Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações do UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/18054 |
Resumo: | Most infected individuals by protozoan Trypanosoma cruzi is in the indeterminate form of Chagas disease (IFCD), which is characterized by the presence of a tissue inflammatory infiltrate composed by mononuclear cells which proliferate and produce pro and anti-inflammatory cytokines, even in the absence apparent morbidity. Inflammation resulting from cellular immune activation is responsible for parasite control and tissue repair. Anti-inflammatory cytokines are important to the regulation of inflammation, preventing immunity-mediated excessive tissue damage. The importance of limiting inflammation in CD is attributed mainly to the prevention of thromboembolic events triggered by infection which leades to progression to chagasic cardiomyopathy, one of the most common causes of death by CD. Purinergic signaling, mediated by ATP and adenosine, plays an important role in immune, inflammatory as vascular responses in CD. At first the inflammation, extracellular ATP works as an endogenous pro-inflammatory and immunostimulatory mediator through the activation of P2X7 receptor in the damaged cells microenvironment. On the other hand, P2Y11 and A2A receptors induce inhibitory effects mediated by ATP and adenosine, respectively, in different immune cells. The profile of serum cytokines involved in Th1, Th2 and Th17 responses was analysed by flow cytometry in order to determine the microenvironment generated by the infection during IFCD, in a study of the case-control. Considering the importance of purinergic receptors to the propagation of ATP and adenosine paracrine and/or autocrine signaling in the immune system, the expression of P2X7, P2Y11 and A2A receptors were evaluated by Real time-CRP in lymphocytes from IFCD patients (n=12) and apparently healthy subjects (control group, n=18) as well as cellular permeability induced by ATP-mediated P2X7R activation. The results showed that the serum levels of IL-2, IFN-ᵧ, IL-17 and IL-10 were not altered in patients with IFCD in relation to control group (P>0.05). However, a positive correlation was observed between TNF-α and IL-10 as well as between IFN-ᵧ and IL-4 showing a regulation of the inflammatory response during IFCD. A significant decrease in the TNF-α/IL-10 ratio was found (P<0.05), demonstrating the presence of a favorable response to control mechanisms of inflammation in IFCD patients. This result is based on the low concentrations of TNF-α in the serum from IFCD patients possibly as a result of high levels of IL-6 which would contribute to the maintenance of an anti-inflammatory response. The balance between Th1/Th2 responses was evaluated through the IFN-ᵧ/IL-4 ratio which was shown to be decreased in IFCD patients (P<0.05), favorable to IL-4 production, establishing a predominance of a Th2 response. While the gene expression of both P2X7R and P2Y11R and the cell permeability to P2X7R did not present significant changes, lower levels of A2AR gene expression in lymphocytes of IFCD patients were statistically observed (P<0.05). Together, these results suggest that an anti-inflammatory microenvironment negatively modulates the signaling pathway mediated by A2AR in lymphocytes so as to limit the immunosuppression induced by high levels of extracellular adenosine. Therefore, the adenosinergic signalling appears to play an important role in the regulation of imune, inflammatory and vascular responses in IFCD, contributing to the host-parasite balance and to control of clinical course of CD. |
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2019-08-28T13:40:41Z2019-08-28T13:40:41Z2016-08-26http://repositorio.ufsm.br/handle/1/18054Most infected individuals by protozoan Trypanosoma cruzi is in the indeterminate form of Chagas disease (IFCD), which is characterized by the presence of a tissue inflammatory infiltrate composed by mononuclear cells which proliferate and produce pro and anti-inflammatory cytokines, even in the absence apparent morbidity. Inflammation resulting from cellular immune activation is responsible for parasite control and tissue repair. Anti-inflammatory cytokines are important to the regulation of inflammation, preventing immunity-mediated excessive tissue damage. The importance of limiting inflammation in CD is attributed mainly to the prevention of thromboembolic events triggered by infection which leades to progression to chagasic cardiomyopathy, one of the most common causes of death by CD. Purinergic signaling, mediated by ATP and adenosine, plays an