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

Nat Med. 2003 Dec;9(12):1484-90. doi: 10.1038/nm960. Epub 2003 Nov 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Autoantigens / administration & dosage
  • Autoimmunity*
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Antigens / metabolism
  • Cardiomyopathy, Dilated / etiology*
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / immunology*
  • Cardiomyopathy, Dilated / pathology
  • Dendritic Cells / immunology*
  • Humans
  • Immunity, Innate
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, SCID
  • Models, Immunological
  • Peptide Fragments / immunology
  • Receptors, Cell Surface / metabolism
  • Toll-Like Receptors
  • Ventricular Myosins / immunology

Substances

  • Autoantigens
  • CD40 Antigens
  • Membrane Glycoproteins
  • Peptide Fragments
  • Receptors, Cell Surface
  • Toll-Like Receptors
  • Ventricular Myosins