Autor(es): Silva, George Allan Villarouco da
Data: 2019
Origem: Oasisbr
Assunto(s): Leishmaniose; Leishmania; Doen??as inflamat??rias da pele; Inflama????o - Aspectos imunol??gicos; CI??NCIAS BIOL??GICAS: IMUNOLOGIA; Leishmaniose Cut??nea; Resposta imune; Inflama????o; Citocinas; Marcador de Resist??ncia
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Made available in DSpace on 2019-10-16T19:17:07Z (GMT). No. of bitstreams: 4 Tese Final _ George 2019_vers??o_corrigida_p??s_defesa.pdf: 913705 bytes, checksum: bc43266c705d448235dbe7829843b617 (MD5) Carta_encaminhamento_autodeposito.pdf: 1705060 bytes, checksum: 361f95865bdb43b1d22362b2c53c471a (MD5) Ata_Defesa_Doutorado_George.pdf: 307778 bytes, checksum: aaa77d51de41fd99c547ec658192784a (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2019-09-10
CNPq - Conselho Nacional de Desenvolvimento Cient??fico e Tecnol??gico
FAPEAM - Funda????o de Amparo ?? Pesquisa do Estado do Amazonas
Cutaneous Leishmaniasis caused by Leishmania species, present an important health problem, as significant morbidity and also lethality of the most severe cases of the disease. Different clinical studies and experimental have related the involvement from inflammatory cytokines in the development of CL. Feactures of CL pathogenicity to be associated with as host immunogenetics components to determine for the outcome of the disease. We investigated whether single nucleotide polymorphisms in IL1B, IL1RN and IFNG may be associated with elevated or decreased risk in the development of the CL. Nucleotide sequencing and PCR-RFLP were performed in 881 patients with CL and 837 controls. Circulating plasma cytokines were also assayed between CL patients and control subjects. The cytokine levels of IL-1??, IL-6, IL-8, MCP-1 and IFN-?? were significantly higher in patients compared to controls (p < 0.0001), levels elevated of IL-1ra were observed among the controls. IL1B and IFNG polymorphisms are associated with CL and cytokine levels. The IL1B rs16944 C/C genotype is related with lower levels of IL-1ra and associated with susceptibility to CL (OR=1.5 [95%CI 1.1???2.0]; p=0.004). Different SNPs and microsatellite of the IFNG gene were associated with protection and susceptibility to CL, those rs2069705 T and rs2430561 T were associated for the risk to CL (OR=1.5 [95%CI 1.2-2.0]; p=0.0004 / OR=1.4 [95%CI 1.2-1.6]; p=0.0002). IFNG alleles related with risk to CL are combined into haplotype (H1), this associated with susceptibility to CL (OR=1.7 [95%CI 1.2-2.2]; p=5x10-5) and related with lower levels of IFN-??. Although, SNPs present in IL1B and IFNG may mark to the development of CL caused by Leishamania guyanensis, genetic variants are associated with the production of the IL-1??, IL-1Ra and IFN-??.
A Leishmaniose Cut??nea (LC) ?? causada por diferentes esp??cies de protozo??rios Leishmania, apresenta importante impacto na sa??de p??blica, com significante morbidade e tamb??m letalidade dos casos mais graves da doen??a. Diferentes estudos cl??nicos e experimentais t??m relatado o envolvimento de citocinas inflamat??rias no desenvolvimento da LC. Aspectos da patogenicidade da LC t??m sido relacionados a caracter??sticas imunogen??ticas do hospedeiro como determinantes para o resultado da doen??a. Neste estudo investigamos se polimorfismos gen??ticos em IL1B, IL1RN e IFNG est??o associados com a suscetibilidade ou a prote????o a LC. A genotipagem dos SNPs foi realizada atrav??s do sequenciamento nucleot??dico e pela PCR-RFLP em 881 pacientes com LC e 837 indiv??duos controles. As concentra????es de citocinas foram tamb??m avaliadas entre pacientes e indiv??duos controles atrav??s do Luminex. Os n??veis das citocinas IL-1??, IL-6, CXCL-8, MCP-1 e IFN-?? foram significativamente superiores em pacientes com LC (p < 0,0001), enquanto elevados n??veis de IL-1Ra foram observados em controles. Polimorfismos gen??ticos de IL1B e IFNG est??o associados com o desenvolvimento da LC e com os n??veis de citocinas. O gen??tipo rs16944 C/C IL1B est?? relacionado a baixos n??veis de IL-1Ra e associado com a suscetibilidade a LC (OR=1.5 [95%CI 1.1???2.0]; p=0.004). Microssat??lite e diferentes SNPs do gene IFNG foram associados com a resist??ncia e a suscetibilidade a LC, como rs2069705 T e rs2430561 T est??o associados ao risco a LC (OR=1.5 [95%CI 1.2-2.0]; p=0.0004 / OR=1.4 [95%CI 1.2-1.6]; p=0.0002). Alelos de IFNG associados ao risco a LC est??o combinados em hapl??tipo (H1), este associado com a suscetibilidade a LC (OR=1.7 [95%CI 1.2-2.2]; p=5x10-5) e relacionado aos baixos n??veis de IFN-??. Polimorfismos gen??ticos em IL1B e IFNG s??o determinantes para o resultado da LC causada por Leishmania guyanensis, portanto varia????es gen??ticas est??o relacionadas com a produ????o de citocinas, como IL-1??, IL-1Ra e IFN-??.
