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

J Allergy Clin Immunol. 2018 Nov;142(5):1571-1588.e9. doi: 10.1016/j.jaci.2018.02.026. Epub 2018 Mar 5.

Authors

Otavio Cabral-Marques¹, Tabata Takahashi França², Ashraf Al-Sbiei³, Lena Friederike Schimke¹, Taj Ali Khan⁴, Claudia Feriotti², Tania Alves da Costa², Osvaldo Reis Junior⁵, Cristina Worm Weber⁶, Janaíra Fernandes Ferreira⁷, Fabiola Scancetti Tavares⁸, Claudia Valente⁸, Regina Sumiko Watanabe Di Gesu⁹, Asif Iqbal¹⁰, Gabriela Riemekasten¹¹, Gustavo Pessini Amarante-Mendes¹², José Alexandre Marzagão Barbuto¹³, Beatriz Tavares Costa-Carvalho¹⁴, Paulo Vitor Soeiro Pereira¹⁵, Maria J Fernandez-Cabezudo¹⁶, Vera Lucia Garcia Calich², Luigi D Notarangelo¹⁷, Troy R Torgerson¹⁸, Basel K Al-Ramadi³, Hans D Ochs¹⁸, Antonio Condino-Neto¹⁹

Affiliations

¹ Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Rheumatology, University Lübeck, Lübeck, Germany.
² Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
³ Department of Medical Microbiology & Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
⁴ Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
⁵ Central Laboratory of High Performance Technologies (LaCTAD), State University of Campinas, Campinas, Brazil.
⁶ Pediatric Allergy & Immunology Clinic, Caxias do Sul, Brazil.
⁷ Albert Sabin Hospital, Fortaleza, Brazil.
⁸ Pediatric Immunology Clinic, Unit of Pediatrics, Hospital de Base do Distrito Federal, Asa Sul, Brazil.
⁹ Division of Allergy and Immunology, Department of Pediatrics, Conceicão Children Hospital, Porto Alegre, Brazil.
¹⁰ Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
¹¹ Department of Rheumatology, University Lübeck, Lübeck, Germany.
¹² Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
¹³ Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Cell and Molecular Therapy Center, NETCEM, University of São Paulo, São Paulo, Brazil.
¹⁴ Division of Allergy-Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil.
¹⁵ Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Pathology, Federal University of Maranhao, São Luis, Brazil.
¹⁶ Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
¹⁷ Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹⁸ Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Wash.
¹⁹ Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: [email protected].

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.

Keywords: CD40 ligand; IFN-γ; Neutrophils; cell development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD40 Ligand / deficiency*
CD40 Ligand / immunology
Female
HL-60 Cells
Humans
Hyper-IgM Immunodeficiency Syndrome, Type 1 / immunology
Interferon-gamma / pharmacology*
Mice, Inbred C57BL
Mice, Knockout
N-Formylmethionine Leucyl-Phenylalanine / pharmacology
Neutrophils / drug effects*
Neutrophils / physiology
Paracoccidioides
Reactive Oxygen Species / metabolism
Recombinant Proteins / pharmacology
Respiratory Burst / drug effects
Staphylococcus aureus
Tetradecanoylphorbol Acetate / pharmacology
Transcriptome / drug effects

Substances

Reactive Oxygen Species
Recombinant Proteins
CD40 Ligand
N-Formylmethionine Leucyl-Phenylalanine
Interferon-gamma
Tetradecanoylphorbol Acetate

Abstract

Publication types

MeSH terms

Substances

Grants and funding