{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:08:50Z","timestamp":1785247730079,"version":"3.55.0"},"reference-count":110,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.<\/jats:p>","DOI":"10.3390\/ijms24087407","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T02:30:03Z","timestamp":1681785003000},"page":"7407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7977-927X","authenticated-orcid":false,"given":"Oscar-Danilo","family":"Ortega-Hernandez","sequence":"first","affiliation":[{"name":"Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol-IGTP, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-8025","authenticated-orcid":false,"given":"Eva M.","family":"Mart\u00ednez-C\u00e1ceres","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitari Germans Trias i Pujol-IGTP, Universitat Aut\u00f2noma de Barcelona, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Presas-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol-IGTP, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8643-5053","authenticated-orcid":false,"given":"Cristina","family":"Ramo-Tello","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol-IGTP, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/ana.20820","article-title":"Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis","volume":"59","author":"Thacker","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2124932","DOI":"10.1001\/jamanetworkopen.2021.24932","article-title":"Association of Infectious Mononucleosis in Childhood and Adolescence With Risk for a Subsequent Multiple Sclerosis Diagnosis Among Siblings","volume":"4","author":"Xu","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1177\/1352458511408991","article-title":"Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: A prospective study among United States military personnel","volume":"17","author":"Munger","year":"2011","journal-title":"Mult. Scler."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1001\/jama.293.20.2496","article-title":"Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis","volume":"293","author":"Levin","year":"2005","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Almohmeed, Y.H., Avenell, A., Aucott, L., and Vickers, M.A. (2013). Systematic Review and Meta-Analysis of the Sero-Epidemiological Association between Epstein Barr Virus and Multiple Sclerosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061110"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.3389\/fneur.2019.01368","article-title":"High Levels of Epstein\u2013Barr Virus Nuclear Antigen-1-Specific Antibodies and Infectious Mononucleosis Act Both Independently and Synergistically to Increase Multiple Sclerosis Risk","volume":"10","author":"Huang","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1126\/science.abj8222","article-title":"Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis","volume":"375","author":"Bjornevik","year":"2022","journal-title":"Science"},{"key":"ref_8","first-page":"e037505","article-title":"Global and regional incidence, mortality and disability-adjusted life-years for Epstein-Barr virus-attributable malignancies, 1990\u20132017","volume":"10","author":"Khan","year":"2020","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Handel, A.E., Williamson, A.J., Disanto, G., Handunnetthi, L., Giovannoni, G., and Ramagopalan, S.V. (2010). An Updated Meta-Analysis of Risk of Multiple Sclerosis following Infectious Mononucleosis. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012496"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1177\/1352458520907901","article-title":"Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors","volume":"26","author":"Jacobs","year":"2020","journal-title":"Mult. Scler."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1177\/1352458517722646","article-title":"Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis","volume":"24","author":"Rolf","year":"2018","journal-title":"Mult. Scler."},{"key":"ref_12","first-page":"e912","article-title":"Overweight\/obesity in young adulthood interacts with aspects of EBV infection in MS etiology","volume":"8","author":"Brenner","year":"2020","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1001\/jama.286.24.3083","article-title":"Epstein-Barr Virus Antibodies and Risk of Multiple Sclerosis","volume":"286","author":"Ascherio","year":"2001","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/ana.410170412","article-title":"Increased prevalence and titer of Epstein-Barr virus antibodies in patients with multiple sclerosis","volume":"17","author":"Sumaya","year":"1985","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1212\/WNL.35.3.435","article-title":"Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis","volume":"35","author":"Larsen","year":"1985","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.4103\/1673-5374.245462","article-title":"The role of Epstein-Barr virus in multiple sclerosis: From molecular pathophysiology to in vivo imaging","volume":"14","author":"Guan","year":"2019","journal-title":"Neural. Regen. