Novos mecanismos imunopatológicos na deficiência de CD40 ligante.

Marques, Otávio Cabral

doi:10.11606/T.42.2012.tde-18042013-094555

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Doctoral Thesis

DOI

https://doi.org/10.11606/T.42.2012.tde-18042013-094555

Document

Doctoral Thesis

Author

Marques, Otávio Cabral (Catálogo USP)

Full name

Otávio Cabral Marques

Institute/School/College

Instituto de Ciências Biomédicas

Knowledge Area

Immunology

Date of Defense

2012-11-07

Published

São Paulo, 2012

Supervisor

Condino Neto, Antonio (Catálogo USP)
Barbuto, Jose Alexandre Marzagao - (Co-supervisor) (Catálogo USP)

Committee

Condino Neto, Antonio (President)
Andrade, Luis Eduardo Coelho
Calich, Vera Lucia Garcia
Lepique, Ana Paula
Solé, Dirceu

Title in Portuguese

Novos mecanismos imunopatológicos na deficiência de CD40 ligante.

Keywords in Portuguese

Células dendríticas
Fungos
Neutrófilos
Paracoccidioidomicose

Abstract in Portuguese

Identificamos em 12 pacientes deficientes de CD40L uma incidência de infecções fúngicas de 83%, incluindo os primeiros casos de paracoccidioidomicose (PCM) e aspergilose. As células dendríticas imaturas (DCs) dos pacientes apresentaram expressão reduzida das moléculas HLA-DR, CD80 e CD86 e as DCs maduras (mDCs) pulsadas com os fungos P. brasiliensis ou C albicans apresentaram baixa expressão das moléculas HLA-DR e CD80. As mDCs dos pacientes secretaram baixa concentração de IL-12 e alta de IL-10. Nas co-culturas das mDCs com os linfócitos autólogos, observamos que a produção de IFN-g foi reduzida e a produção de IL-4 e IL-5 foi aumentada. Após tratamento com CD40L solúvel os defeitos observados foram revertidos. Os neutrófilos dos pacientes falharam na atividade fungicida em resposta ao P. brasiliensis, reduzida produção de H₂O₂ e sinalização via TLR1/TLR2 e TLR2/TLR6 foram observadas. Falhas na resposta de DCs e neutrófilos sugerem que esses são mecanismos imunopatológicos subjacentes à suscetibilidade às infecções fúngicas em pacientes deficientes de CD40L.

Title in English

Novel immunopathological mechanisms in the CD40L deficiency.

Keywords in English

Dendritic cells
Fungi
Neutrophils
Paracoccidioidomycosis

Abstract in English

We identified 12 CD40L-deficient patients with an incidence of fungal infections of 83%, including the first case of paracoccidioidomycosis and aspergillosis. The immature DCs (iDCs) from the patients present reduced protein expression of HLA-DR, CD80 and CD86 and mature DCs (mDCs) pulsed with P. brasiliensis (mDCs) presented low expression of HLA-DR and CD80 molecules The mDCs from the patients secreted low levels of IL-12 and high of IL-10. In co-cultures of mDCs and autologous T lymphocytes we found low production of IFN-g and high production of IL-4 and IL-5. After treatment with soluble CD40L, the defects were reversed. The neutrophils from these patients showed impaired fungicidal activity in response P. brasiliensis and low production of H₂O₂. Additionally defective TLR1/TLR2 and TLR2/TLR6 signaling were observed. Failure in DCs and neutrophils responses are imunophatological mechanisms underlying the suscetibility to fungal infections in CD40L-deficient patients.

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Publishing Date

2013-05-23

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