important role in immune, inflammatory as vascular responses in CD. At first the inflammation, extracellular ATP works as an endogenous pro-inflammatory and immunostimulatory mediator through the activation of P2X7 receptor in the damaged cells microenvironment. On the other hand, P2Y11 and A2A receptors induce inhibitory effects mediated by ATP and adenosine, respectively, in different immune cells. The profile of serum cytokines involved in Th1, Th2 and Th17 responses was analysed by flow cytometry in order to determine the microenvironment generated by the infection during IFCD, in a study of the case-control. Considering the importance of purinergic receptors to the propagation of ATP and adenosine paracrine and/or autocrine signaling in the immune system, the expression of P2X7, P2Y11 and A2A receptors were evaluated by Real time-CRP in lymphocytes from IFCD patients (n=12) and apparently healthy subjects (control group, n=18) as well as cellular permeability induced by ATP-mediated P2X7R activation. The results showed that the serum levels of IL-2, IFN-ᵧ, IL-17 and IL-10 were not altered in patients with IFCD in relation to control group (P>0.05). However, a positive correlation was observed between TNF-α and IL-10 as well as between IFN-ᵧ and IL-4 showing a regulation of the inflammatory response during IFCD. A significant decrease in the TNF-α/IL-10 ratio was found (P<0.05), demonstrating the presence of a favorable response to control mechanisms of inflammation in IFCD patients. This result is based on the low concentrations of TNF-α in the serum from IFCD patients possibly as a result of high levels of IL-6 which would contribute to the maintenance of an anti-inflammatory response. The balance between Th1/Th2 responses was evaluated through the IFN-ᵧ/IL-4 ratio which was shown to be decreased in IFCD patients (P<0.05), favorable to IL-4 production, establishing a predominance of a Th2 response. While the gene expression of both P2X7R and P2Y11R and the cell permeability to P2X7R did not present significant changes, lower levels of A2AR gene expression in lymphocytes of IFCD patients were statistically observed (P<0.05). Together, these results suggest that an anti-inflammatory microenvironment negatively modulates the signaling pathway mediated by A2AR in lymphocytes so as to limit the immunosuppression induced by high levels of extracellular adenosine. Therefore, the adenosinergic signalling appears to play an important role in the regulation of imune, inflammatory and vascular responses in IFCD, contributing to the host-parasite balance and to control of clinical course of CD.A maioria dos indivíduos infectados com o protozoário Trypanosoma cruzi encontra-se na forma indeterminada da doença de Chagas (FIDC), que é caracterizada pela presença de um infiltrado inflamatório tecidual, composto por células mononucleares que proliferam e produzem citocinas pró e anti-inflamatórias, mesmo na ausência de morbidade aparente. A inflamação, resultante da ativação do sistema imune celular, é responsável pelo controle do parasitismo e pelo reparo tecidual. Citocinas anti-inflamatórias são importantes para a regulação da inflamação, impedindo que ocorram danos teciduais exacerbados mediados pela imunidade. A importância de limitar a inflamação na DC é atribuída, principalmente, à prevenção de eventos tromboembólicos desencadeados pela infecção, o que acarreta a progressão para a cardiomiopatia chagásica, uma das maiores causas de morte da DC. A sinalização purinérgica, mediada pelo ATP e pela adenosina, desempenha importante papel nas respostas imunes, inflamatórias e vasculares na DC. No primeiro momento da inflamação, o ATP extracelular funciona como um mediador endógeno pró-inflamatório e imuno-estimulatório no microambiente de células danificadas, através da ativação do receptor P2X7. Já os receptores P2Y11 e A2A induzem efeitos inibitórios mediados pelo ATP e adenosina extracelulares, respectivamente, nas diferentes células imunes. A partir de um estudo do tipo caso-controle, foi analisado o perfil de citocinas séricas referente às respostas Th1, Th2 e Th17 por citometria de fluxo a fim de determinar o microambiente gerado pela infecção durante a FIDC. Considerando a importância dos receptores purinérgicos para a propagação das sinalizações parácrinas e/ou autócrinas do ATP e da adenosina no sistema imune, foram avaliadas as expressões dos receptores P2X7, P2Y11 e A2A em linfócitos de pacientes com FIDC (n=12) e de indivíduos saudáveis (grupo controle, n=18) por PCR em tempo real, bem como a permeabilidade celular induzida pela ligação do ATP ao receptor