Fatal eosinophilic myocarditis develops in the absence of IFN-γ and IL-17A.
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-γ-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-γ(-/-)IL-17A(-/-) mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN-γ(-/-) mice. Surprisingly, IFN-γ(-/-)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-γ(-/-)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-γ 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.
Immunology Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Jobert G
JG
Barin
G Christian
GC
Baldeviano
Monica V
MV
Talor
Lei
L
Wu
SuFey
S
Ong
DeLisa
D
Fairweather
Djahida
D
Bedja
Natalie R
NR
Stickel
Jillian A
JA
Fontes
Ashley B
AB
Cardamone
Dongfeng
D
Zheng
Kathleen L
KL
Gabrielson
Noel R
NR
Rose
Daniela
D
Ciháková
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D024722:Cardiac Myosins / Q000276:immunology; D009202:Cardiomyopathies / Q000276:immunology; D054413:Chemokine CCL11 / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology*; D007249:Inflammation; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D009206:Myocardium / Q000276:immunology; D009220:Myositis
D015415:Biomarkers; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D020381:Interleukin-17; D007371:Interferon-gamma; D024722:Cardiac Myosins