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.molmed.2019.11.003","article-title":"Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies","volume":"26","author":"Pender","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41579-022-00770-5","article-title":"Epstein\u2013Barr virus and multiple sclerosis","volume":"21","author":"Soldan","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1084\/jem.20071030","article-title":"Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain","volume":"204","author":"Serafini","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1093\/brain\/awp200","article-title":"Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain","volume":"132","author":"Willis","year":"2009","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1212\/WNL.0b013e3181d865a1","article-title":"Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis","volume":"74","author":"Sargsyan","year":"2010","journal-title":"Neurology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1093\/brain\/awr197","article-title":"Epstein-Barr virus in the multiple sclerosis brain: A controversial issue--report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria","volume":"134","author":"Lassmann","year":"2011","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e466","DOI":"10.1212\/NXI.0000000000000466","article-title":"Molecular signature of Epstein-Barr virus infection in MS brain lesions","volume":"5","author":"Moreno","year":"2018","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00980-19","DOI":"10.1128\/JVI.00980-19","article-title":"Epstein-Barr Virus-Specific CD8 T Cells Selectively Infiltrate the Brain in Multiple Sclerosis and Interact Locally with Virus-Infected Cells: Clue for a Virus-Driven Immunopathological Mechanism","volume":"93","author":"Serafini","year":"2019","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1212\/WNL.55.2.178","article-title":"Association between clinical disease activity and Epstein\u2013Barr virus reactivation in MS","volume":"55","author":"Wandinger","year":"2000","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1468-1331.2007.02009.x","article-title":"Epstein\u2013Barr virus reactivation and multiple sclerosis","volume":"15","author":"Torkildsen","year":"2008","journal-title":"Eur. J. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1212\/WNL.0b013e3181aa29fe","article-title":"Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI","volume":"73","author":"Farrell","year":"2009","journal-title":"Neurology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1111\/j.1468-1331.2010.03083.x","article-title":"Anti-EBNA-1 IgG is not a reliable marker of multiple sclerosis clinical disease activity","volume":"17","author":"Ingram","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12974-017-1049-5","article-title":"Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis","volume":"15","author":"Veroni","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"22932","DOI":"10.1073\/pnas.2008523117","article-title":"A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis","volume":"117","author":"Ramesh","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e160468","DOI":"10.1172\/JCI160468","article-title":"The enigmatic links between Epstein-Barr virus infection and multiple sclerosis","volume":"132","author":"Tyler","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1191\/1352458505ms1185oa","article-title":"A randomized clinical trial of valacyclovir in multiple sclerosis","volume":"11","author":"Friedman","year":"2005","journal-title":"Mult. Scler."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.msard.2018.06.002","article-title":"A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study","volume":"24","author":"Gold","year":"2018","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e12471","DOI":"10.1172\/jci.insight.124714","article-title":"Epstein-Barr virus\u2013specific T cell therapy for progressive multiple sclerosis","volume":"3","author":"Pender","year":"2018","journal-title":"JCI. Insight"},{"key":"ref_35","unstructured":"Nantes University Hospital (2023, January 14). Trial to Assess the Safety and Feasibility of Adoptive Cell Therapy with Autologous EBV-Specific Cytotoxic T Lymphocytes (CTL) in Patients with a First Clinical Episode Highly Suggestive of Multiple Sclerosis (MS and EBV-CTL), ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02912897."},{"key":"ref_36","unstructured":"Queen Mary University of London (2023, January 14). A Phase 2 Open Label Clinical Trial to Determine the Effect of Famciclovir on Epstein-Barr Virus Activity as Measured by EBV Shedding in Saliva of Patients with Multiple Sclerosis, ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05283551."},{"key":"ref_37","first-page":"151","article-title":"EBV Persistence\u2014Introducing the Virus","volume":"390","year":"2015","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"386","DOI":"10.12688\/f1000research.10591.1","article-title":"Recent advances in understanding Epstein-Barr virus","volume":"6","author":"Stanfield","year":"2017","journal-title":"F1000Research"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"16955","DOI":"10.1073\/pnas.1902623116","article-title":"Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk","volume":"116","author":"Tengvall","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41586-022-04432-7","article-title":"Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM","volume":"603","author":"Lanz","year":"2022","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3389\/fonc.2018.00211","article-title":"Epstein-Barr Virus Epidemiology, Serology, and Genetic Variability of LMP-1 Oncogene Among Healthy Population: An Update","volume":"8","author":"Smatti","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/s41579-019-0249-7","article-title":"Latency and lytic replication in Epstein\u2013Barr virus-associated oncogenesis","volume":"17","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"a013029","DOI":"10.1101\/cshperspect.a013029","article-title":"Replication of Epstein-Barr Viral DNA","volume":"5","author":"Hammerschmidt","year":"2013","journal-title":"Cold. Spring. Harb. Perspect. