and IL-17A g the Absence of IFN-Fatal Eosinophilic Myocarditis Develops in

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- g –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- g 2 / 2 IL-17A 2 / 2 mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN- g 2 / 2 mice. Surprisingly, IFN- g 2 / 2 IL-17A 2 / 2 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- g 2 / 2 IL-17A 2 / 2 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- g 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