title: Cardiac myosin-Th17 responses promote heart failure in human myocarditis.
abstract: In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF-secreting CD4+T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17-producing T cells and IL-17-promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14+monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option.
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Myers
authors.affiliation: Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Leslie T
authors.initials: LT
authors.lastname: Cooper
authors.affiliation: Department of Medicine/Endocrinology.
authors.forename: David C
authors.initials: DC
authors.lastname: Kem
authors.affiliation: Medicine/Cardiology, and.
authors.forename: Stavros
authors.initials: S
authors.lastname: Stavrakis
authors.affiliation: Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Kosanke
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
authors.affiliation: Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, Florida, USA.|Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: DeLisa
authors.initials: D
authors.lastname: Fairweather
authors.affiliation: Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stoner
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Cox
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Madeleine W
authors.initials: MW
authors.lastname: Cunningham