P2X7. Os resultados demonstraram que não há alteração nos níveis séricos de IL-2, IFN-ᵧ, IL-17 e IL-10 nos pacientes com a FIDC em relação ao grupo controle (P>0,05). No entanto, observou-se uma correlação positiva entre TNF-α e IL-10 bem como IFN-ᵧ e IL-4 demonstrando que há uma regulação da resposta inflamatória durante a FIDC. Uma diminuição significativa na relação TNF-α/IL-10 nos pacientes FIDC (P<0.05) foi encontrada, demonstrando que há uma resposta favorável aos mecanismos de controle da inflamação. Este resultado foi baseado nas baixas concentrações séricas de TNF-α nos pacientes FIDC, como possível resultado da ação dos altos níveis de IL-6 que estaria contribuindo para a manutenção da resposta anti-inflamatória. O equilíbrio das respostas Th1/Th2 foi avaliado a partir da relação IFN-ᵧ/IL-4 que mostrou estar significativamente diminuída (P<0.05) nos pacientes FIDC, sendo favorável à produção de IL-4, estabelecendo um predomínio de uma resposta Th2. Enquanto, a expressão gênica dos receptores P2X7 e P2Y11 bem como a permeabilidade celular do receptor P2X7 não apresentaram alterações significativas, uma redução na expressão gênica do receptor A2A em linfócitos dos pacientes FIDC foi observada estatisticamente (P<0.05). Em conjunto, os resultados sugerem que um microambiente anti-inflamatório modula negativamente a via de sinalização mediada pelo receptor A2A em linfócitos a fim de limitar a imunossupressão induzida por altos níveis de adenosina extracelular durante a FIDC. Portanto, a sinalização adenosinérgica parece desempenhar um papel importante na regulação das respostas imunes, inflamatórias e vasculares na FIDC, contribuindo para o equilíbrio entre o hospedeiro e o parasito bem como para o controle da evolução clínica da DC.porUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessDoença de ChagasReceptores purinérgicosLinfócitoSistema purinérgicoCitocinasChagas diseasePurinergic receptorsLymphocytePurinergic signlingCytokinesCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAAvaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de ChagasEvaluation of immune response profile and P2X7, P2Y11 and A2A receptors expression in the indeterminate form of Chagas diseaseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisLeal, Daniela Bitencourt Rosahttp://lattes.cnpq.br/3639683273462361Spanevello, Roselia Mariahttp://lattes.cnpq.br/3446031341157893Cruz, Ivana Beatrice Mânica dahttp://lattes.cnpq.br/3426369324110716http://lattes.cnpq.br/7579821337007289Souza, Viviane do Carmo Gonçalves200800000002600ebd6d0bc-4e14-43fd-8d4e-ad9ebe640af26c4ab946-b17f-49dd-af96-e6d2258f005a2c5b3e7b-5bee-4ab4-92a9-97c6a36565e33e70f8d1-28e2-435e-ae3a-51a0a48a38cdreponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGCBBT_2016_SOUZA_VIVIANE.pdfTES_PPGCBBT_2016_SOUZA_VIVIANE.pdfTese de Doutoradoapplication/pdf3372313http://repositorio.ufsm.br/bitstream/1/18054/1/TES_PPGCBBT_2016_SOUZA_VIVIANE.pdf5ff996e506715f2953453a96d8e0b420MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
dc.title.alternative.eng.fl_str_mv |
Evaluation of immune response profile and P2X7, P2Y11 and A2A receptors expression in the indeterminate form of Chagas disease |
title |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
spellingShingle |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas Souza, Viviane do Carmo Gonçalves Doença de Chagas Receptores purinérgicos Linfócito Sistema purinérgico Citocinas Chagas disease Purinergic receptors Lymphocyte Purinergic signling Cytokines CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
title_full |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
title_fullStr |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
title_full_unstemmed |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
title_sort |
Avaliação do perfil de resposta imune e da expressão dos receptores P2X7, P2Y11 e A2A na forma indeterminada da doença de Chagas |
author |
Souza, Viviane do Carmo Gonçalves |
author_facet |
Souza, Viviane do Carmo Gonçalves |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Leal, Daniela Bitencourt Rosa |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3639683273462361 |
dc.contributor.referee1.fl_str_mv |
Spanevello, Roselia Maria |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/3446031341157893 |
dc.contributor.referee2.fl_str_mv |
Cruz, Ivana Beatrice Mânica da |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/3426369324110716 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/7579821337007289 |
dc.contributor.author.fl_str_mv |
Souza, Viviane do Carmo Gonçalves |
contributor_str_mv |
