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Doctoral Thesis
DOI
Document
Author
Full name
Nuria Bengala Zurro
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Condino Neto, Antonio (President)
Andrade, Luiz Eduardo Coelho
Lago, Carolina Sanchez Aranda
Muscara, Marcelo Nicolas
Peron, Jean Pierre Schatzmann
Title in Portuguese
Caracterização clínica e genética de pacientes brasileiros com doença granulomatosa crônica e susceptibilidade mendeliana a infecções por micobactérias
Keywords in Portuguese
Doença Granulomatosa Crônica
Eixo IL-12/IFN-γ
Eixo IL-12/IFN-γ Doença Granulomatosa Crônica
Fagócitos
Sistema NADPH oxidase
Susceptibilidade Mendeliana à infecções por micobactérias
Abstract in Portuguese
Dentre pacientes com imunodeficiências primárias, existem aqueles com defeitos de fagócitos e outros componentes da imunidade inata. A doença granulomatosa crônica (DGC) é uma imunodeficiência primária (IDP) causada por mutações em um dos componentes protéicos, gp91-phox, p22-phox, p47-phox, p67-phox e p40-phox, da nicotinamida adenina dinucleotídeo fosfato (NADPH) dos fagócitos. Pacientes com DGC apresentam maior susceptibilidade a infecções, assim como hiperinflamação e reação adversa à vacinas como à do Bacilo Calmette-Guérin (BCG), como consequência da atividade microbicida defeituosa dos fagócitos. Por outro lado, a susceptibilidade mendeliana a micobactérias (MSMD) é uma condição que predispõe os pacientes a infecções pelo gênero Mycobacterium sp, levando a infecções graves e por vezes à morte. O objetivo deste trabalho foi realizar o diagnóstico clínico e a análise genético-molecular de pacientes brasileiros com DGC e MSMD. A explosão respiratória de granulócitos foi avaliada pelo ensaio de dihidrorodamina (DHR). A dosagem de citocinas do eixo IL-12/IFN-γ foi realizada mediante o ensaio de ELISA após estimulo com lisado de micobactérias (LM), proteína purifica (PPD) e BCG. O DNA genômico dos pacientes foi extraído, amplificado e sequenciado pelo método de Sanger e seqüenciamento completo de exoma. Durante o período de 2014-2018, 181 pacientes com histórico clínico sugestivo de DGC e 75 pacientes com diagnóstico sugestivo de MSMD foram encaminhados ao nosso laboratório. Após avaliação clínica e bioquímica dos pacientes, 23 deles foram diagnosticadas com DGC e 16 com MSMD. A análise genético-molecular permitiu identificar mutações em 14 pacientes com DGC, nove deles com DGC ligada ao cromossomo X (DGC-X) e 5 com DGC autossômica recessiva (DGC-AR). Identificamos mutações em 5 pacientes com MSMD, sendo três delas no receptor de IL-12 e duas no receptor da IL-17.
Title in English
Clinical and Genetic Characterization of Brazilian Patients with Chronic Granulomatous Disease and Mendelian Susceptibility to Mycobacterial Disease
Keywords in English
Chronic Granulomatous Disease
IL-12/IFN-γ axis
Mendelian susceptibility to mycobacterial disease
NADPH oxidase system
Phagocytes
Abstract in English
Among patients with primary immunodeficiencies, there are those with defects in phagocytes and other components of the innate immunity. Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID) caused by mutations in one of the protein components, gp91-phox, p22-phox, p47-phox, p67-phox and p40-phox of the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase of phagocytes. Patients with CDG are susceptible to infections, as well as hyperinflammation and adverse reactions to vaccines such as Bacilo Calmette-Guérin (BCG) as a consequence of defective phagocytes microbicidal activity. On the other hand, Mendelian susceptibility to mycobacterial diseases (MSMD) is a condition that predisposes patients to infections by the genus Mycobacterium sp , leading to serious infections and sometimes death. The main goal of this study was to perform the clinical diagnosis and genetic-molecular analysis of Brazilian patients with CDG and MSMD. The respiratory burst of granulocytes was evaluated by the dihydrorhodamine (DHR) assay. Cytokine dosing of IL-12 / IFN-γ axis was performed by the ELISA assay after stimulation with mycobacterium lysate (LM), purified protein (PPD) and BCG. Patients genomic DNA was extracted, amplified and sequenced by the Sanger method and whole exome sequencing. During the period of 2014 to 2018, 181 patients with a clinical history suggestive of CDG and 75 patients with a diagnosis suggestive of MSMD were referred to our laboratory. After clinical and biochemical evaluation, 23 of them were diagnosed with CDG and 16 with MSMD. Genetic-molecular analysis allowed the identification of mutations in 14 patients with CDG, of those 9 had X-linked DGC (X-CGD) and 5 had autosomal recessive CGD (AR-CGD). Mutations were identified in 5 MSMD patients, three in the IL-12 receptor and two in the IL-17 receptor.
 
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Release Date
2021-04-28
Publishing Date
2019-05-06
 
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