TY - JOUR
T1 - CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ
AU - Cabral-Marques, Otavio
AU - França, Tabata Takahashi
AU - Al-Sbiei, Ashraf
AU - Schimke, Lena Friederike
AU - Khan, Taj Ali
AU - Feriotti, Claudia
AU - da Costa, Tania Alves
AU - Junior, Osvaldo Reis
AU - Weber, Cristina Worm
AU - Ferreira, Janaíra Fernandes
AU - Tavares, Fabiola Scancetti
AU - Valente, Claudia
AU - Di Gesu, Regina Sumiko Watanabe
AU - Iqbal, Asif
AU - Riemekasten, Gabriela
AU - Amarante-Mendes, Gustavo Pessini
AU - Marzagão Barbuto, José Alexandre
AU - Costa-Carvalho, Beatriz Tavares
AU - Pereira, Paulo Vitor Soeiro
AU - Fernandez-Cabezudo, Maria J.
AU - Calich, Vera Lucia Garcia
AU - Notarangelo, Luigi D.
AU - Torgerson, Troy R.
AU - al-Ramadi, Basel K.
AU - Ochs, Hans D.
AU - Condino-Neto, Antonio
N1 - Funding Information:
We thank all the patients and their families for their participation in this study. We thank Dr Antje Muller from the Department of Rheumatology, University of Lübeck, and Dr Jing Sun from the University of Cincinnati College of Medicine, Cincinnati, Ohio, for critical reading of the manuscript.
Publisher Copyright:
© 2018 American Academy of Allergy, Asthma & Immunology
PY - 2018/11
Y1 - 2018/11
N2 - 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.
AB - 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.
KW - CD40 ligand
KW - IFN-γ
KW - Neutrophils
KW - cell development
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U2 - 10.1016/j.jaci.2018.02.026
DO - 10.1016/j.jaci.2018.02.026
M3 - Article
C2 - 29518426
AN - SCOPUS:85045886887
SN - 0091-6749
VL - 142
SP - 1571-1588.e9
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 5
ER -