Detailed characterization of the immune response to Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment

Detailed characterization of the immune response to Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Detailed characterization of the immune response to Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment Klara Asplund Högelin, Majid Pahlevan Kakhki, Yu Gao, Curtis Cai, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9232525/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Aim : To define the viral load and immune response to Epstein-Barr virus (EBV) in multiple sclerosis (MS) and the effect of B cell depleting therapy (BCDT). Methods : The study included healthy controls (HC) and persons with MS (pwMS). EBV viral load was quantified from whole blood DNA. Humoral immune responses were assessed in plasma, and cellular immune responses in peripheral blood mononuclear cells. T cell receptor Vβ (TCRVβ) analysis was performed on sorted blood and cerebrospinal fluid (CSF) cells. Results : EBV viral load did not differ between pwMS and HC. In contrast, distinct differences were found in both humoral and cellular EBV-specific immunity in MS. Antibodies against EBV were increased in pwMS, whereas CD8+ T cell reactivity against lytic antigens, including BZLF1, was reduced. Notably, during periods of disease activity, both CD4+ and CD8+ T cell responses to lytic antigens increased. In addition, BZLF1-specific T cell clones recognizing the peptide RAKFKQLL were the most clonally expanded population in the intrathecal compartment of a pwMS with high CSF T cell counts. BCDT reduced EBV viral load and was coupled to a pronounced reduction in CD8+ T cell responses to all lytic EBV antigens. Conclusion : These findings delineate distinct alterations in EBV-specific immunity in MS and demonstrate that BCDT modulates both viral load and T cell responses. The data support a potential role for CD8+ T cell clones targeting lytic EBV proteins in MS pathogenesis. Biological sciences/Immunology/Adaptive immunity Biological sciences/Neuroscience/Diseases of the nervous system/Multiple sclerosis Multiple sclerosis Epstein-Barr virus humoral immunity cellular immunity B cell depletion Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9232525","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":615925505,"identity":"9ba54f04-cc34-4be6-8db5-12ef752e617c","order_by":0,"name":"Klara Asplund 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Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Multiple sclerosis, Epstein-Barr virus, humoral immunity, cellular immunity, B cell depletion","lastPublishedDoi":"10.21203/rs.3.rs-9232525/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9232525/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e: To define the viral load and immune response to Epstein-Barr virus (EBV) in multiple sclerosis (MS) and the effect of B cell depleting therapy (BCDT).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The study included healthy controls (HC) and persons with MS (pwMS). EBV viral load was quantified from whole blood DNA. Humoral immune responses were assessed in plasma, and cellular immune responses in peripheral blood mononuclear cells. T cell receptor Vβ (TCRVβ) analysis was performed on sorted blood and cerebrospinal fluid (CSF) cells.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: EBV viral load did not differ between pwMS and HC. In contrast, distinct differences were found in both humoral and cellular EBV-specific immunity in MS. Antibodies against EBV were increased in pwMS, whereas CD8+ T cell reactivity against lytic antigens, including BZLF1, was reduced. Notably, during periods of disease activity, both CD4+ and CD8+ T cell responses to lytic antigens increased. In addition, BZLF1-specific T cell clones recognizing the peptide RAKFKQLL were the most clonally expanded population in the intrathecal compartment of a pwMS with high CSF T cell counts. BCDT reduced EBV viral load and was coupled to a pronounced reduction in CD8+ T cell responses to all lytic EBV antigens.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: These findings delineate distinct alterations in EBV-specific immunity in MS and demonstrate that BCDT modulates both viral load and T cell responses. The data support a potential role for CD8+ T cell clones targeting lytic EBV proteins in MS pathogenesis.\u003c/p\u003e","manuscriptTitle":"Detailed characterization of the immune response to Epstein-Barr virus in multiple sclerosis and following B cell depleting treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-02 03:34:04","doi":"10.21203/rs.3.rs-9232525/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"141c138c-30fc-4966-b0f3-c424936b963e","owner":[],"postedDate":"April 2nd, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-06T07:35:36+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-05T09:32:06+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-03T11:50:02+00:00","index":3,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65543228,"name":"Biological sciences/Immunology/Adaptive immunity"},{"id":65543229,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Multiple sclerosis"}],"tags":[],"updatedAt":"2026-04-02T03:34:04+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-02 03:34:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9232525","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9232525","identity":"rs-9232525","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}