{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:43:03Z","timestamp":1786470183917,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T00:00:00Z","timestamp":1625788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Current models stipulate that B cells and antibodies function during atherosclerosis in two distinct ways based on antibody isotype, where IgM is protective and IgG is inflammatory. To examine this model, we generated <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup> Aid<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice, which are unable to produce IgG antibodies due to the absence of activation-induced deaminase (AID) but maintain high plasma cholesterol due to the absence of apolipoprotein E (APOE). We saw a dramatic decrease in plaque formation in <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup> Aid<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice compared to <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice. Rigorous analysis of serum antibodies revealed both <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup><\/jats:italic> and <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup> Aid<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice had substantially elevated titers of IgM antibodies compared to C57BL\/6J controls, suggesting a more complex dynamic than previously described. Analysis of antigen specificity demonstrated that <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup> Aid<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice had elevated titers of antibodies specific to malondialdehyde-oxidized low density lipoprotein (MDA-oxLDL), which has been shown to block macrophage recruitment into plaques. Conversely, <jats:italic>ApoE<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice showed low levels of MDA-oxLDL specificity, but had antibodies specific to numerous self-proteins. We provide evidence for a hierarchical order of antibody specificity, where elevated levels of MDA-oxLDL specific IgM antibodies inhibit plaque formation. If the level of MDA-oxLDL specific IgM is insufficient, self-reactive IgM and IgG antibodies are generated against debris within the arterial plaque, resulting in increased inflammation and further plaque expansion.<\/jats:p>","DOI":"10.3389\/fimmu.2021.695220","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T11:03:53Z","timestamp":1625828633000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Auto-Antibody Production During Experimental Atherosclerosis in ApoE-\/- Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Mark A.","family":"Hutchinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Sol","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly J.","family":"Zanotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Alvarez-Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Telljohann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward G.","family":"Lakatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia J.","family":"Gearhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Maul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis","volume":"118","author":"Gimbrone","year":"2016","journal-title":"Circ Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1172\/JCI87425","article-title":"Immune Activation Caused by Vascular Oxidation Promotes Fibrosis and Hypertension","volume":"126","author":"Wu","year":"2016","journal-title":"J Clin Invest"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00719","article-title":"Perivascular Adipose Tissue Harbors Atheroprotective IgM-Producing B Cells","volume":"8","author":"Srikakulapu","year":"2017","journal-title":"Front Physiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7272","article-title":"Protective Immunity Against Atherosclerosis Carried by B Cells of Hypercholesterolemic Mice","volume":"109","author":"Caligiuri","year":"2002","journal-title":"J Clin Invest"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000039169.47943.EE","article-title":"And Linton MF. 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