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

Otavio Cabral-Marques; Tabata Takahashi França; Ashraf Al-Sbiei; Lena Friederike Schimke; Taj Ali Khan; Claudia Feriotti; Tania Alves da Costa; Osvaldo Reis Junior; Cristina Worm Weber; Janaíra Fernandes Ferreira; Fabiola Scancetti Tavares; Claudia Valente; Regina Sumiko Watanabe Di Gesu; Asif Iqbal; Gabriela Riemekasten; Gustavo Pessini Amarante-Mendes; José Alexandre Marzagão Barbuto; Beatriz Tavares Costa-Carvalho; Paulo Vitor Soeiro Pereira; Maria J. Fernandez-Cabezudo; Vera Lucia Garcia Calich; Luigi D. Notarangelo; Troy R. Torgerson; Basel K. al-Ramadi; Hans D. Ochs; Antonio Condino-Neto

doi:10.1016/j.jaci.2018.02.026

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

Otavio Cabral-Marques, Tabata Takahashi França, Ashraf Al-Sbiei, Lena Friederike Schimke, Taj Ali Khan, Claudia Feriotti, Tania Alves da Costa, Osvaldo Reis Junior, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Claudia Valente, Regina Sumiko Watanabe Di Gesu, Asif Iqbal, Gabriela Riemekasten, Gustavo Pessini Amarante-Mendes, José Alexandre Marzagão Barbuto, Beatriz Tavares Costa-Carvalho, Paulo Vitor Soeiro Pereira, Maria J. Fernandez-CabezudoVera Lucia Garcia Calich, Luigi D. Notarangelo, Troy R. Torgerson, Basel K. al-Ramadi, Hans D. Ochs, Antonio Condino-Neto^*

^*Corresponding author for this work

Clinic of Rheumatology

24 Citations (Scopus)

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.

Original language	English
Journal	Journal of Allergy and Clinical Immunology
Volume	142
Issue number	5
Pages (from-to)	1571-1588.e9
ISSN	0091-6749
DOIs	https://doi.org/10.1016/j.jaci.2018.02.026
Publication status	Published - 11.2018

Funding

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 L?beck, and Dr Jing Sun from the University of Cincinnati College of Medicine, Cincinnati, Ohio, for critical reading of the manuscript.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1016/j.jaci.2018.02.026

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Cabral-Marques, O., França, T. T., Al-Sbiei, A., Schimke, L. F., Khan, T. A., Feriotti, C., da Costa, T. A., Junior, O. R., Weber, C. W., Ferreira, J. F., Tavares, F. S., Valente, C., Di Gesu, R. S. W., Iqbal, A., Riemekasten, G., Amarante-Mendes, G. P., Marzagão Barbuto, J. A., Costa-Carvalho, B. T., Pereira, P. V. S., ... Condino-Neto, A. (2018). CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ. Journal of Allergy and Clinical Immunology, 142(5), 1571-1588.e9. https://doi.org/10.1016/j.jaci.2018.02.026

@article{28654a2aa65f48cbaa014ba9962342f4,

title = "CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ",

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.",

author = "Otavio Cabral-Marques and Fran{\c c}a, \{Tabata Takahashi\} and Ashraf Al-Sbiei and Schimke, \{Lena Friederike\} and Khan, \{Taj Ali\} and Claudia Feriotti and \{da Costa\}, \{Tania Alves\} and Junior, \{Osvaldo Reis\} and Weber, \{Cristina Worm\} and Ferreira, \{Jana{\'i}ra Fernandes\} and Tavares, \{Fabiola Scancetti\} and Claudia Valente and \{Di Gesu\}, \{Regina Sumiko Watanabe\} and Asif Iqbal and Gabriela Riemekasten and Amarante-Mendes, \{Gustavo Pessini\} and \{Marzag{\~a}o Barbuto\}, \{Jos{\'e} Alexandre\} and Costa-Carvalho, \{Beatriz Tavares\} and Pereira, \{Paulo Vitor Soeiro\} and Fernandez-Cabezudo, \{Maria J.\} and Calich, \{Vera Lucia Garcia\} and Notarangelo, \{Luigi D.\} and Torgerson, \{Troy R.\} and al-Ramadi, \{Basel K.\} and Ochs, \{Hans D.\} and Antonio Condino-Neto",

note = "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 L?beck, and Dr Jing Sun from the University of Cincinnati College of Medicine, Cincinnati, Ohio, for critical reading of the manuscript. Publisher Copyright: {\textcopyright} 2018 American Academy of Allergy, Asthma \& Immunology Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

year = "2018",

month = nov,

doi = "10.1016/j.jaci.2018.02.026",

language = "English",

volume = "142",

pages = "1571--1588.e9",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "5",

}

Cabral-Marques, O, França, TT, Al-Sbiei, A, Schimke, LF, Khan, TA, Feriotti, C, da Costa, TA, Junior, OR, Weber, CW, Ferreira, JF, Tavares, FS, Valente, C, Di Gesu, RSW, Iqbal, A, Riemekasten, G, Amarante-Mendes, GP, Marzagão Barbuto, JA, Costa-Carvalho, BT, Pereira, PVS, Fernandez-Cabezudo, MJ, Calich, VLG, Notarangelo, LD, Torgerson, TR, al-Ramadi, BK, Ochs, HD & Condino-Neto, A 2018, 'CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ', Journal of Allergy and Clinical Immunology, vol. 142, no. 5, pp. 1571-1588.e9. https://doi.org/10.1016/j.jaci.2018.02.026

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 L?beck, 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 Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

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.

UR - https://www.scopus.com/pages/publications/85045886887

U2 - 10.1016/j.jaci.2018.02.026

DO - 10.1016/j.jaci.2018.02.026

M3 - Journal articles

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 -

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

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