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

Autor: Cabral-Marques O; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Rheumatology, University Lübeck, Lübeck, Germany., França TT; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Al-Sbiei A; Department of Medical Microbiology & Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates., Schimke LF; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Rheumatology, University Lübeck, Lübeck, Germany., Khan TA; 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., Feriotti C; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., da Costa TA; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Junior OR; Central Laboratory of High Performance Technologies (LaCTAD), State University of Campinas, Campinas, Brazil., Weber CW; Pediatric Allergy & Immunology Clinic, Caxias do Sul, Brazil., Ferreira JF; Albert Sabin Hospital, Fortaleza, Brazil., Tavares FS; Pediatric Immunology Clinic, Unit of Pediatrics, Hospital de Base do Distrito Federal, Asa Sul, Brazil., Valente C; Pediatric Immunology Clinic, Unit of Pediatrics, Hospital de Base do Distrito Federal, Asa Sul, Brazil., Di Gesu RSW; Division of Allergy and Immunology, Department of Pediatrics, Conceicão Children Hospital, Porto Alegre, Brazil., Iqbal A; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil., Riemekasten G; Department of Rheumatology, University Lübeck, Lübeck, Germany., Amarante-Mendes GP; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Marzagão Barbuto JA; 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., Costa-Carvalho BT; Division of Allergy-Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil., Pereira PVS; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Pathology, Federal University of Maranhao, São Luis, Brazil., Fernandez-Cabezudo MJ; Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates., Calich VLG; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Notarangelo LD; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., Torgerson TR; Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Wash., Al-Ramadi BK; Department of Medical Microbiology & Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates., Ochs HD; Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Wash., Condino-Neto A; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: antoniocondino@gmail.com.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2018 Nov; Vol. 142 (5), pp. 1571-1588.e9. Date of Electronic Publication: 2018 Mar 05.
DOI: 10.1016/j.jaci.2018.02.026
Abstrakt: 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.
(Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: