Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

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Abstract

Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Aβo and HLA-DQ8.Aβo transgenic mice in NOD and HLA-DQ8.Aβo in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Aβo, the transgene negative littermates, NOD, and B10.DQ8 Aβo mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggests that NOD.DQ8 may harbor autoreactive cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for the predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.

Original languageEnglish (US)
Pages (from-to)1054-1064
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number6
DOIs
StatePublished - Jun 1 2007

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Keywords

  • Anti-myosin antibodies
  • Background genes
  • Cellular and humoral response
  • Gender bias
  • HLA transgenic mice
  • MHC polymorphism
  • Myocarditis
  • Tolerance

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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