{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:34:02Z","timestamp":1793158442361,"version":"4.5.0"},"reference-count":83,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T00:00:00Z","timestamp":1717632000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT093580MA"],"award-info":[{"award-number":["WT093580MA"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000381","name":"Multiple Sclerosis Society","doi-asserted-by":"publisher","award":["981\/12"],"award-info":[{"award-number":["981\/12"]}],"id":[{"id":"10.13039\/501100000381","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and <jats:italic>HLA-DRB1*15<\/jats:italic>:<jats:italic>01<\/jats:italic>. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined <jats:italic>ex vivo<\/jats:italic> by intracellular cytokine staining (ICS) and cross-reactivity of <jats:italic>in vitro<\/jats:italic>-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 <jats:italic>p = 0<\/jats:italic>.<jats:italic>0079<\/jats:italic>, VCA <jats:italic>p = 0<\/jats:italic>.<jats:italic>0298<\/jats:italic>) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 <jats:italic>p = 0<\/jats:italic>.<jats:italic>042<\/jats:italic> and EBNA3 <jats:italic>p = 0<\/jats:italic>.<jats:italic>005<\/jats:italic>). In <jats:italic>ex vivo<\/jats:italic> assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.ppat.1012177","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T17:58:27Z","timestamp":1717696707000},"page":"e1012177","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":27,"title":["Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis"],"prefix":"10.1371","volume":"20","author":[{"given":"Olivia G.","family":"Thomas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey A.","family":"Haigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Croom-Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Leese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Van Wijck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Douglas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Rickinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill M.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4807-2797","authenticated-orcid":true,"given":"Graham S.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"issue":"14","key":"ppat.1012177.ref001","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1177\/1352458520970841","article-title":"Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition","volume":"26","author":"C Walton","year":"2020","journal-title":"Mult Scler"},{"issue":"4","key":"ppat.1012177.ref002","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S1474-4422(14)70305-9","article-title":"Role of the innate and adaptive immune responses in the course of multiple sclerosis","volume":"14","author":"B Hemmer","year":"2015","journal-title":"Lancet Neurol"},{"issue":"1","key":"ppat.1012177.ref003","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nrneurol.2016.187","article-title":"Interactions between genetic, lifestyle 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