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1.
Luciana Gabriel Nogueira Ronaldo Honorato Barros Santos Barbara Maria Ianni Alfredo Inácio Fiorelli Eliane Conti Mairena Luiz Alberto Benvenuti Amanda Frade Eduardo Donadi Fabrício Dias Bruno Saba Hui-Tzu Lin Wang Abilio Fragata Marcelo Sampaio Mario Hiroyuki Hirata Paula Buck Charles Mady Edimar Alcides Bocchi Noedir Antonio Stolf Jorge Kalil Edecio Cunha-Neto 《PLoS neglected tropical diseases》2012,6(10)
Background
Chronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium.Methods and Results
Using confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2–6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes.Conclusions
Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC. 相似文献2.
3.
Fonseca SG Moins-Teisserenc H Clave E Ianni B Nunes VL Mady C Iwai LK Sette A Sidney J Marin ML Goldberg AC Guilherme L Charron D Toubert A Kalil J Cunha-Neto E 《Microbes and infection / Institut Pasteur》2005,7(4):688-697
Chronic Chagas disease occurs in 16 million individuals chronically infected by the protozoan Trypanosoma cruzi in Latin America, and may lead to a dilated cardiomyopathy in 10-30% of patients. A vigorous cellular immune response holds parasitism in check. However, up to now, few T. cruzi proteins have been shown to be recognized by CD8+ T cells from Chagas disease patients. In this study, we designed 94 peptides derived from T. cruzi proteins cruzipain and FL-160, predicted to bind to HLA-A2 molcules. After in vitro binding assays to HLA-A*0201, 26 peptides were selected, and their recognition by PBMC from Chagas disease patients was tested with the IFN-gamma ELISPOT assay. All 26 peptides were recognized by PBMC from at least one patient. Furthermore, a tetrameric HLA-A*0201 complex built with the cruzipain 60-68 peptide that was frequently recognized in the periphery also bound to CD8+ T cells from a heart-infiltrating T cell line obtained from a single patient with Chagas disease cardiomyopathy. Thus, our results suggest that the recognition of CD8+ T cell epitopes in cruzipain and FL-160 may have a pathogenic or protective role in chronic Chagas disease. 相似文献
4.
Bosco Christiano Maciel da Silva Maria Fernanda Rios Grassi Raimundo Coutinho Rita Elizabeth Moreira Mascarenhas Viviana Nilla Olavarria Adriana Coutinho-Borgo Jorge Kalil Edecio Cunha Neto Simone Gon?alves Fonseca 《Memórias do Instituto Oswaldo Cruz》2014,109(8):999-1004
The interferon (IFN)-γ response to peptides can be a useful diagnostic marker of
Mycobacterium tuberculosis (MTB) latent infection. We identified promiscuous and
potentially protective CD4+ T-cell epitopes from the most conserved
regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2,
phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm.
Seven peptide sequences predicted to bind to multiple human leukocyte antigen
(HLA)-DR molecules were synthesised and tested with IFN-γ enzyme-linked immunospot
(ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from 16 Mantoux
tuberculin skin test (TST)-positive and 16 TST-negative healthy donors. Eighty-eight
percent of TST-positive donors responded to at least one of the peptides, compared to
25% of TST-negative donors. Each individual peptide induced IFN-γ production by PBMCs
from at least 31% of the TST-positive donors. The magnitude of the response against
all peptides was 182 ± 230 x 106 IFN-γ spot forming cells (SFC) among
TST-positive donors and 36 ± 62 x 106 SFC among TST-negative donors (p =
0.007). The response to GroEL2 (463-477) was only observed in the TST-positive group.
This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort
of individuals with latent tuberculosis (TB) to evaluate its potential to diagnose
latent TB and it may be included in ELISPOT-based IFN-γ assays to identify
individuals with this condition. 相似文献
5.
Pereira CM Franco da Silveira J Duranti M Cunha-Neto E Zingales B Castilho BA 《FEMS microbiology letters》2004,235(2):237-242
B13, one of the immunodominant antigens of Trypanosoma cruzi, is composed of repeats of a 12-amino-acid motif. Using synthetic peptides, the sequence FGQAAAGDK was previously shown to contain the B13 immunodominant epitope recognized by chagasic patients sera. To investigate the effects of neighboring sequences in the immunodominance, we tested serum recognition of two B13 sequences fused to LamB. GDKPSPFGQAAA-LamB and FGQAAAGDKPSP-LamB were recognized, respectively, by 15% and 80% of 80 sera reactive to B13 antigen. Recognition of FGQAAAGDKPSP-LamB was inhibited by AAAGDK-containing synthetic peptides. FGQAAAGDKPSP-LamB competed with a B13 recombinant protein containing 16.6 repeats for binding to chagasic antibodies. These results strengthen previous conclusions on the immunodominant epitope of B13 and provide a comparison of two methods for epitope mapping. 相似文献
6.
Aline S. Bossa Vera M. C. Salemi Susan P. Ribeiro Daniela S. Rosa Ludmila Rodrigues Pinto Ferreira Suzete C. Ferreira Anna Shoko Nishiya Charles Mady Jorge Kalil Edecio Cunha-Neto 《PloS one》2014,9(10)
Background
The participation of immune/inflammatory mechanisms in the pathogenesis of tropical endomyocardial fibrosis (EMF) has been suggested by the finding of early blood and myocardial eosinophilia. However, the inflammatory activation status of late-stage EMF patients is still unknown.Methodology/Principal findings
We evaluated pro- and anti-inflammatory cytokine levels in plasma samples from late stage EMF patients. Cytokine levels of Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-γ, Interleukin (IL)-2, IL-4, IL-6, and IL-10 were assayed in plasma samples from 27 EMF patients and compared with those of healthy control subjects. All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-α, IL-6, IL-4, and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL-10, IL-4, and TNF-α were significantly higher than those of controls. Plasma levels of such cytokines positively correlated with each other.Conclusions/Significance
The mixed pro- and anti-inflammatory/Th2circulating cytokine profile in EMF is consistent with the presence of a persistent inflammatory stimulus. On the other hand, the detection of increased levels of TNF-α may be secondary to the cardiovascular involvement observed in these patients, whereas IL-4 and IL-10 may have been upregulated as a homeostatic mechanism to buffer both production and deleterious cardiovascular effects of pro-inflammatory cytokines. Further studies might establish whether these findings play a role in disease pathogenesis. 相似文献7.
8.
Kalil J Cunha-Neto E 《Parasitology today (Personal ed.)》1997,13(9):362; author reply 362-362; author reply 363
9.
Drigo SA Cunha-Neto E Ianni B Cardoso MR Braga PE Faé KC Nunes VL Buck P Mady C Kalil J Goldberg AC 《Microbes and infection / Institut Pasteur》2006,8(3):598-603
Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-alpha in the progression of heart failure, and the increased TNF-alpha plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the -308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction相似文献
10.
Xutao Deng Ester C. Sabino Edecio Cunha-Neto Antonio L. Ribeiro Barbara Ianni Charles Mady Michael P. Busch Mark Seielstad the REDSII Chagas study group from the NHLBI Retrovirus Epidemiology Donor Study-II International Component 《PloS one》2013,8(11)