title: Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease.
abstract: BACKGROUND
  Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease.
  
  
  RESULTS
  First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500).
  
  
  CONCLUSIONS
  These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.
authors.affiliation: Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal, Brazil.
authors.forename: Paulo Marcos Matta
authors.initials: PM
authors.lastname: Guedes
authors.forename: Fredy Roberto Salazar
authors.initials: FR
authors.lastname: Gutierrez
authors.forename: Grace Kelly
authors.initials: GK
authors.lastname: Silva
authors.forename: Renata
authors.initials: R
authors.lastname: Dellalibera-Joviliano
authors.forename: Gerson Jhonatan
authors.initials: GJ
authors.lastname: Rodrigues
authors.forename: Lusiane Maria
authors.initials: LM
authors.lastname: Bendhack
authors.forename: Anis
authors.initials: A
authors.lastname: Rassi
authors.forename: Anis
authors.initials: A
authors.lastname: Rassi
authors.forename: André
authors.initials: A
authors.lastname: Schmidt
authors.forename: Benedito Carlos
authors.initials: BC
authors.lastname: Maciel
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Marin Neto
authors.forename: João Santana
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015704:CD4 Antigens / Q000032:analysis; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit