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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-gamma

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Autor(es):
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Cabral-Marques, Otavio [1, 2] ; Franca, Tabata Takahashi [1] ; Al-Sbiei, Ashraf [3] ; Schimke, Lena Friederike [1, 2] ; Khan, Taj Ali [1, 4] ; Feriotti, Claudia [1] ; da Costa, Tania Alves [1] ; Reis Junior, Osvaldo [5] ; Weber, Cristina Worm [6] ; Ferreira, Janaira Fernandes [7] ; Tavares, Fabiola Scancetti [8] ; Valente, Claudia [8] ; Watanabe Di Gesu, Regina Sumiko [9] ; Lqbal, Asif [10] ; Riemekasten, Gabriela [2] ; Amarante-Mendes, Gustavo Pessini [11] ; Marzagio Barbuto, Jose Alexandre [1, 12] ; Costa-Carvalho, Beatriz Tavares [13] ; Soeiro Pereira, Paulo Vitor [1, 14] ; Fernandez-Cabezudo, Maria J. [15] ; Garcia Calich, Vera Lucia [1] ; Notarangelo, Luigi D. [16] ; Torgerson, Troy R. [17, 18] ; al-Ramadi, Basel K. [3] ; Ochs, Hans D. [17, 18] ; Condino-Neto, Antonio [1]
Número total de Autores: 26
Afiliação do(s) autor(es):
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[1] Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, 1730 Linen Prestes Ave, BR-05508000 Sao Paulo - Brazil
[2] Univ Lubeck, Dept Rheumatol, Lubeck - Germany
[3] UAE Univ, Dept Med Microbiol & Immunol, Coll Med & Hlth Sci, Al Ain - U Arab Emirates
[4] Kohat Univ Sci & Technol, Dept Microbiol, Kohat - Pakistan
[5] Univ Estadual Campinas, Cent Lab High Performance Technol LaCTAD, Campinas, SP - Brazil
[6] Pediat Allergy & Immunol Clin, Caxias Do Sul - Brazil
[7] Albert Sabin Hosp, Fortaleza, Ceara - Brazil
[8] Hosp Base Dist Fed, Unit Pediat, Pediat Immunol Clin, Asa Sul - Brazil
[9] Conceicao Children Hosp, Div Allergy & Immunol, Dept Pediat, Porto Alegre, RS - Brazil
[10] Univ Sao Paulo, Dept Biochem, Inst Chem, Sao Paulo - Brazil
[11] Univ Sao Paulo, Dept Parasitol, Inst Biomed Sci, Sao Paulo - Brazil
[12] Univ Sao Paulo, NETCEM, Cell & Mol Therapy Ctr, Sao Paulo - Brazil
[13] Univ Fed Sao Paulo, Div Allergy & Immunol, Dept Pediat, Sao Paulo - Brazil
[14] Univ Fed Maranhao, Dept Pathol, Sao Luis - Brazil
[15] UAE Univ, Dept Biochem, Coll Med & Hlth Sci, Al Ain - U Arab Emirates
[16] NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA
[17] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 - USA
[18] Seattle Childrens Res Inst, Seattle, WA - USA
Número total de Afiliações: 18
Tipo de documento: Artigo Científico
Fonte: Journal of Allergy and Clinical Immunology; v. 142, n. 5, p. 1571+, NOV 2018.
Citações Web of Science: 5
Resumo

Background: Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. Objectives: We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-gamma (rhIFN-gamma) on neutrophil function. Methods: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. Results: Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-gamma but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. Conclusion: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-gamma, indicating a potential novel therapeutic application for this cytokine. (AU)

Processo FAPESP: 12/50515-4 - O papel da interação CD40L-CD40 na resposta imune antifúngica mediada por neutrófilos e macrófagos em humanos
Beneficiário:Otávio Cabral Marques
Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 16/22158-3 - Mecanismos genético-moleculares nas imunodeficiências primárias
Beneficiário:Antonio Condino Neto
Modalidade de apoio: Auxílio à Pesquisa - Temático
Processo FAPESP: 12/51745-3 - O papel da interação CD40L-CD40 na resposta imune antifúngica mediada por neutrófilos e macrófagos em humanos
Beneficiário:Antonio Condino Neto
Modalidade de apoio: Auxílio à Pesquisa - Regular