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3389\/fmicb.2018.00454","article-title":"Epstein\u2013Barr Virus Acquires Its Final Envelope on Intracellular Compartments With Golgi Markers","volume":"9","author":"Nanbo","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Croft, N.P., Shannon-Lowe, C., Bell, A.I., Horst, D., Kremmer, E., Ressing, M.E., Wiertz, E.J.H.J., Middeldorp, J., Rowe, M., and Rickinson, A.B. (2009). Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000490"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1038\/emm.2014.84","article-title":"Epstein\u2013Barr virus latent genes","volume":"47","author":"Kang","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00430-018-0570-1","article-title":"Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis","volume":"208","author":"Yin","year":"2019","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13073-019-0640-z","article-title":"Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility","volume":"11","author":"Afrasiabi","year":"2019","journal-title":"Genome Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1136\/jclinpath-2019-205822","article-title":"Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors","volume":"72","author":"Kerr","year":"2019","journal-title":"J. Clin. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.msard.2018.07.041","article-title":"Epstein Barr virus shedding in multiple sclerosis: Similar frequencies of EBV in saliva across separate patient cohorts","volume":"25","author":"Holden","year":"2018","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_51","first-page":"305","article-title":"Post-transplant lymphoproliferative disorders. Cancer","volume":"165","author":"Singavi","year":"2015","journal-title":"Treat. Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Germini, D., Sall, F.B., Shmakova, A., Wiels, J., Dokudovskaya, S., Drouet, E., and Vassetzky, Y. (2020). Oncogenic Properties of the EBV ZEBRA Protein. Cancers, 12.","DOI":"10.3390\/cancers12061479"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41598-019-55850-z","article-title":"The interaction of Multiple Sclerosis risk loci with Epstein-Barr virus phenotypes implicates the virus in pathogenesis","volume":"10","author":"Afrasiabi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1101\/gr.264705.120","article-title":"Epstein-Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci","volume":"31","author":"Hong","year":"2021","journal-title":"Genome Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"103572","DOI":"10.1016\/j.ebiom.2021.103572","article-title":"The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype","volume":"71","author":"Keane","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_56","unstructured":"International Multiple Sclerosis Genetics Consortium (2019). Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science, 365, eaav7188."},{"key":"ref_57","first-page":"35","article-title":"EBNA2 and Its Coactivator EBNA-LP","volume":"391","author":"Kempkes","year":"2015","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41588-018-0102-3","article-title":"Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity","volume":"50","author":"Harley","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"R3","DOI":"10.1186\/ar4429","article-title":"Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus","volume":"16","author":"Hanlon","year":"2014","journal-title":"Arthritis. Res. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"587380","DOI":"10.3389\/fimmu.2020.587380","article-title":"Epstein-Barr Virus and Systemic Autoimmune Diseases","volume":"11","author":"Houen","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"565","DOI":"10.7150\/ijbs.24562","article-title":"Epstein-Barr virus-encoded microRNAs as regulators in host immune responses","volume":"14","author":"Wang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"695","DOI":"10.3389\/fimmu.2019.00695","article-title":"Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis?","volume":"10","author":"Hassani","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.it.2019.10.001","article-title":"Impact of Historic Migrations and Evolutionary Processes on Human Immunity","volume":"40","author":"Netea","year":"2019","journal-title":"Trends Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/eji.202048739","article-title":"The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: Impact of immunotherapies","volume":"51","author":"Samijn","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e126","DOI":"10.1038\/cti.2016.87","article-title":"Defective T-cell control of Epstein\u2013Barr virus infection in multiple sclerosis","volume":"6","author":"Pender","year":"2017","journal-title":"Clin. Transl. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1177\/1352458514536252","article-title":"Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis","volume":"20","author":"Pender","year":"2014","journal-title":"Mult. Scler."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Angelini, D.F., Serafini, B., Piras, E., Severa, M., Coccia, E.M., Rosicarelli, B., Ruggieri, S., Gasperini, C., Buttari, F., and Centonze, D. (2013). Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003220"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"103563","DOI":"10.1016\/j.msard.2022.103563","article-title":"Identification of multiple sclerosis-related genes regulated by EBV-encoded microRNAs in B cells","volume":"59","author":"Rang","year":"2022","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5194","DOI":"10.1128\/JVI.78.10.5194-5204.2004","article-title":"Acute infection with Epstein-Barr virus targets and overwhelms the peripheral memory B-cell compartment with resting, latently infected cells","volume":"78","author":"Hochberg","year":"2004","journal-title":"J. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16046","DOI":"10.1073\/pnas.1901314116","article-title":"Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection","volume":"116","author":"Buschle","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/s41598-018-36312-4","article-title":"Epstein-Barr Virus Latent Membrane Protein-1 Induces the Expression of SUMO-1 and SUMO-2\/3 in LMP1-positive Lymphomas and Cells","volume":"9","author":"Salahuddin","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Afrasiabi, A., Fewings, N.L., Schibeci, S.D., Keane, J.T., Booth, D.R., Parnell, G.P., and Swaminathan, S. (2021). The Interaction of Human and Epstein\u2013Barr Virus miRNAs with Multiple Sclerosis Risk Loci. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062927"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1177\/1073858410381531","article-title":"The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis","volume":"17","author":"Pender","year":"2011","journal-title":"Neuroscientist"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.1093\/brain\/awp312","article-title":"Does Epstein-Barr virus infection in the brain drive the development of multiple sclerosis?","volume":"132","author":"Pender","year":"2009","journal-title":"Brain"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00109-008-0421-4","article-title":"Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE","volume":"87","author":"Huizinga","year":"2009","journal-title":"J. Mol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"248ra107","DOI":"10.1126\/scitranslmed.3008879","article-title":"B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes","volume":"6","author":"Stern","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.it.2017.04.006","article-title":"The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance?","volume":"38","author":"Geginat","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1080\/08916930802024772","article-title":"Regulation and dysregulation of Epstein-Barr virus latency: Implications for the development of autoimmune diseases","volume":"41","author":"Niller","year":"2008","journal-title":"Autoimmunity"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1084\/jem.179.4.1173","article-title":"Functionally active Epstein-Barr virus-transformed follicular dendritic cell-like cell lines","volume":"179","author":"Lindhout","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41577-019-0244-2","article-title":"B cell memory: Building two walls of protection against pathogens","volume":"20","author":"Akkaya","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Styles, C.T., Bazot, Q., Parker, G.A., White, R.E., Paschos, K., and Allday, M.J. (2017). EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency. PLoS Biol., 15.","DOI":"10.1371\/journal.pbio.2001992"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Gonzalez-Quevedo, A. (2016). Trending Topics in Multiple Sclerosis, IntechOpen. Available online: https:\/\/www.intechopen.com\/chapters\/50603.","DOI":"10.5772\/61417"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"25690","DOI":"10.1073\/pnas.2012249117","article-title":"B cells reappear less mature and more activated after their anti-CD20\u2013mediated depletion in multiple sclerosis","volume":"117","author":"Nissimov","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/ana.20016","article-title":"Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion","volume":"55","author":"Barnett","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00401-016-1653-y","article-title":"An updated histological classification system for multiple sclerosis lesions","volume":"133","author":"Kuhlmann","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1097\/NEN.0000000000000082","article-title":"Epstein-barr virus in the central nervous system and cervical lymph node of a patient with primary progressive multiple sclerosis","volume":"73","author":"Serafini","year":"2014","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s12308-014-0209-0","article-title":"Detection of EBV in reactive and neoplastic lymphoproliferations in adults\u2014When and how?","volume":"7","author":"Oschlies","year":"2014","journal-title":"J. Hematop."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s00401-012-1023-3","article-title":"Tertiary lymphoid organ development coincides with determinant spreading of the myelin-specific T cell response","volume":"124","author":"Kuerten","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Hassani, A., Corboy, J.R., Al-Salam, S., and Khan, G. (2018). Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192109"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e157","DOI":"10.1093\/brain\/awq223","article-title":"Detection of Epstein-Barr virus and B-cell follicles in the multiple sclerosis brain: What you find depends on how and where you look","volume":"133","author":"Aloisi","year":"2010","journal-title":"Brain"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e030309","DOI":"10.1136\/bmjopen-2019-030309","article-title":"Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): A harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration","volume":"9","author":"Willekens","year":"2019","journal-title":"BMJ Open"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1007\/s11481-013-9470-8","article-title":"Drainage of cells and soluble antigen from the CNS to regional lymph nodes","volume":"8","author":"Laman","year":"2013","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41467-021-27887-0","article-title":"Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes","volume":"13","author":"Albayram","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e20220035","DOI":"10.1084\/jem.20220035","article-title":"Conserved meningeal lymphatic drainage circuits in mice and humans","volume":"219","author":"Jacob","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1177\/1352458520914844","article-title":"The multiple sclerosis prodrome: Emerging evidence, challenges, and opportunities","volume":"27","author":"Tremlett","year":"2021","journal-title":"Mult. Scler."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"761408","DOI":"10.3389\/fneur.2021.761408","article-title":"The Multiple Sclerosis Prodrome: Evidence to Action","volume":"12","author":"Tremlett","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"E422","DOI":"10.1503\/cmaj.171154","article-title":"Consolidated principles for screening based on a systematic review and consensus process","volume":"190","author":"Dobrow","year":"2018","journal-title":"Can. Med. Assoc. J."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1177\/1352458515587598","article-title":"Neurodegeneration in multiple sclerosis is a process separate from inflammation: Yes","volume":"21","author":"Louapre","year":"2015","journal-title":"Mult. Scler."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1177\/1352458515612244","article-title":"Neurodegeneration in multiple sclerosis is a process separate from inflammation: No","volume":"21","author":"Hutchinson","year":"2015","journal-title":"Mult. Scler."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molmed.2013.11.007","article-title":"Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis","volume":"20","author":"Witte","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_101","first-page":"15","article-title":"Targeting the signaling in Epstein\u2013Barr virus-associated diseases: Mechanism, regulation, and clinical study. Signal. Transduct","volume":"6","author":"Cao","year":"2021","journal-title":"Target. Ther."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Vernon, S.D., Whistler, T., Cameron, B., Hickie, I.B., Reeves, W.C., and Lloyd, A. (2006). Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus. BMC. Infect. Dis., 6.","DOI":"10.1186\/1471-2334-6-15"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1001\/jamaneurol.2019.3238","article-title":"Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis","volume":"77","author":"Bjornevik","year":"2020","journal-title":"JAMA. Neurol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ana.24954","article-title":"Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis","volume":"81","author":"Disanto","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e422","DOI":"10.1212\/NXI.0000000000000422","article-title":"Neurofilament light chain predicts disease activity in relapsing-remitting MS","volume":"5","author":"Varhaug","year":"2018","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1177\/13524585221114441","article-title":"Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial","volume":"28","author":"Williams","year":"2022","journal-title":"Mult. Scler."},{"key":"ref_107","unstructured":"National Institute of Allergy and Infectious Diseases (NIAID) (2023, January 14). Safety and Immunogenicity of an Epstein-Barr Virus (EBV) gp350-Ferritin Nanoparticle Vaccine in Healthy Adults with or without EBV Infection, ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04645147."},{"key":"ref_108","unstructured":"Moderna, TX Inc. (2023, January 14). A Study of an Epstein-Barr Virus (EBV) Candidate Vaccine, mRNA-1189, in 18- to 30-Year-Old Healthy Adults, ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05164094."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"103678","DOI":"10.1016\/j.msard.2022.103678","article-title":"The elimination of circulating Epstein-Barr virus infected B cells underlies anti-CD20 monoclonal antibody activity in multiple sclerosis: A hypothesis","volume":"59","author":"Berger","year":"2022","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1056\/NEJMoa1606468","article-title":"Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis","volume":"376","author":"Montalban","year":"2017","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7407\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:17:34Z","timestamp":1760123854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7407"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":110,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087407"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087407","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,17]]}}}