title: Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses.
abstract: BACKGROUND
  Chronic Chagas disease presents different clinical manifestations ranging from asymptomatic (namely indeterminate) to severe cardiac and/or digestive. Previous results have shown that the immune response plays an important role, although no all mechanisms are understood. Immunoregulatory mechanisms such as apoptosis are important for the control of Chagas disease, possibly affecting the morbidity in chronic clinical forms. Apoptosis has been suggested to be an important mechanism of cellular response during T. cruzi infection. We aimed to further understand the putative role of apoptosis in Chagas disease and its relation to the clinical forms of the disease.
  
  
  METHODS
  Apoptosis of lymphocytes, under antigenic stimuli (soluble T. cruzi antigens - TcAg) where compared to that of non-stimulated cells. Apoptosis was evaluated using the expression of annexin and caspase 3(+) by T cells and the percentage of cells positive evaluated by flow cytometry. In addition activation and T cell markers were used for the identification of TCD4(+) and TCD8(+) subpopulations. The presence of intracellular and plasma cytokines were also evaluated. Analysis of the activation status of the peripheral blood cells showed that patients with Chagas disease presented higher levels of activation determined by the expression of activation markers, after TcAg stimulation. PCR array were used to evaluate the contribution of this mechanism in specific cell populations from patients with different clinical forms of human Chagas disease.
  
  
  RESULTS
  Our results showed a reduced proliferative response associated a high expression of T CD4(+)CD62L(-) cells in CARD patients when compared with IND group and NI individuals. We also observed that both groups of patients presented a significant increase of CD4(+) and CD8(+) T cell subsets in undergoing apoptosis after in vitro stimulation with T. cruzi antigens. In CARD patients, both CD4(+) and CD8(+) T cells expressing TNF-α were highly susceptible to undergo apoptosis after in vitro stimulation. Interestingly, the in vitro TcAg stimulation increased considerably the expression of cell death TNF/TNFR superfamily and Caspase family receptors genes in CARD patients.
  
  
  CONCLUSIONS
  Taken together, our results suggest that apoptosis may be an important mechanism for the control of morbidity in T. cruzi infection by modulating the expression of apoptosis genes, the cytokine environment and/or killing of effector cells.
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil.
authors.forename: Ana Thereza
authors.initials: AT
authors.lastname: Chaves
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil.|Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Brazil.|Programa de Pós graduação em Medicina Tropical e Infectologia, Faculdade de Medicina, UFMG, Belo Horizonte, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: de Assis Silva Gomes Estanislau
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil.
authors.forename: Jacqueline Araújo
authors.initials: JA
authors.lastname: Fiuza
authors.affiliation: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil.
authors.forename: Andréa Teixeira
authors.initials: AT
authors.lastname: Carvalho
authors.affiliation: Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Brazil.
authors.forename: Karine Silvestre
authors.initials: KS
authors.lastname: Ferreira
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil.
authors.forename: Rafaelle Christine Gomes
authors.initials: RC
authors.lastname: Fares
authors.affiliation: Laboratório de Imunologia e Genômica de Parasitos, Departamento de Parasitologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Brazil.
authors.forename: Pedro Henrique Gazzinelli
authors.initials: PH
authors.lastname: Guimarães
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Brazil.
authors.forename: Elaine Maria
authors.initials: EM
authors.lastname: de Souza Fagundes
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Morato
authors.affiliation: Laboratório de Imunologia e Genômica de Parasitos, Departamento de Parasitologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Brazil.
authors.forename: Ricardo Toshio
authors.initials: RT
authors.lastname: Fujiwara
authors.affiliation: Programa de Pós graduação em Medicina Tropical e Infectologia, Faculdade de Medicina, UFMG, Belo Horizonte, Brazil.
authors.forename: Manoel Otávio
authors.initials: MO
authors.lastname: da Costa Rocha
authors.affiliation: Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Brazil. correa@cpqrr.fiocruz.br.|Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais - INCT-DT, Minas Gerais, Brazil. correa@cpqrr.fiocruz.br.|NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Brazil. correa@cpqrr.fiocruz.br.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Correa-Oliveira
mesh_terms: D000328:Adult; D000368:Aged; D000953:Antigens, Protozoan / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D009202:Cardiomyopathies / Q000469:parasitology; D049109:Cell Proliferation; D014355:Chagas Disease / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets; D014349:Trypanosoma cruzi / Q000276:immunology / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin
keywords: Apoptosis; Caspase family; Chagas disease; Immunoregulation; T lymphocytes; TNF/TNFR superfamily; Trypanosoma cruzi