Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

Huijuan Lv, Evis Havari, Sheena Pinto, Raju V S R K Gottumukkala, Lizbeth Cornivelli, Khadir Raddassi, Takashi Matsui, Anthony Rosenzweig, Roderick T Bronson, Ross Smith, Anne L Fletcher, Shannon J Turley, Kai Wucherpfennig, Bruno Kyewski, Myra A Lipes

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)


Autoimmunity has long been linked to myocarditis and its sequela, dilated cardiomyopathy, the leading causes of heart failure in young patients. However, the underlying mechanisms are poorly defined, with most clinical investigations focused on humoral autoimmunity as the target for intervention. Here, we show that the α-isoform of myosin heavy chain (α-MyHC, which is encoded by the gene Myh6) is the pathogenic autoantigen for CD4+ T cells in a spontaneous mouse model of myocarditis. Further, we found that Myh6 transcripts were absent in mouse medullary thymic epithelial cells (mTECs) and peripheral lymphoid stromal cells, which have been implicated in mediating central and peripheral T cell tolerance, respectively. Transgenic expression of α-MyHC in thymic epithelium conferred tolerance to cardiac myosin and prevented myocarditis, demonstrating that α-MyHC is a primary autoantigen in this disease process. Remarkably, we found that humans also lacked α-MyHC in mTECs and had high frequencies of α-MyHC-specific T cells in peripheral blood, with markedly augmented T cell responses to α-MyHC in patients with myocarditis. Since α-MyHC constitutes a small fraction of MyHC in human heart, these findings challenge the longstanding notion that autoimmune targeting of MyHC is due to its cardiac abundance and instead suggest that it is targeted as a result of impaired T cell tolerance mechanisms. These results thus support a role for T cell-specific therapies for myocarditis.

Original languageEnglish
Pages (from-to)1561-73
Number of pages13
JournalJournal of Clinical Investigation
Issue number4
Publication statusPublished - Apr 2011


  • Animals
  • Autoantigens
  • Autoimmunity
  • Base Sequence
  • CD4-Positive T-Lymphocytes
  • Cardiac Myosins
  • DNA Primers
  • Disease Models, Animal
  • Female
  • HLA-DQ Antigens
  • Humans
  • Immune Tolerance
  • Infant
  • Infant, Newborn
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Myocarditis
  • Myocardium
  • Myosin Heavy Chains
  • Thymus Gland
  • Ventricular Myosins


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