: A veiled relationship. 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Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 36Issue 7Sep 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Rochelle Y. Benoit and Craig S. Moore.Epstein Barr Virus and Multiple Sclerosis: Is a Cure Possible?.Viral Immunology.Sep 2023.435-437.http://doi.org/10.1089/vim.2023.0109Published in Volume: 36 Issue 7: September 15, 2023PDF download