Novel molecular genetic defects and immunopathological mechanisms in Brazilian patients with mycobacterial diseases.

Khan, Taj Ali

doi:10.11606/T.42.2014.tde-14032015-102901

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Doctoral Thesis

DOI

https://doi.org/10.11606/T.42.2014.tde-14032015-102901

Document

Doctoral Thesis

Author

Khan, Taj Ali (Catálogo USP)

Full name

Taj Ali Khan

Institute/School/College

Instituto de Ciências Biomédicas

Knowledge Area

Immunology

Date of Defense

2014-12-10

Published

São Paulo, 2014

Supervisor

Condino Neto, Antonio (Catálogo USP)

Committee

Condino Neto, Antonio (President)
Câmara, Niels Olsen Saraiva
Carvalho, Beatriz Tavares Costa
Forti, Fábio Luís
Steiner, Alexandre Alarcon

Title in English

Novel molecular genetic defects and immunopathological mechanisms in Brazilian patients with mycobacterial diseases.

Keywords in English

Macrophage
Mutation
Mycobacterial infection

Abstract in English

We aimed to characterize well-know PIDs, novel genetic defects and immunopathological mechanisms in Brazilian patients with susceptibility to mycobacterial diseases. The patients developed different mycobacterial diseases and M. tuberculosis was the most frequent species. Molecular and genetic analysis revealed mutations in different genes: RAG1 (P1), CD40LG (P2, P3, P4), NEMO (P5), NCF1 (P6), TLR2 (P7) IL-12Rb2 (P8), IL-12Rb1 (P9), TLR10 (P10), DKC1(P11), SOCS-1(P12) and IRAK2 (P13). Finally, MDMs from patients phagocytose normally but were unable to appropriately control intracellular M. tuberculosis growth in comparison to MDMs from healthy subjects. We concluded that the Brazilian patients have heterogeneous mutations previously associated with susceptibility to mycobacterial diseases and novel genetic variations were identified suggesting novel PIDs. In addition, the inability of MDMs to control the intracellular growth of M. tuberculosis indicates this contributes to patients´ susceptibility to mycobacterial infections.

Title in Portuguese

Novos defeitos genético-moleculares e mecanismos imunopatológicos de pacientes brasileiros com suscetibilidade a infecções por micobactérias.

Keywords in Portuguese

Infecçoes por micobactérias
Macrófagos
Mutações

Abstract in Portuguese

Objetivamos identificar novos defeitos genéticos e mecanismos imunopatológicos em pacientes brasileiros com suscetibilidade a infecções por micobactérias. Os pacientes foram investigados se portadores de imunodeficiencias previamente caracterizadas tais como SCID, deficiência de CD40L, MSMD, defeitos na sinalização via TLRs e CGD. A análise genética foi realizada por sequenciamento Sanger e ''whole exome sequencing'' para identificar possíveis novas imunodeficiências primárias. Além disso a função dos macrófagos dos pacientes foi avaliada. Infecções por diferentes espécies de micobactérias foram apresentadas pelos pacientes, sendo M. tuberculosis a espécie mais frequentemente identificada. Mutações em diferentes genes foram encontradas: RAG1 (P1), CD40LG (P2, P3, P4), NEMO (P5), NCF1 (P6), TLR2 (P7), IL-12Rb2 (P8), IL-12Rb1 (P9), IRAK2 (P10), SOCS-1 (P11) e TLR10 (P12). MDMs dos pacientes fagocitaram normalmente M. tuberculosis, porém reduzida capacidade em inibir o crescimento da M. tuberculosis foi observada. Concluímos que os pacientes estudados possuem defeitos moleculares heterogêneos e que os MDMs desses indivíduos apresentam falhas no controle do crescimento da M. tuberculosis. Nossos dados sugerem que esses são fatores subjacentes à susceptibilidade a infecções por micobactérias nesses indivíduos.

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Publishing Date

2015-03-14

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