Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1093/infdis/jix522 http://hdl.handle.net/11449/163664 |
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. |
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Repositório Institucional da UNESP |
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Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma ImmunitySTAT4 deficiencyprimary immunodeficiencyIL-12/IFN-gamma axisparacoccidioidomycosisBackground. 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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Sao Paulo, Dept Immunol, Sao Paulo, BrazilUniv Lubeck, Dept Rheumatol & Clin Immunol, Lubeck, GermanyUniv Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USASeattle Childrens Res Inst, Seattle, WA USARockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USASao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, BrazilButantan Inst, Lab Biochem & Biophys, Sao Paulo, BrazilUniv Sao Paulo, Human Genome & Stem Cell Res Ctr, Sao Paulo, BrazilParis Descartes Univ, Imagine Inst, Paris, FranceNecker Hosp Sick Children, Lab Human Genet Infect Dis, Paris, FranceNecker Hosp Sick Children, Ctr Study Primary Immunodeficiencies, Paris, FranceNecker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris, FranceRockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USAUniv Sao Paulo, Inst Trop Med, Sao Paulo, BrazilSao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, BrazilFAPESP: 2011/2507-1FAPESP: 2/51745-3FAPESP: 13/50303-0Oxford Univ Press IncUniversidade de São Paulo (USP)Univ LubeckUniv WashingtonSeattle Childrens Res InstRockefeller UnivUniversidade Estadual Paulista (Unesp)Butantan InstNecker Hosp Sick ChildrenSchimke, Lena F.Hibbard, JamesMartinez-Barricarte, RubenKhan, Taj AliCavalcante, Ricardo de Souza [UNESP]Oliveira Junior, Edgar Borges deFranca, Tabata TakahashiIqbal, AsifYamamoto, GuilhermeArslanian, ChristinaFeriotti, ClaudiaCosta, Tania AlvesBustamante, JacintaBoisson-Dupuis, StephanieCasanova, Jean-LaurentMarzagao Barbuto, Jose AlexandreZatz, MayanaMendes, Rinaldo Poncio [UNESP]Garcia Calich, Vera LuciaOchs, Hans D.Torgerson, Troy R.Cabral-Marques, OtavioCondino-Neto, Antonio2018-11-26T17:44:29Z2018-11-26T17:44:29Z2017-12-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1623-1634application/pdfhttp://dx.doi.org/10.1093/infdis/jix522Journal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017.0022-1899http://hdl.handle.net/11449/16366410.1093/infdis/jix522WOS:000418720000017WOS000418720000017.pdfWeb of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal Of Infectious Diseases3,302info:eu-repo/semantics/openAccess2024-08-15T15:22:48Zoai:repositorio.unesp.br:11449/163664Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-15T15:22:48Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
title |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
spellingShingle |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity Schimke, Lena F. STAT4 deficiency primary immunodeficiency IL-12/IFN-gamma axis paracoccidioidomycosis |
title_short |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
title_full |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
title_fullStr |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
title_full_unstemmed |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
title_sort |
Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity |
author |
Schimke, Lena F. |
author_facet |
Schimke, Lena F. Hibbard, James Martinez-Barricarte, Ruben Khan, Taj Ali Cavalcante, Ricardo de Souza [UNESP] Oliveira Junior, Edgar Borges de Franca, Tabata Takahashi Iqbal, Asif Yamamoto, Guilherme Arslanian, Christina Feriotti, Claudia Costa, Tania Alves Bustamante, Jacinta Boisson-Dupuis, Stephanie Casanova, Jean-Laurent Marzagao Barbuto, Jose Alexandre Zatz, Mayana Mendes, Rinaldo Poncio [UNESP] Garcia Calich, Vera Lucia Ochs, Hans D. Torgerson, Troy R. Cabral-Marques, Otavio Condino-Neto, Antonio |
author_role |
author |
author2 |
Hibbard, James Martinez-Barricarte, Ruben Khan, Taj Ali Cavalcante, Ricardo de Souza [UNESP] Oliveira Junior, Edgar Borges de Franca, Tabata Takahashi Iqbal, Asif Yamamoto, Guilherme Arslanian, Christina Feriotti, Claudia Costa, Tania Alves Bustamante, Jacinta Boisson-Dupuis, Stephanie Casanova, Jean-Laurent Marzagao Barbuto, Jose Alexandre Zatz, Mayana Mendes, Rinaldo Poncio [UNESP] Garcia Calich, Vera Lucia Ochs, Hans D. Torgerson, Troy R. Cabral-Marques, Otavio Condino-Neto, Antonio |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Univ Lubeck Univ Washington Seattle Childrens Res Inst Rockefeller Univ Universidade Estadual Paulista (Unesp) Butantan Inst Necker Hosp Sick Children |
dc.contributor.author.fl_str_mv |
Schimke, Lena F. Hibbard, James Martinez-Barricarte, Ruben Khan, Taj Ali Cavalcante, Ricardo de Souza [UNESP] Oliveira Junior, Edgar Borges de Franca, Tabata Takahashi Iqbal, Asif Yamamoto, Guilherme Arslanian, Christina Feriotti, Claudia Costa, Tania Alves Bustamante, Jacinta Boisson-Dupuis, Stephanie Casanova, Jean-Laurent Marzagao Barbuto, Jose Alexandre Zatz, Mayana Mendes, Rinaldo Poncio [UNESP] Garcia Calich, Vera Lucia Ochs, Hans D. Torgerson, Troy R. Cabral-Marques, Otavio Condino-Neto, Antonio |
dc.subject.por.fl_str_mv |
STAT4 deficiency primary immunodeficiency IL-12/IFN-gamma axis paracoccidioidomycosis |
topic |
STAT4 deficiency primary immunodeficiency IL-12/IFN-gamma axis paracoccidioidomycosis |
description |
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. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-12-15 2018-11-26T17:44:29Z 2018-11-26T17:44:29Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1093/infdis/jix522 Journal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017. 0022-1899 http://hdl.handle.net/11449/163664 10.1093/infdis/jix522 WOS:000418720000017 WOS000418720000017.pdf |
url |
http://dx.doi.org/10.1093/infdis/jix522 http://hdl.handle.net/11449/163664 |
identifier_str_mv |
Journal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017. 0022-1899 10.1093/infdis/jix522 WOS:000418720000017 WOS000418720000017.pdf |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal Of Infectious Diseases 3,302 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1623-1634 application/pdf |
dc.publisher.none.fl_str_mv |
Oxford Univ Press Inc |
publisher.none.fl_str_mv |
Oxford Univ Press Inc |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808128145199464448 |