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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]
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“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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BackgroundEpstein-Barr Virus in Multiple Sclerosis
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“In a notable recent case, longitudinal studies on an unprecedented scale provided a compelling causal link between the relatively common disorder multiple sclerosis and infection by Epstein-Barr virus (Bjornevik et al., 2022).”
Exploring the Pathophysiology, Diagnosis, and Treatment Options of Multiple Sclerosis
Lorenzut, S., Negro, I. D., Pauletto, G., Verriello, L., Spadea, L., Salati, C., Musa, M., Gagliano, C., & Zeppieri, M. (2025) · Journal of Integrative Neuroscience · doi:10.31083/jin25081 · Cited by 36
SP140–RESIST pathway regulates interferon mRNA stability and antiviral immunity
Witt, K. C., Dziulko, A., An, J., Pekovic, F., Cheng, A. X., Liu, G. Y., Lee, O. V., Turner, D. J., Lari, A., Gaidt, M. M., et al. (2025) · Nature · doi:10.1038/s41586-025-09152-2 · Cited by 30
Ruggieri, S., Quartuccio, M. E., & Prosperini, L. (2022) · Degenerative Neurological and Neuromuscular Disease · doi:10.2147/dnnd.s313825 · Cited by 29
Guilty by association: Epstein–Barr virus in multiple sclerosis
Bar‐Or, A., Banwell, B., Berger, J. R., & Lieberman, P. M. (2022) · Nature Medicine · doi:10.1038/s41591-022-01823-1 · Cited by 27
IFI16 Partners with KAP1 to Maintain Epstein-Barr Virus Latency
Xu, H., Li, X., Rousseau, B. A., Akinyemi, I. A., Frey, T. R., Zhou, K., Droske, L. E., Mitchell, J. A., McIntosh, M. T., & Bhaduri‐McIntosh, S. (2022) · Journal of Virology · doi:10.1128/jvi.01028-22 · Cited by 28
Evolution of functional antibodies following acute Epstein-Barr virus infection
Karsten, C. B., Bartsch, Y. C., Shin, S. A., Slein, M. D., Heller, H. M., Kolandaivelu, K., Middeldorp, J. M., Alter, G., & Jülg, B. D. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010738 · Cited by 27
Siblings reduce multiple sclerosis risk by preventing delayed primary Epstein–Barr virus infection
Rostgaard, K., Nielsen, N. M., Melbye, M., Frisch, M., & Hjalgrim, H. (2022) · Brain · doi:10.1093/brain/awac401 · Cited by 27
Immunopathogenesis, Diagnosis, and Treatment of Multiple Sclerosis
Pérez, C. A., Cuascut, F. X., & Hutton, G. J. (2022) · Neurologic Clinics · doi:10.1016/j.ncl.2022.05.004 · Cited by 33
Antigenic mimicry – The key to autoimmunity in immune privileged organs
Wildner, G. (2022) · Journal of Autoimmunity · doi:10.1016/j.jaut.2022.102942 · Cited by 32
A common mechanism links Epstein‐Barr virus infections and autoimmune diseases
Zhang, L. (2022) · Journal of Medical Virology · doi:10.1002/jmv.28363 · Cited by 27
Monaco, M. C., Soldan, S. S., Su, C., Clauze, A., Cooper, J. F., Patel, R. J., Lu, F., Hughes, R. J., Messick, T. E., Andrada, F. C., et al. (2023) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200149 · Cited by 28
Banko, A. V., Cirkovic, A. M., Mišković, R., Jeremić, I., Grk, M., Basaric, M., Lazarević, I., Rašković, S., Despotović, A., & Miljanovic, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1307589 · Cited by 27
LMP1 and EBNA2 constitute a minimal set of EBV genes for transformation of human B cells
Zhang, J., Sommermann, T. G., Li, X., Gieselmann, L., de la Rosa, K., Stecklum, M., Klein, F., Kocks, C., & Rajewsky, K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1331730 · Cited by 27
Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review
Kettunen, P., Koıstınaho, J., & Rõlova, T. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03139-y · Cited by 30
“Up to 32-fold increase in MS risk has been reported following EBV infection [8, 134, 135].”
BackgroundCantoni, C., Smirnov, R. A., Firulyova, M. M., Andhey, P. S., Bradstreet, T. R., Esaulova, E., Terekhova, M., Schwarzkopf, E. A., Abdalla, N. M., Kleverov, M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci177793 · Cited by 26
“It is intriguing to consider whether EBV, postulated to be required for the development of MS (65), may have a role in triggering an atypical memory B cell signature, or alternatively whether these cells may facilitate EBV persistence or reactivation.”
Talwar, S., Harker, J. A., Openshaw, P., & Thwaites, R. S. (2025) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2025.02.005 · Cited by 34
Podbielska, M., Ariga, T., & Pokryszko‐Dragan, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105330 · Cited by 29
Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria
Fadda, G., Waters, P. J., Woodhall, M. R., Brown, R. A., O’Mahony, J., Castro, D. A., Longoni, G., Yeh, E. A., Marrie, R. A., Arnold, D. L., et al. (2022) · Multiple Sclerosis Journal · doi:10.1177/13524585221093789 · Cited by 26
James, L. M., & Georgopoulos, A. P. (2022) · Neuroscience Insights · doi:10.1177/26331055221114817 · Cited by 27
Wagner, R., Lieckfeldt, P., Piyadasa, H., Markel, M., Riedel, J., Stefanovici, C., Peukert, N., Patel, D., Derraugh, G., Min, S. A. L., et al. (2022) · Annals of Surgery · doi:10.1097/sla.0000000000005656 · Cited by 25
Are Viral Infections Key Inducers of Autoimmune Diseases? Focus on Epstein–Barr Virus
Takei, M., Kitamura, N., Nagasawa, Y., Tsuzuki, H., Iwata, M., Nagatsuka, Y., Nakamura, H., Imai, K., & Fujiwara, S. (2022) · Viruses · doi:10.3390/v14091900 · Cited by 26
Sen, M. K., Hossain, M. J., Mahns, D. A., & Brew, B. J. (2022) · Journal of Neurology · doi:10.1007/s00415-022-11507-y · Cited by 29
DePaula-Silva, A. B. (2024) · Viruses · doi:10.3390/v16010119 · Cited by 29
“…the di ff erent roles played macrophages in each mouse model, focusing on its contribution to disease closely associated with the development of neuroin fl ammatory and neurodegenerative diseases such as multiple sclerosis (MS) [6–11], Alzheimer’s [10,12,13], epilepsy [14–25], and others [26–30].”
BackgroundInfluential
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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