{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:48:26Z","timestamp":1791877706222,"version":"4.3.4"},"reference-count":162,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:00:00Z","timestamp":1688601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Multiple sclerosis (MS) is characterized by the chronic inflammatory destruction of myelinated axons in the central nervous system. Several ideas have been put forward to clarify the roles of the peripheral immune system and neurodegenerative events in such destruction. Yet, none of the resulting models appears to be consistent with all the experimental evidence. They also do not answer the question of why MS is exclusively seen in humans, how Epstein-Barr virus contributes to its development but does not immediately trigger it, and why optic neuritis is such a frequent early manifestation in MS.<\/jats:p>\n               <jats:p>Here we describe a scenario for the development of MS that unifies existing experimental evidence as well as answers the above questions. We propose that all manifestations of MS are caused by a series of unfortunate events that usually unfold over a longer period of time after a primary EBV infection and involve periodic weakening of the blood\u2013brain barrier, antibody-mediated CNS disturbances, accumulation of the oligodendrocyte stress protein \u03b1B-crystallin and self-sustaining inflammatory damage.<\/jats:p>","DOI":"10.1093\/cei\/uxad075","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T18:45:57Z","timestamp":1688669157000},"page":"1-17","source":"Crossref","is-referenced-by-count":15,"title":["The pathogenesis of multiple sclerosis: a series of unfortunate events"],"prefix":"10.1093","volume":"214","author":[{"given":"Johannes M","family":"van Noort","sequence":"first","affiliation":[{"name":"Department of Pathology , Amsterdam UMC, Location VUmc, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8872-8711","authenticated-orcid":false,"given":"David","family":"Baker","sequence":"additional","affiliation":[{"name":"Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Kipp","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center , Rostock , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6169-9845","authenticated-orcid":false,"given":"Sandra","family":"Amor","sequence":"additional","affiliation":[{"name":"Department of Pathology , Amsterdam UMC, Location VUmc, Amsterdam , The Netherlands"},{"name":"Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , London , UK"},{"name":"Institute of Anatomy, Rostock University Medical Center , Rostock , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"2023121106364656300_CIT0001","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","article-title":"Multiple sclerosis","volume":"372","author":"Compston","year":"2008","journal-title":"Lancet"},{"key":"2023121106364656300_CIT0002","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/j.1749-6632.1984.tb14793.x","article-title":"Immune responses to myelin antigens in multiple sclerosis","volume":"436","author":"Lisak","year":"1984","journal-title":"Ann N Y Acad Sci"},{"key":"2023121106364656300_CIT0003","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/ni1507","article-title":"Multiple sclerosis: a complicated picture of autoimmunity","volume":"89","author":"McFarland","year":"2007","journal-title":"Nat Immunol"},{"key":"2023121106364656300_CIT0004","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41579-022-00770-5","article-title":"Epstein-Barr virus and multiple sclerosis","volume":"21","author":"Soldan","year":"2023","journal-title":"Nat Rev Microbiol"},{"key":"2023121106364656300_CIT0005","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":"2023121106364656300_CIT0006","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12967-018-1450-6","article-title":"HLA alleles modulate EBV viral load in multiple sclerosis","volume":"16","author":"Agostini","year":"2018","journal-title":"J Transl Med"},{"key":"2023121106364656300_CIT0007","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1093\/brain\/awy239","article-title":"Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis","volume":"141","author":"Baker","year":"2018","journal-title":"Brain"},{"key":"2023121106364656300_CIT0008","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1093\/brain\/awr197","article-title":"NeuroproMiSe EBV Working Group. 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":"2023121106364656300_CIT0009","doi-asserted-by":"crossref","first-page":"eadg3032","DOI":"10.1126\/sciadv.adg3032","article-title":"Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis","volume":"9","author":"Thomas","year":"2023","journal-title":"Sci Adv"},{"key":"2023121106364656300_CIT0010","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.molimm.2003.11.003","article-title":"T cell receptor cross-reactivity as a general property of T cell recognition","volume":"40","author":"Wucherpfennig","year":"2004","journal-title":"Mol 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