Leal, Daniela Bitencourt Rosa Spanevello, Roselia Maria Cruz, Ivana Beatrice Mânica da |
dc.subject.por.fl_str_mv |
Doença de Chagas Receptores purinérgicos Linfócito Sistema purinérgico Citocinas |
topic |
Doença de Chagas Receptores purinérgicos Linfócito Sistema purinérgico Citocinas Chagas disease Purinergic receptors Lymphocyte Purinergic signling Cytokines CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Chagas disease Purinergic receptors Lymphocyte Purinergic signling Cytokines |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Most infected individuals by protozoan Trypanosoma cruzi is in the indeterminate form of Chagas disease (IFCD), which is characterized by the presence of a tissue inflammatory infiltrate composed by mononuclear cells which proliferate and produce pro and anti-inflammatory cytokines, even in the absence apparent morbidity. Inflammation resulting from cellular immune activation is responsible for parasite control and tissue repair. Anti-inflammatory cytokines are important to the regulation of inflammation, preventing immunity-mediated excessive tissue damage. The importance of limiting inflammation in CD is attributed mainly to the prevention of thromboembolic events triggered by infection which leades to progression to chagasic cardiomyopathy, one of the most common causes of death by CD. Purinergic signaling, mediated by ATP and adenosine, plays an important role in immune, inflammatory as vascular responses in CD. At first the inflammation, extracellular ATP works as an endogenous pro-inflammatory and immunostimulatory mediator through the activation of P2X7 receptor in the damaged cells microenvironment. On the other hand, P2Y11 and A2A receptors induce inhibitory effects mediated by ATP and adenosine, respectively, in different immune cells. The profile of serum cytokines involved in Th1, Th2 and Th17 responses was analysed by flow cytometry in order to determine the microenvironment generated by the infection during IFCD, in a study of the case-control. Considering the importance of purinergic receptors to the propagation of ATP and adenosine paracrine and/or autocrine signaling in the immune system, the expression of P2X7, P2Y11 and A2A receptors were evaluated by Real time-CRP in lymphocytes from IFCD patients (n=12) and apparently healthy subjects (control group, n=18) as well as cellular permeability induced by ATP-mediated P2X7R activation. The results showed that the serum levels of IL-2, IFN-ᵧ, IL-17 and IL-10 were not altered in patients with IFCD in relation to control group (P>0.05). However, a positive correlation was observed between TNF-α and IL-10 as well as between IFN-ᵧ and IL-4 showing a regulation of the inflammatory response during IFCD. A significant decrease in the TNF-α/IL-10 ratio was found (P<0.05), demonstrating the presence of a favorable response to control mechanisms of inflammation in IFCD patients. This result is based on the low concentrations of TNF-α in the serum from IFCD patients possibly as a result of high levels of IL-6 which would contribute to the maintenance of an anti-inflammatory response. The balance between Th1/Th2 responses was evaluated through the IFN-ᵧ/IL-4 ratio which was shown to be decreased in IFCD patients (P<0.05), favorable to IL-4 production, establishing a predominance of a Th2 response. While the gene expression of both P2X7R and P2Y11R and the cell permeability to P2X7R did not present significant changes, lower levels of A2AR gene expression in lymphocytes of IFCD patients were statistically observed (P<0.05). Together, these results suggest that an anti-inflammatory microenvironment negatively modulates the signaling pathway mediated by A2AR in lymphocytes so as to limit the immunosuppression induced by high levels of extracellular adenosine. Therefore, the adenosinergic signalling appears to play an important role in the regulation of imune, inflammatory and vascular responses in IFCD, contributing to the host-parasite balance and to control of clinical course of CD. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016-08-26 |
dc.date.accessioned.fl_str_mv |
2019-08-28T13:40:41Z |
dc.date.available.fl_str_mv |
2019-08-28T13:40:41Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/18054 |
url |
http://repositorio.ufsm.br/handle/1/18054 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
200800000002 |
dc.relation.confidence.fl_str_mv |
600 |
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openAccess |
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Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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