Myers Jennifer M, Cooper Leslie T, Kem David C, Stavrakis Stavros, Kosanke Stanley D, Shevach Ethan M, Fairweather DeLisa, Stoner Julie A, Cox Carol J, Cunningham Madeleine W
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, Florida, USA.
JCI Insight. 2016 Jun 16;1(9). doi: 10.1172/jci.insight.85851.
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 CD4IL17 T cells and Th17-promoting cytokines IL-6, TGF-, 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-, 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.
在人类心肌炎及其后遗症扩张型心肌病（DCM）中，导致疾病及后续心力衰竭的机制和免疫表型尚不清楚。在此，我们确定了人类心肌炎/DCM的一种Th17细胞免疫表型，其特征为CD4IL17 T细胞以及促进Th17细胞生成的细胞因子白细胞介素-6（IL-6）、转化生长因子-β（TGF-β）和白细胞介素-23（IL-23）水平升高，还有分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）的CD4 T细胞。Th17表型与心肌肌球蛋白对CD14单核细胞、Toll样受体2（TLR2）的作用以及心力衰竭相关。持续性心力衰竭与产生IL-17的T细胞和促进IL-17生成的细胞因子的高比例有关，而心肌炎/DCM表型中叉头框蛋白P3（FOXP3）调节性T细胞（Tregs）的比例显著降低，这可能导致疾病严重程度增加。我们证明了人类心肌炎/DCM中一种潜在的新机制，即来自人类心肌肌球蛋白的TLR2肽配体在体外刺激心肌炎CD14单核细胞产生包括TGF-β、IL-6和IL-23在内的过度的Th17相关细胞因子，而抗TLR2抗体可消除细胞因子反应。我们的转化研究解释了在人类心肌炎和心力衰竭中，免疫表型如何由心肌肌球蛋白TLR配体刺激单核细胞引发，从而产生促进Th17细胞生成的细胞因子并导致致病性Th17细胞的发育，并为将IL-17A作为一种治疗选择提供了理论依据。
