Fatal Eosinophilic Myocarditis Develops in the Absence of IFN-γ and IL-17A
Fatal Eosinophilic Myocarditis Develops in the Absence of IFN-γ and IL-17A
复制标题
DOI：
10.4049/jimmunol.1301282
复制
发表时间：
2013-10-15
影响因子：
4.4
通讯作者：
Cihakova, Daniela
中科院分区：
文献类型：
--
作者：
Barin, Jobert G.;Baldeviano, G. Christian;Cihakova, Daniela
CD4(+) T 细胞在炎症性心脏病中发挥着核心作用，这表明与 Th 细胞效应功能相关的细胞因子产物是该病理生理学的必要介质。 IFN-γ缺陷小鼠出现严重的实验性自身免疫性心肌炎（EAM），用心肌肌球蛋白肽对小鼠进行免疫，而IL-17A缺陷小鼠则得到保护，免于进展为扩张型心肌病。我们生成了 IFN-gamma-/-IL-17A(-/-) 小鼠，以评估 IL-17 信号传导是否与 IFN-gamma(-/-) 小鼠的严重 EAM 有关。令人惊讶的是，IFN-gamma-/-IL-17A(-/-) 小鼠出现了快速致命的 EAM。嗜酸性粒细胞占浸润白细胞的三分之一，将这种疾病定义为嗜酸性粒细胞性心肌炎。我们发现心脏浸润的 CD4(+) 细胞中 CCL11/eotaxin 的心脏生成增加，并且 Th2 偏差也增加。消除嗜酸性粒细胞发育可改善 IFN-gamma(-/-)2/2 IL-17A(-/-) 小鼠的存活率，证明嗜酸性粒细胞在致命性心力衰竭中的必要性。在 IFN-γ 和 IL-17A 联合缺乏的情况下产生的严重且迅速致命的自身免疫炎症构成了人类嗜酸粒细胞性心脏病的新模型。据我们所知，这也是首次证明嗜酸性粒细胞有能力在自身免疫过程中充当发病的必要介质。
CD4(+) T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with Th cell effector function as a necessary mediator of this pathophysiology. IFN-gamma-deficient mice developed severe experimental autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, whereas IL-17A-deficient mice were protected from progression to dilated cardiomyopathy. We generated IFN-gamma-/-IL-17A(-/-) mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN-gamma(-/-) mice. Surprisingly, IFN-gamma-/-IL-17A(-/-) mice developed a rapidly fatal EAM. Eosinophils constituted a third of infiltrating leukocytes, qualifying this disease as eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, as well as Th2 deviation, among heart-infiltrating CD4(+) cells. Ablation of eosinophil development improved survival of IFN-gamma(-/-)2/2 IL-17A(-/-) mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFN-gamma and IL-17A constitutes a novel model of eosinophilic heart disease in humans. This is also, to our knowledge, the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.