anti-ALDH4A1 autoreactive B cells accumulate as age associated B cells and expand in atherosclerosis

anti-ALDH4A1 autoreactive B cells accumulate as age associated B cells and expand in atherosclerosis | 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 anti-ALDH4A1 autoreactive B cells accumulate as age associated B cells and expand in atherosclerosis Almudena R. Ramiro This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8711437/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 Autoreactive antibodies are the hallmark of many autoimmune diseases. Atherosclerosis is a disease of the arteries that underlies most cardiovascular deaths and has a strong autoimmune component. Some atherosclerosis-associated antibodies can have protective roles, such as those recognizing oxidized low-density lipoprotein or the ALDH4A1 mitochondrial protein. However, whether autoreactive atherosclerosis antibodies arise from B cells that escape tolerance checkpoints or from responses to disease-induced neo-epitopes not subject to central tolerance, is not known. Here we have addressed this question by generating a BCR mouse model expressing A12, an atherosclerosis-associated antibody recognizing ALDH4A1 (IghA12/+ mice). We found that the majority of A12-expressing cells are subject to classical tolerance checkpoints. Peripheral A12-expressing cells accumulated as aged-associated B cells (ABC), a subset of memory-like B cells linked to age and autoimmune diseases, and efficiently differentiated into anti-ALDH4A1 antibody-secreting plasma cells. Finally, induction of atherosclerosis in IghA12/+ mice promoted expansion of A12-expressing cells and increased A12 antibody titers. Collectively, our work identifies a mechanistic link between autoimmunity, atherosclerosis, and ageing through the generation and expansion of ABCs. Biological sciences/Immunology/Autoimmunity Biological sciences/Immunology/Lymphocytes/B cells Full Text Additional Declarations There is NO Competing Interest. Supplementary Files FigureSupplementary15.pdf Figure S1-S5 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-8711437","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":584437234,"identity":"6375f8e5-6d78-42d3-b192-8bafd5e83d55","order_by":0,"name":"Almudena R. 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Atherosclerosis is a disease of the arteries that underlies most cardiovascular deaths and has a strong autoimmune component. Some atherosclerosis-associated antibodies can have protective roles, such as those recognizing oxidized low-density lipoprotein or the ALDH4A1 mitochondrial protein. However, whether autoreactive atherosclerosis antibodies arise from B cells that escape tolerance checkpoints or from responses to disease-induced neo-epitopes not subject to central tolerance, is not known. Here we have addressed this question by generating a BCR mouse model expressing A12, an atherosclerosis-associated antibody recognizing ALDH4A1 (IghA12/+ mice). We found that the majority of A12-expressing cells are subject to classical tolerance checkpoints. Peripheral A12-expressing cells accumulated as aged-associated B cells (ABC), a subset of memory-like B cells linked to age and autoimmune diseases, and efficiently differentiated into anti-ALDH4A1 antibody-secreting plasma cells. Finally, induction of atherosclerosis in IghA12/+ mice promoted expansion of A12-expressing cells and increased A12 antibody titers. Collectively, our work identifies a mechanistic link between autoimmunity, atherosclerosis, and ageing through the generation and expansion of ABCs.","manuscriptTitle":"anti-ALDH4A1 autoreactive B cells accumulate as age associated B cells and expand in atherosclerosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-03 07:51:31","doi":"10.21203/rs.3.rs-8711437/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-cardiovascular-research","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcardiovascres","sideBox":"Learn more about [Nature Cardiovascular Research](https://www.nature.com/natcardiovascres/)","snPcode":"","submissionUrl":"https://mts-natcardiovascres.nature.com/cgi-bin/main.plex","title":"Nature Cardiovascular Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4a3610d1-d9d5-484e-a917-c09b05eca9e0","owner":[],"postedDate":"February 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":62172294,"name":"Biological sciences/Immunology/Autoimmunity"},{"id":62172295,"name":"Biological sciences/Immunology/Lymphocytes/B cells"}],"tags":[],"updatedAt":"2026-03-05T14:12:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-03 07:51:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8711437","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8711437","identity":"rs-8711437","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}