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Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.
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“This phenomenon is particularly relevant considering recent data demonstrating that EBV infection is a necessary risk factor for MS and that cross-reactive immune responses between EBV antigens and CNS proteins may contribute to disease initiation [211, 212].”
From Insights and challenges on animal models for progressive multiple sclerosis (2026) · cites this paper as [212]
In the citing paper
“For example, type 1 diabetes mellitus was linked to enterovirus infections185 and multiple sclerosis to Epstein–Barr virus (EBV) infections186.”
From COVID-19 and cellular senescence (2023) · cites this paper as [186]
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“EBV infection preceded both the onset of symptoms and the first detectable pathological changes, suggesting that EBV is a major cause of MS (Table 2) [84].”
Timofeeva, A. M., Aulova, K. S., Mustaev, E. A., & Nevinsky, G. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26188793 · Cited by 15
“For example, infection with the Epstein–Barr virus has been linked to an over-30-fold increased risk of multiple sclerosis [9–12].”
Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis
Sorosina, M., Santoro, S., Ferrè, L., Mascia, E., Clarelli, F., Giordano, A., Cannizzaro, M., Moiola, L., Martinelli, V., Filippi, M., et al. (2023) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200093 · Cited by 13
The Role of MRI in Differentiating Demyelinating and Inflammatory (not Infectious) Myelopathies
Tamanini, J. V. G., Sabino, J. V., Cordeiro, R. A., Mizubuti, V., Villarinho, L. D. L., Duarte, J. Á., Pereira, F. V., Appenzeller, S., Damasceno, A., & Reis, F. (2023) · Seminars in Ultrasound CT and MRI · doi:10.1053/j.sult.2023.03.017 · Cited by 14
Lorrey, S., Polania, J. W., Wachsmuth, L. P., Hoyt-Miggelbrink, A. M., Tritz, Z. P., Edwards, R. M., Wolf, D. M., Johnson, A. J., Fecci, P. E., & Ayasoufi, K. (2023) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdad035 · Cited by 14
Adult‐onset depletion of sulfatide leads to axonal degeneration with relative myelin sparing
Dustin, E., McQuiston, A. R., Honke, K., Palavicini, J. P., Han, X., & Dupree, J. L. (2023) · Glia · doi:10.1002/glia.24423 · Cited by 11
Boukhvalova, M. S., Kastrukoff, L. F., & Blanco, J. C. G. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1204852 · Cited by 11
Could Mathematics be the Key to Unlocking the Mysteries of Multiple Sclerosis?
Weatherley, G. R., Araujo, R. P., Dando, S. J., & Jenner, A. L. (2023) · Bulletin of Mathematical Biology · doi:10.1007/s11538-023-01181-0 · Cited by 13
Loonstra, F. C., de Ruiter, L. R. J., Schoonheim, M. M., Moraal, B., Strijbis, E. M. M., de Jong, B. A., & Uitdehaag, B. M. J. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51788 · Cited by 13
Tavazzi, E., Pichiecchio, A., Colombo, E., Rigoni, E., Asteggiano, C., Vegezzi, E., Masi, F., Greco, G., Bastianello, S., & Bergamaschi, R. (2023) · Viruses · doi:10.3390/v15071569 · Cited by 12
Yuan, X., Xie, L., Shi, Z., & Zhou, M. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1200157 · Cited by 12
Massey, J. C., Artuz, C. M., Dyer, Z., Jackson, K., Khoo, M., Visweswaran, M., Withers, B., Moore, J. J., Ma, D. D. F., & Sutton, I. (2023) · Clinical Immunology · doi:10.1016/j.clim.2023.109709 · Cited by 12
Modulation of Epstein-Barr-Virus (EBV)-Associated Cancers by Co-Infections
Münz, C. (2023) · Cancers · doi:10.3390/cancers15245739 · Cited by 12
Autoimmune demyelination alters hypothalamic transcriptome and endocrine function
Carver, J. J., Lau, K. M., Puckett, A. E., & Didonna, A. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-023-03006-2 · Cited by 13
“In this light, it is intriguing that Epstein–Barr virus (EBV) infection has been recently characterized as the main environmental factor for MS susceptibility [36].”
BackgroundEid, K., Bjørk, M., Gilhus, N. E., & Torkildsen, Ø. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031520 · Cited by 14
“Epstein-Barr Virus (EBV) infection is hypothesized to be a causal risk factor for MS and is associated with a 32-fold increase in MS risk [1].”
