Dendritic cell–induced autoimmune heart failure requires cooperation between adaptive and innate immunity

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Here we show that dendritic cells (DCs) loaded with a heart-specific self peptide induce CD4+ T-cell-mediated myocarditis in nontransgenic mice. Toll-like receptor (TLR) stimulation, in concert with CD40 triggering of self peptide–loaded dendritic cells, was shown to be required for disease induction. After resolution of acute myocarditis, DC-immunized mice developed heart failure, and TLR stimulation of these mice resulted in relapse of inflammatory infiltrates. Injection of damaged, syngeneic cardiomyocytes also induced myocarditis in mice if TLRs were activated in vivo. DC–induced myocarditis provides a unifying theory as to how tissue damage and activation of TLRs during infection can induce autoimmunity, relapses and cardiomyopathy.","datePublished":"2003-11-16T00:00:00Z","dateModified":"2003-11-16T00:00:00Z","pageStart":"1484","pageEnd":"1490","sameAs":"https://doi.org/10.1038/nm960","keywords":["Biomedicine","general","Cancer Research","Metabolic Diseases","Infectious Diseases","Molecular 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<meta name="dc.source" content="Nature Medicine 2003 9:12"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Nature Publishing Group"/> <meta name="dc.date" content="2003-11-16"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2003 Springer Nature America, Inc."/> <meta name="dc.rights" content="2003 Springer Nature America, Inc."/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="Genetic susceptibility and autoimmunity triggered by microbial infections are factors implicated in the pathogenesis of dilated cardiomyopathy, the most common cause of heart failure in young patients. 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Here we show that dendritic cells (DCs) loaded with a heart-specific self peptide induce CD4+ T-cell-mediated myocarditis in nontransgenic mice. Toll-like receptor (TLR) stimulation, in concert with CD40 triggering of self peptide–loaded dendritic cells, was shown to be required for disease induction. After resolution of acute myocarditis, DC-immunized mice developed heart failure, and TLR stimulation of these mice resulted in relapse of inflammatory infiltrates. Injection of damaged, syngeneic cardiomyocytes also induced myocarditis in mice if TLRs were activated in vivo. 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class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Urs-Eriksson-Aff1-Aff2" data-author-popup="auth-Urs-Eriksson-Aff1-Aff2" data-author-search="Eriksson, Urs" data-corresp-id="c1">Urs Eriksson<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Romeo-Ricci-Aff1" data-author-popup="auth-Romeo-Ricci-Aff1" data-author-search="Ricci, Romeo">Romeo Ricci</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Lukas-Hunziker-Aff2" data-author-popup="auth-Lukas-Hunziker-Aff2" data-author-search="Hunziker, Lukas">Lukas Hunziker</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael_O-Kurrer-Aff3" data-author-popup="auth-Michael_O-Kurrer-Aff3" data-author-search="Kurrer, Michael O">Michael O Kurrer</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Gavin_Y-Oudit-Aff4" data-author-popup="auth-Gavin_Y-Oudit-Aff4" data-author-search="Oudit, Gavin Y">Gavin Y Oudit</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Tania_H-Watts-Aff5" data-author-popup="auth-Tania_H-Watts-Aff5" data-author-search="Watts, Tania H">Tania H Watts</a><sup class="u-js-hide"><a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ivo-Sonderegger-Aff6" data-author-popup="auth-Ivo-Sonderegger-Aff6" data-author-search="Sonderegger, Ivo">Ivo Sonderegger</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup>, </li><li class="c-article-author-list__item 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id="figure-5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5: Combined tissue injury and TLR activation induce myocarditis.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm960/MediaObjects/41591_2003_Article_BFnm960_Fig5_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm960/MediaObjects/41591_2003_Article_BFnm960_Fig5_HTML.jpg" alt="" loading="lazy" width="312" height="306"></picture></div></div></figure></div> </div> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> 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U.E. was supported by the Swiss Foundation for Medical-Biological Grants, the Novartis Foundation, AstraZeneca and the Department of Internal Medicine, Basel University Hospital. J.M.P. holds a Canada Chair in Cell Biology.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 7, A-1030, Vienna, Austria</p><p class="c-article-author-affiliation__authors-list">Urs Eriksson, Romeo Ricci, Kurt Bachmaier & Josef M Penninger</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Research and Medicine A, University Hospital, Petersgraben 4, Basel, CH-4031, Switzerland</p><p class="c-article-author-affiliation__authors-list">Urs Eriksson & Lukas Hunziker</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Pathology, University Hospital, Rämistrasse 100, Zurich, CH-8091, Switzerland</p><p class="c-article-author-affiliation__authors-list">Michael O Kurrer</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">The Heart & Stroke/Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, University Avenue, Toronto, M5G 2M9, Ontario, Canada</p><p class="c-article-author-affiliation__authors-list">Gavin Y Oudit</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Department of Immunology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada</p><p class="c-article-author-affiliation__authors-list">Tania H Watts & Josef M Penninger</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistr. 27, Zurich-Schlieren, CH-8952, Switzerland</p><p class="c-article-author-affiliation__authors-list">Ivo Sonderegger & Manfred Kopf</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Medical Biophysics, University Health Network, University of Toronto, Princess Margaret Hospital, 620 University Ave, Toronto, M5G 2C1, Ontario, Canada</p><p class="c-article-author-affiliation__authors-list">Kurt Bachmaier & Josef M Penninger</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Urs-Eriksson-Aff1-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Urs Eriksson</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item 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