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Previous issue date: 2013-12-20 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Nutritional status is an important determinant to the response against Leishmania infection, although few studies have characterized the molecular basis for the association found between malnutrition and the disease. Vitamin A supplementation has long been used in developing countries to prevent mortality by diarrheal and respiratory diseases, but there are no studies on the role of vitamin A in Leishmania infection, although we and others have found vitamin A deficiency in visceral Leishmaniasis (VL). Regulatory T cells are induced in vitro by vitamin A metabolites and are considered important cells implicated T CD4+ cell suppression in human VL. This work aimed to examine the correlation of nutritional status and the effect of vitamin A in the response against Leishmania infantum infection. A total of 179 children were studied: 31 had active VL, 33 VL history, 44 were DTH+ and 71 were DTH- and had negative antibody to Leishmania (DTH-/Ac-). Peripheral blood monuclear cells were isolated in a subgroup of 10 active VL and 16 DTH-/Ac- children and cultivated for 20h under 5 different conditions: 1) Medium, 2) Soluble promastigote L. infantum antigens (SLA), 3) All-trans retinoic acid (ATRA), 4) SLA + ATRA and 5) Concanavalin A. T CD4+CD25highFoxp3+, T CD4+CD25-Foxp3- and CD14+ monocytes were stained and studied by flow cytometry for IL-10, TGF-β and IL-17 production. Nutritional status was compromised in VL children, which presented lower BMI/Age and retinol concentrations when compared to healthy controls. We found a negative correlation between nutritional status (measured by BMI/Age and serum retinol) and anti-Leishmania antibodies and acute phase proteins. There was no correlation between nutritional status and parasite load. ATRA presented a dual effect in Treg cells and monocytes: In healthy children (DTH-/Ac-), it induced a regulatory response, increasing IL-10 and TGF-β production; in VL children it modulated the immune response, preventing increased IL-10 production after SLA stimulation. Furthermore, we found a positive correlation between BMI/Age and IL-17 production and negative correlation between serum retinol and IL-10 and TGF-β production in T CD4+CD25highFoxp3+ cells after SLA stimulus. Our results show a potential dual role of vitamin A in the immune system: improvement of regulatory profile during homeostasis and down modulation of IL-10 in Treg cells and monocytes during symptomatic VL. Therefore, the use of vitamin A concomitant to VL therapy might improve recovery from disease status in Leishmania infantum infection / O estado nutricional ? importante determinante da resposta ? infec??o por Leishmania. No entanto, s?o poucos os trabalhos que caracterizem as bases moleculares das associa??es encontradas entre a desnutri??o e a doen?a. A suplementa??o de vitamina A ? utilizada em pa?ses em desenvolvimento para reduzir a mortalidade por diarreia e doen?as respirat?rias. Apesar disso, n?o existem estudos sobre o papel da vitamina A na infec??o por Leishmania apesar de nosso grupo e outros terem demonstrando a defici?ncia de vitamina A durante a leishmaniose visceral (LV). As c?lulas T regulat?rias s?o consideradas c?lulas supressoras durante a LV e s?o induzidas por metab?litos de vitamina A. Este trabalho teve como objetivo verificar a correla??o do estado nutricional e o efeito da vitamina A na resposta frente ? infec??o por Leishmania infantum. Foram estudadas 179 crian?as, sendo 31 casos de LV ativa, 33 com hist?ria pregressa de LV, 44 DTH+ e 71 DTH- e Anticorpo anti-Leishmania negativo (DTH-/Ac-). C?lulas mononucleadas de sangue perif?rico foram isoladas em um subgrupo de 10 crian?as com LV e 16 DTH-/Ac-, sendo cultivadas por 20h sob as seguintes condi??es: 1) Meio, 2) Ant?genos sol?veis de promastigotas de L. infantum (SLA), 3) ?cido all-trans retin?ico (ATRA), 4) SLA + ATRA e 5) Concanavalina A. As c?lulas T CD4+CD25highFoxp3+, T CD4+CD25-Foxp3- e mon?citos CD14+ foram marcadas e estudadas por citometria de fluxo quanto ? produ??o de IL-10, TGF-β e IL-17. O estado nutricional apresentou-se comprometido nas crian?as com LV, que apresentaram menor IMC/idade e baixas concentra??es de retinol s?rico quando comparadas aos controles sadios. Observou-se correla??o negativa entre o estado nutricional (medido por ?ndice de Massa Corporal/Idade e retinol s?rico) e anticorpos anti-Leishmania e prote?nas de fase aguda. N?o foi encontrada correla??o entre o estado nutricional e a carga parasit?ria. O ATRA apresentou efeito distinto nas c?lulas Treg e mon?citos: Em crian?as saud?veis (DTH-/Ac-), induziu resposta regulat?ria, com aumento na produ??o de IL-10 e TGF-β; e, em crian?as com LV, modulou a resposta imune, diminuindo a produ??o de IL-10 ap?s o est?mulo com SLA. Foi encontrada correla??o positiva entre o IMC/Idade e a produ??o de IL-17 e correla??o negativa entre o retinol s?rico e a produ??o de IL-10 e TGF-β nas c?luas T CD4+CD25highFoxp3+ ap?s est?mulo com SLA. Os dados deste estudo permitem concluir que o estado nutricional comprometido durante a LV ? correlacionado com a resposta imune e inflamat?ria frente ? Leishmania. Al?m disso, possivelmente, a vitamina A apresenta duplo efeito na resposta imune: em crian?as sadias, promove resposta regulat?ria; durante a LV, reduz a produ??o de IL-10 em c?lulas Treg e mon?citos. Dessa forma, o uso de vitamina A durante a LV pode promover a recupera??o de pacientes em tratamento para a doen?a
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/12575 |
| Date | 20 December 2013 |
| Creators | Maciel, Bruna Leal Lima |
| Contributors | CPF:15603016434, http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4785584A3&dataRevisao=null, Brand?o Neto, Jos?, CPF:07658281115, http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783031A0, Schwarzschild, L?cia de F?tima Campos Pedrosa, CPF:17547644449, http://lattes.cnpq.br/1863589790139155, Carvalho, Lucas Pedreira de, CPF:88323145504, http://lattes.cnpq.br/7308383096084856, Passos, Sara Tim?teo, CPF:93063083534, http://lattes.cnpq.br/1834035455867904, Jer?nimo, Selma Maria Bezerra |
| Publisher | Universidade Federal do Rio Grande do Norte, Programa de P?s-Gradua??o em Bioqu?mica, UFRN, BR, Bioqu?mica; Biologia Molecular |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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