Uncovering Immune Surveillance Deficiency in B Cell-Driven Autoimmune Disease

Uncovering Immune Surveillance Deficiency in B Cell-Driven Autoimmune Disease | 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 Uncovering Immune Surveillance Deficiency in B Cell-Driven Autoimmune Disease Hui Shi, Haoyu Pan, Xiaohan Wei, Jinyi Qian, Shuyi Yu, Chenyu Fan, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5762949/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Antiphospholipid syndrome (APS) serves as a prototypical disease model for investigating immune tolerance breakdown in systemic autoimmunity of B cell. Single-cell RNA and V(D)J repertoire sequencing on paired bone marrow and peripheral blood from untreated primary APS patients enabled an integral “central-to-periphery” B cell blueprint at single-cell resolution, wherein we observed a substantial increase in B cell subsets across nearly all developmental stages. Notably, interferon pathway activation is detected throughout the B cell developmental trajectory, indicating that B cell dysregulation may originate as early as the progenitor stages. Meanwhile, APS patients exhibit sharply decreased abundance, upregulated expressions of inhibitory receptor (PD1 and LAG3), energy supply shortage and loss of mitochondria homeostasis in terminal effector T and NK cells, which collectively suggest an exhausted phenotype. This exhaustion likely impairs immune surveillance, facilitating the escape of autoreactive B cells through HLA-E-NKG2A interactions. Our research presents an in-depth immune cell atlas, and reveal early-stage interferon-driven B cell abnormalities and effector cell exhaustion as shared mechanisms in B cell-driven autoimmunity, highlighting potential therapeutic targets for immune tolerance restoration. Health sciences/Diseases/Immunological disorders/Autoimmune diseases Biological sciences/Immunology/Autoimmunity Health sciences/Pathogenesis/Immunopathogenesis/Adaptive immunity/Cellular immunity/Immunological surveillance antiphospholipid syndrome single-cell RNA sequencing interferon pathway activation B cell autoimmunity cell exhaustion Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted 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-5762949","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":401666169,"identity":"b0fec507-39b0-4c17-a565-758e81a407e4","order_by":0,"name":"Hui 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Single-cell RNA and V(D)J repertoire sequencing on paired bone marrow and peripheral blood from untreated primary APS patients enabled an integral “central-to-periphery” B cell blueprint at single-cell resolution, wherein we observed a substantial increase in B cell subsets across nearly all developmental stages. Notably, interferon pathway activation is detected throughout the B cell developmental trajectory, indicating that B cell dysregulation may originate as early as the progenitor stages. Meanwhile, APS patients exhibit sharply decreased abundance, upregulated expressions of inhibitory receptor (PD1 and LAG3), energy supply shortage and loss of mitochondria homeostasis in terminal effector T and NK cells, which collectively suggest an exhausted phenotype. This exhaustion likely impairs immune surveillance, facilitating the escape of autoreactive B cells through HLA-E-NKG2A interactions. 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