CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ.
J Allergy Clin Immunol
; 142(5): 1571-1588.e9, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-29518426
ABSTRACT
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-γ (rhIFN-γ) 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-γ 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-γ, indicating a potential novel therapeutic application for this cytokine.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
4_TD
Base de dados:
MEDLINE
Assunto principal:
Interferon gama
/
Ligante de CD40
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Neutrófilos
Tipo de estudo:
Etiology_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2018
Tipo de documento:
Article