Neoantigens recognized by T and B cells are generated by aberrant mRNA splicing in lupus neutrophils

Neoantigens recognized by T and B cells are generated by aberrant mRNA splicing in lupus neutrophils | 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 Biological Sciences - Article Neoantigens recognized by T and B cells are generated by aberrant mRNA splicing in lupus neutrophils Tomas Mustelin, Rayan Najjar, Xiaoxing Wang, Farheen Shaikh, Ning Wang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7668471/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 Proteome diversity is generated through alternative mRNA splicing1. In tumors, mis-spliced transcripts that contain intronic sequences, skipped exons, or noncanonical donor/acceptor splice junctions resulting in frame-shifts are often translated into neoantigens that drive anti-tumor immunity2,3. Here we report that neutrophils from patients with systemic lupus erythematosus (SLE), unlike neutrophils from healthy donors or patients with rheumatoid arthritis, contain numerous aberrantly spliced gene transcripts, the translation of which was predicted to result in novel amino acid sequences absent in normal splice variants or any other proteins. 21 peptides derived from these novel amino acid sequences were detected by mass spectrometry on class I major histocompatibility complex (MHC) molecules in patient samples. Co-culture of patient T cells with overlapping sets of 15-mer peptides from the novel sequences resulted in the expansion of CD4 and CD8 T cells that were rapidly reactivated by them to secrete γ-interferon and IL-17. Serum from SLE patients also contained IgG autoantibodies that recognized epitopes within the novel amino acid sequences, particularly those patients predicted to harbor the corresponding cryptic splicing event. Our findings demonstrate that dysregulated mRNA splicing in SLE neutrophils generates neoantigens that have caused T and B cell activation, clonal expansion, IgG class-switch, and autoimmunity. Health sciences/Diseases/Immunological disorders/Autoimmune diseases/Systemic lupus erythematosus Biological sciences/Immunology/Adaptive immunity/Cellular immunity/Antigen presentation lupus splicing neoantigen neutrophils T cell activation autoimmunity Full Text Additional Declarations Yes there is potential Competing Interest. TM reports consulting fees from Cugene, Evolved, Codify, and Rome Therapeutics. He serves on the Scientific Advisory Board of the Tri-Institutional Drug Discovery Institute (non-profit), and the University of Copenhagen LEO Skin Immunology Centre (non-profit). Supplementary Files Supplementalmaterial.pdf Neoantigens recognized by T and B cells are generated by aberrant mRNA splicing in lupus neutrophils 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7668471","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":520615294,"identity":"08ff3f92-2f61-432c-b7ef-b25e88ee5c94","order_by":0,"name":"Tomas 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In tumors, mis-spliced transcripts that contain intronic sequences, skipped exons, or noncanonical donor/acceptor splice junctions resulting in frame-shifts are often translated into neoantigens that drive anti-tumor immunity2,3. Here we report that neutrophils from patients with systemic lupus erythematosus (SLE), unlike neutrophils from healthy donors or patients with rheumatoid arthritis, contain numerous aberrantly spliced gene transcripts, the translation of which was predicted to result in novel amino acid sequences absent in normal splice variants or any other proteins. 21 peptides derived from these novel amino acid sequences were detected by mass spectrometry on class I major histocompatibility complex (MHC) molecules in patient samples. Co-culture of patient T cells with overlapping sets of 15-mer peptides from the novel sequences resulted in the expansion of CD4 and CD8 T cells that were rapidly reactivated by them to secrete γ-interferon and IL-17. Serum from SLE patients also contained IgG autoantibodies that recognized epitopes within the novel amino acid sequences, particularly those patients predicted to harbor the corresponding cryptic splicing event. Our findings demonstrate that dysregulated mRNA splicing in SLE neutrophils generates neoantigens that have caused T and B cell activation, clonal expansion, IgG class-switch, and autoimmunity.","manuscriptTitle":"Neoantigens recognized by T and B cells are generated by aberrant mRNA splicing in lupus neutrophils","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 10:26:51","doi":"10.21203/rs.3.rs-7668471/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"995897a6-58ee-4630-8eee-e2a966c39f8b","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":55340443,"name":"Health sciences/Diseases/Immunological disorders/Autoimmune diseases/Systemic lupus erythematosus"},{"id":55340444,"name":"Biological sciences/Immunology/Adaptive immunity/Cellular immunity/Antigen presentation"}],"tags":[],"updatedAt":"2026-05-10T22:40:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-26 10:26:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7668471","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7668471","identity":"rs-7668471","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}