Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity

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Arquivos
art_SCHIMKE_Paracoccidioidomycosis_Associated_With_a_Heterozygous_STAT4_Mutation_and_2017.PDF (1.93 MB)
Citações na Scopus
26
Tipo de produção
article
Data de publicação
2017
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
OXFORD UNIV PRESS INC
Autores
SCHIMKE, Lena F.
HIBBARD, James
MARTINEZ-BARRICARTE, Ruben
KHAN, Taj Ali
CAVALCANTE, Ricardo de Souza
OLIVEIRA JUNIOR, Edgar Borges de
FRANCA, Tabata Takahashi
IQBAL, Asif
ARSLANIAN, Christina
Citação
JOURNAL OF INFECTIOUS DISEASES, v.216, n.12, p.1623-1634, 2017
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background. Mutations in genes affecting interferon-gamma (IFN-gamma) immunity have contributed to understand the role of IFN-gamma in protection against intracellular pathogens. However, inborn errors in STAT4, which controls interleukin-12 (IL-12) responses, have not yet been reported. Our objective was to determine the genetic defect in a family with a history of paracoccidioidomycosis. Methods. Genetic analysis was performed by whole-exome sequencing and Sanger sequencing. STAT4 phosphorylation (pSTAT4) and translocation to the nucleus, IFN-gamma release by patient lymphocytes, and microbicidal activity of patient monocytes/macrophages were assessed. The effect on STAT4 function was evaluated by site-directed mutagenesis using a lymphoblastoid B cell line (B-LCL) and U3A cells. Results. A heterozygous missense mutation, c.1952 A > T (p.E651V) in STAT4 was identified in the index patient and her father. Patient's and father's lymphocytes showed reduced pSTAT4, nuclear translocation, and impaired IFN-gamma production. Mutant B-LCL and U3A cells also displayed reduced pSTAT4. Patient's and father's peripheral blood mononuclear cells and macrophages demonstrated impaired fungicidal activity compared with those from healthy controls that improved in the presence of recombinant human IFN-gamma, but not rhIL-12. Conclusion. Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-gamma immunity associated with susceptibility to paracoccidioidomycosis.
Palavras-chave
STAT4 deficiency, primary immunodeficiency, IL-12/IFN-gamma axis, paracoccidioidomycosis
URI
https://observatorio.fm.usp.br/handle/OPI/25775
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Coleções
Artigos e Materiais de Revistas Científicas - HC/ICr
Artigos e Materiais de Revistas Científicas - LIM/46
Artigos e Materiais de Revistas Científicas - ODS/03