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Noninvasive Assessment of Cardiac Abnormalities in Experimental Autoimmune Myocarditis by Magnetic Resonance Microscopy Imaging in the Mouse
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Cardiac myosin-Th17 responses promote heart failure in human myocarditis

Jennifer M Myers1, Leslie T Cooper2, David C Kem3

  • 1Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

JCI Insight
|July 2, 2016
PubMed

Insights

A specific immune cell (Th17) and related cytokines are key in myocarditis and heart failure. Cardiac myosin triggers this response via TLR2, suggesting IL-17A as a potential therapy.

Area of Science:

  • Immunology
  • Cardiology
  • Translational Medicine

Background:

  • Mechanisms and immune phenotypes in human myocarditis and dilated cardiomyopathy (DCM) leading to heart failure remain unclear.
  • Understanding these immune pathways is crucial for developing effective treatments for heart failure secondary to myocarditis.

Purpose of the Study:

  • To identify the specific immune cell phenotype and molecular mechanisms involved in human myocarditis and DCM.
  • To elucidate the role of cardiac myosin and Toll-like receptor 2 (TLR2) in initiating the immune response.
  • To explore potential therapeutic targets for myocarditis and heart failure.

Main Methods:

  • Analysis of immune cell populations (CD4+ T cells, Tregs) and cytokine profiles (IL-17, IL-6, TGF-β, IL-23, GM-CSF) in patients.
  • In vitro studies using CD14+ monocytes stimulated with cardiac myosin peptide ligands and TLR2.
  • Assessment of cytokine responses and the effect of anti-TLR2 antibodies.

Main Results:

  • A distinct Th17 cell immunophenotype characterized by elevated CD4+IL17+ T cells and Th17-promoting cytokines was identified in human myocarditis/DCM.
  • This Th17 phenotype correlated with cardiac myosin effects on CD14+ monocytes, TLR2 activation, and heart failure severity.
  • Low percentages of FOXP3+ regulatory T cells (Tregs) were observed, potentially contributing to disease severity.
  • Cardiac myosin-derived TLR2 ligands stimulated exaggerated Th17-related cytokine production from monocytes in vitro, which was blocked by an anti-TLR2 antibody.

Conclusions:

  • A novel mechanism in human myocarditis/DCM involves cardiac myosin TLR2 ligand stimulation of monocytes, leading to Th17-promoting cytokines and pathogenic Th17 cell development.
  • The identified Th17 immune phenotype and its link to cardiac myosin and TLR2 provide a molecular explanation for disease progression.
  • Targeting IL-17A presents a promising therapeutic strategy for managing human myocarditis and heart failure.

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