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 - 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
UR - https://www.scopus.com/pages/publications/85045886887
UR - https://www.scopus.com/pages/publications/85045886887#tab=citedBy
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 -