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Cardiac myosin-Th17 responses promote heart failure in human myocarditis
Jennifer M. Myers, … , Carol J. Cox, Madeleine W. Cunningham
Jennifer M. Myers, … , Carol J. Cox, Madeleine W. Cunningham
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e85851. https://doi.org/10.1172/jci.insight.85851.
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Research Article Immunology

Cardiac myosin-Th17 responses promote heart failure in human myocarditis

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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

Jennifer M. Myers, Leslie T. Cooper, David C. Kem, Stavros Stavrakis, Stanley D. Kosanke, Ethan M. Shevach, DeLisa Fairweather, Julie A. Stoner, Carol J. Cox, Madeleine W. Cunningham

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Figure 1

Th17 immunophenotype contributes to myocarditis and dilated cardiomyopathy (DCM).

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Th17 immunophenotype contributes to myocarditis and dilated cardiomyopat...
(A) Peripheral blood mononuclear cells (PBMCs) from myocarditis/DCM subjects (n = 28) (baseline blood sample) or healthy controls (n = 26) were stained for CD4, CD3, and IL-17 and analyzed using a flow cytometer. Mann-Whitney, P = 0.0008. (B) Representative CD3+CD4+IL-17+ Th17 FACS diagrams are shown from myocarditis/DCM (n = 2) and a healthy control (n = 1). (C) Th1 (IFN-γ+) cells were not significantly high in myocarditis/DCM as a group in baseline blood samples. PBMCs from myocarditis/DCM subjects (n = 15) and healthy controls (n = 10) were stained for CD4, CD3, and IFN-γ and analyzed using FACS. Mann-Whitney, P = 0.72. (D) IL-17A in myocarditis/DCM males (n = 27) was significantly elevated at baseline compared to myocarditis/DCM females (n = 14) and trended toward a significant interaction by case/control status. Healthy controls: males (n = 16), females (n = 8). Three male and 4 female myocarditis/DCM samples had undetectable IL-17A and were placed on the graph halfway between zero and the lowest detectable value of 1.5 pg/ml. Two-way ANOVA, P = 0.029 (gender by group interaction, P = 0.15). FACS analysis was performed on fresh PBMCs, which were analyzed immediately upon receiving the blood sample. Only 1 sample per time point was analyzed by FACS and compared to isotype controls. Cytokine analysis was performed in triplicate to determine the serum cytokine concentration.

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