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Cunha-Neto E.,University of Sao Paulo | Cunha-Neto E.,Institute for Investigation in Immunology III | Chevillard C.,Aix - Marseille University
Mediators of Inflammation | Year: 2014

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects ca. 10 million people worldwide. About 30% of Chagas disease patients develop chronic Chagas disease cardiomyopathy (CCC), a particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic. Mortality rate is higher than that of noninflammatory cardiomyopathy. CCC heart lesions present a Th1 T-cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Data suggest that the myocarditis plays a major pathogenetic role in disease progression. Major unmet goals include the thorough understanding of disease pathogenesis and therapeutic targets and identification of prognostic genetic factors. Chagas disease thus remains a neglected disease, with no vaccines or antiparasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed. Both familial aggregation of CCC cases and the fact that only 30% of infected patients develop CCC suggest there might be a genetic component to disease susceptibility. Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC. In this paper, we will review the immunopathogenesis and genetics of Chagas disease, highlighting studies that shed light on the differential progression of Chagas disease patients to CCC. © 2014 Edecio Cunha-Neto and Christophe Chevillard. Source

Doimo N.T.S.,University of Sao Paulo | Zarate-Blades C.R.,University of Sao Paulo | Zarate-Blades C.R.,U.S. National Institutes of Health | Rodrigues R.F.,University of Sao Paulo | And 12 more authors.
Human Vaccines and Immunotherapeutics | Year: 2014

Despite substantial efforts in recent years toward the development of new vaccines and drugs against tuberculosis (TB), success has remained elusive. Immunotherapy of TB with mycobacterial Hsp65 as a DNA vaccine (DNA-hsp65) results in a reduction of systemic bacterial loads and lung tissue damage, but the high homology of Hsp65 with the mammalian protein raises concern that pathological autoimmune responses may also be triggered. We searched for autoimmune responses elicited by DNA-hsp65 immunotherapy in mice chronically infected with TB by evaluating the humoral immune response and comprehensive histopathology using stereology. Cross-reactive antibodies between mycobacterial and mammalian Hsp60/65 were detected; however, no signs of pathological autoimmunity were found up to 60 days after the end of the therapy. © 2014 Landes Bioscience. Source

Bossa A.S.,University of Sao Paulo | Salemi V.M.C.,University of Sao Paulo | Ribeiro S.P.,University of Sao Paulo | Rosa D.S.,Federal University of Sao Paulo | And 6 more authors.
PLoS ONE | Year: 2014

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. Flowever, 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-a, 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-a were significantly higher than those of controls. Plasma levels of such cytokines positively correlated with each other. Conciusions/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. © 2014 Bossa et al. Source

Ferreira L.R.P.,University of Sao Paulo | Ferreira L.R.P.,Institute for Investigation in Immunology III | Frade A.F.,University of Sao Paulo | Frade A.F.,Institute for Investigation in Immunology III | And 17 more authors.
International Journal of Cardiology | Year: 2014

Background/methods Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi, and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs in myocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified. Results We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways. Conclusion These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools. © 2014 Elsevier Ireland Ltd. All rights reserved. Source

Abel L.C.J.,University of Sao Paulo | Ferreira L.R.P.,University of Sao Paulo | Ferreira L.R.P.,Institute for Investigation in Immunology III | Cunha Navarro I.,University of Sao Paulo | And 11 more authors.
Mediators of Inflammation | Year: 2014

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-γ secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products - like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins) - are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-γ primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-γ. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins. © 2014 Lúcia Cristina Jamli Abel et al. Source

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