BackgroundMultiscale networks in multiple sclerosis
Kennedy, K., de Rosbo, N. K., Uccelli, A., Cellerino, M., Ivaldi, F., Contini, P., Palma, R. D., Harbo, H. F., Berge, T., Bos, S. D., et al. (2024) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1010980 · Cited by 12
Rapamycin rescues loss of function in blood-brain barrier–interacting Tregs
Baeten, P., Hamad, I., Hoeks, C., Hiltensperger, M., Wijmeersch, B. V., Popescu, V., Aly, L., Somers, V. A., Korn, T., Kleinewietfeld, M., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.167457 · Cited by 12
Shi, F., Li, S., Zhou, M., Lv, C., Li, Y., Luo, C., Liu, N., Lu, J., Tang, M., Luo, X., et al. (2024) · Journal of Medical Virology · doi:10.1002/jmv.29634 · Cited by 12
A parasite odyssey: An RNA virus concealed in Toxoplasma gondii
Gupta, P., Hiller, A., Chowdhury, J., Lim, D., Lim, D. Y., Saeij, J. P. J., Babaian, A., Rodriguez, F., Pereira, L., & Morales-Tapia, A. (2024) · Virus Evolution · doi:10.1093/ve/veae040 · Cited by 12
“The EBV-MS association has long been statistically postulated, yet clear evidence for causality was only established recently, on a background of increasing awareness of the role of neuroinflammation in neurodegeneration (Bjornevik et al. 2022; Lanz et al. 2022; Soldan and Lieberman 2023).”
BackgroundMultiple Sclerosis: Immune Cells, Histopathology, and Therapeutics
Patil, M. S., Lin, L. Y., Marsh‐Wakefield, F., James, E. J., Palendira, M., Hawke, S. H., & Grau, G. E. (2024) · Sclerosis · doi:10.3390/sclerosis2030009 · Cited by 15
Bondt, M. D., Renders, J., de Prado, P. P., Berghmans, N., Pörtner, N., Vanbrabant, L., de Oliveira, V. L. S., Duran, G., Baeten, P., Broux, B., et al. (2024) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiae160 · Cited by 15
Microglia as potential key regulators in viral-induced neuroinflammation
Ismail, F. S., Faustmann, T. J., Faustmann, P. M., & Corvace, F. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1426079 · Cited by 13
The refined Pathways to Cures Research Roadmap for multiple sclerosis cures
Bebo, B. F., Banwell, B., Whitacre, C. C., Coetzee, T., Dalgas, U., Jager, P. L. D., Pröbstel, A., Yong, V. W., Benveniste, E. N., & Thompson, A. J. (2024) · Multiple Sclerosis Journal · doi:10.1177/13524585241266483 · Cited by 12
Lünemann, J. D., Sao‐Avilés, A., Tintoré, M., Midaglia, L. S., Fissolo, N., Gutiérrez, L., Wiendl, H., Montalbán, X., & Comabella, M. (2024) · Multiple Sclerosis Journal · doi:10.1177/13524585241274571 · Cited by 12
Metadata
- Authors
- Bjornevik, K., Cortese, M., Healy, B. C., Kuhle, J., Mina, M. J., Leng, Y., Elledge, S. J., Niebuhr, D. W., Scher, A. I., Munger, K. L., & Ascherio, A.
- Affiliations
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.
- Uniformed Services University of the Health Sciences (US)
- Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Corresponding author
- Cortese, Marianna
- Munger, Kassandra L.
- Ascherio, Alberto
- ORCID
- Venue
- Science
- Published
- 2022-01-21
- Volume
- 375
- Issue
- 6578
- Pages
- 296-301
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4205972999
- Cited by
- 2,049
- References
- 51
- Citations by year
- 2026: 354 · 2025: 412 · 2024: 461 · 2023: 432 · 2022: 388
- FWCI
- 289.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke (R01NS042194, R01NS046635, R01NS103891)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Keywords
- multiple sclerosis, Epstein-Barr virus, viral etiology, neurofilament light chain, neuroaxonal degeneration, cytomegalovirus, demyelinating disease, military personnel
- MeSH terms
- Antibodies, Viral, Cytomegalovirus, Herpesvirus 4, Human, Female, Humans, Longitudinal Studies, Male, Military Personnel, Multiple Sclerosis, Risk Factors, Cohort Studies, Biomarkers, Prevalence, Neurofilament Proteins, Age of Onset, Epstein-Barr Virus Infections, Young Adult
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