Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome

Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome | 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 Letter Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome Rachael Bashford-Rogers, Alexander Long, Antonio Choi Chiu, Orthi Onupom, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6836742/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 Fibromyalgia syndrome (FMS) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive dysfunction, with no definitive biomarkers or mechanism-based treatments. Emerging evidence suggests that immune dysregulation may contribute to the FMS pathogenesis, particularly involving B cells, which have been implicated in autoantibody production and neuronal sensitisation. However, whether peripheral B cell tolerance, a critical safeguard against autoimmunity, is compromised in FMS remains unknown. Here, we combined high-resolution B cell receptor (BCR) repertoire sequencing, deep immunophenotyping, and functional assays in a well-characterised FMS cohort to uncover profound defects in peripheral B cell tolerance. We reveal significant defects in peripheral B cell tolerance in FMS, including: (1) impaired naïve B cell anergy, marked by elevated CD21, CD22, and CD24 expression; (2) exaggerated proliferative responses and rapid CD24 downregulation upon stimulation; and (3) altered BCR selection patterns, with increased IGHV6-1/IGHJ6 usage, skewed class switching toward IGHA1, and enhanced clonal expansion. These features closely resemble immune pathology profiles observed in classical autoimmune diseases. These findings redefine FMS as a disorder of immune dysregulation, with defective B cell tolerance contributing to disease mechanisms. The convergence of interferon-driven B cell activation, clonal expansion, and autoantibody production suggests shared pathways with classical autoimmune diseases. Our study provides a foundation for mechanism-based diagnostics and targeted immunomodulatory therapies, offering new avenues for intervention in this debilitating condition. Biological sciences/Immunology/Autoimmunity Biological sciences/Immunology/Adaptive immunity/Immune tolerance/Peripheral tolerance Health sciences/Diseases/Immunological disorders Fibromyalgia B cell tolerance autoimmunity BCR repertoire anergy immune dysregulation Full Text Additional Declarations Yes there is potential Competing Interest. R.J.M.B.-R. is a co-founder of Alchemab Therapeutics Ltd and consultant for Alchemab Therapeutics Ltd, Roche, Enara Bio, UCB and GSK. A.G. has received consultancy fees from UCB. R.J.B has received consultancy fees from UCB and BioHaven. D.P. is an employee of Immunocore Ltd. Supplementary Files SupplementalTables.xlsx Supplemental tables RawBCRsequences.zip Raw BCR sequences 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6836742","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Letter","associatedPublications":[],"authors":[{"id":472678473,"identity":"fd890cd0-a9f5-48d3-86d7-74c3a49a4cf6","order_by":0,"name":"Rachael 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D.P. is an employee of Immunocore Ltd.","formattedTitle":"Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome","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":"Fibromyalgia, B cell tolerance, autoimmunity, BCR repertoire, anergy, immune dysregulation","lastPublishedDoi":"10.21203/rs.3.rs-6836742/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6836742/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Fibromyalgia syndrome (FMS) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive dysfunction, with no definitive biomarkers or mechanism-based treatments. Emerging evidence suggests that immune dysregulation may contribute to the FMS pathogenesis, particularly involving B cells, which have been implicated in autoantibody production and neuronal sensitisation. However, whether peripheral B cell tolerance, a critical safeguard against autoimmunity, is compromised in FMS remains unknown. Here, we combined high-resolution B cell receptor (BCR) repertoire sequencing, deep immunophenotyping, and functional assays in a well-characterised FMS cohort to uncover profound defects in peripheral B cell tolerance. We reveal significant defects in peripheral B cell tolerance in FMS, including: (1) impaired naïve B cell anergy, marked by elevated CD21, CD22, and CD24 expression; (2) exaggerated proliferative responses and rapid CD24 downregulation upon stimulation; and (3) altered BCR selection patterns, with increased IGHV6-1/IGHJ6 usage, skewed class switching toward IGHA1, and enhanced clonal expansion. These features closely resemble immune pathology profiles observed in classical autoimmune diseases. These findings redefine FMS as a disorder of immune dysregulation, with defective B cell tolerance contributing to disease mechanisms. The convergence of interferon-driven B cell activation, clonal expansion, and autoantibody production suggests shared pathways with classical autoimmune diseases. Our study provides a foundation for mechanism-based diagnostics and targeted immunomodulatory therapies, offering new avenues for intervention in this debilitating condition.","manuscriptTitle":"Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 17:22:38","doi":"10.21203/rs.3.rs-6836742/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-immunology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ni","sideBox":"Learn more about [Nature Immunology](http://www.nature.com/ni/)","snPcode":"","submissionUrl":"","title":"Nature Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"eaddbb16-369e-426a-aa7e-cd2610daabde","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":50199235,"name":"Biological sciences/Immunology/Autoimmunity"},{"id":50199236,"name":"Biological sciences/Immunology/Adaptive immunity/Immune tolerance/Peripheral tolerance"},{"id":50199237,"name":"Health sciences/Diseases/Immunological disorders"}],"tags":[],"updatedAt":"2026-05-13T13:51:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-18 17:22:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6836742","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6836742","identity":"rs-6836742","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}