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

Nature Medicine volume 9, pages 1484–1490 (2003)Cite this article

A Corrigendum to this article was published on 01 January 2004

Abstract

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. 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.

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Figure 1: Self antigen–loaded, activated DCs induce myocarditis.
Figure 2: Cardiomyopathy after immunization with MYHC-α(614–629)-loaded DCs.
Figure 3: CD40 is essential in DC-mediated myocarditis.
Figure 4: TLR stimulation renders DCs autoaggressive.
Figure 5: Combined tissue injury and TLR activation induce myocarditis.

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Acknowledgements

This work was supported by grants from the Institute of Molecular Biotechnology and the Swiss National Foundation. 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.

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Authors and Affiliations

  1. Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 7, A-1030, Vienna, Austria

    Urs Eriksson, Romeo Ricci, Kurt Bachmaier & Josef M Penninger

  2. Department of Research and Medicine A, University Hospital, Petersgraben 4, Basel, CH-4031, Switzerland

    Urs Eriksson & Lukas Hunziker

  3. Department of Pathology, University Hospital, Rämistrasse 100, Zurich, CH-8091, Switzerland

    Michael O Kurrer

  4. The Heart & Stroke/Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Gavin Y Oudit

  5. Department of Immunology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Tania H Watts & Josef M Penninger

  6. Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistr. 27, Zurich-Schlieren, CH-8952, Switzerland

    Ivo Sonderegger & Manfred Kopf

  7. Department of Medical Biophysics, University Health Network, University of Toronto, Princess Margaret Hospital, 620 University Ave, Toronto, M5G 2C1, Ontario, Canada

    Kurt Bachmaier & Josef M Penninger

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  1. Urs Eriksson
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Correspondence to Urs Eriksson or Josef M Penninger.

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Eriksson, U., Ricci, R., Hunziker, L. et al. Dendritic cell–induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 9, 1484–1490 (2003). https://doi.org/10.1038/nm960

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