Myocardial Gene Expression ofT-bet,GATA-3,Ror-γt,FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

Abstract

Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence ofTrypanosoma cruziinfection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg) in CCC, NIC, and heart donor myocardial samples.Methods and Results. Quantitative PCR showed markedly upregulated expression ofIFN-γand transcription factorT-bet, and minor increases ofGATA-3;FoxP3andCTLA-4;IL-17andIL-18in CCC as compared with NIC samples. Conversely, cytokines expressed byTH2 cells (IL-4,IL-5, andIL-13) or associated with Treg (TGF-βandIL-10) were not upregulated in CCC myocardium. Expression ofTH1-related genes such asT-bet,IFN-γ, andIL-18correlated with ventricular dilation,FoxP3, andCTLA-4.Conclusions. Results are consistent with a strong localTH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+Treg cell population, which is unable to completely curb IFN-γproduction in CCC myocardium, therefore fueling inflammation.