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. 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: antoniocondino@gmail.com.
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.
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-deficientpatients 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-deficientpatients 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-deficientpatients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. RESULTS: Neutrophils from CD40L-deficientpatients 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-deficientpatients, 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-deficientpatients. 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.
Authors: J Levy; T Espanol-Boren; C Thomas; A Fischer; P Tovo; P Bordigoni; I Resnick; A Fasth; M Baer; L Gomez; E A Sanders; M D Tabone; D Plantaz; A Etzioni; V Monafo; M Abinun; L Hammarstrom; T Abrahamsen; A Jones; A Finn; T Klemola; E DeVries; O Sanal; M C Peitsch; L D Notarangelo Journal: J Pediatr Date: 1997-07 Impact factor: 4.406
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Authors: Otavio Cabral-Marques; Alexandre Marques; Lasse Melvær Giil; Roberta De Vito; Judith Rademacher; Jeannine Günther; Tanja Lange; Jens Y Humrich; Sebastian Klapa; Susanne Schinke; Lena F Schimke; Gabriele Marschner; Silke Pitann; Sabine Adler; Ralf Dechend; Dominik N Müller; Ioana Braicu; Jalid Sehouli; Kai Schulze-Forster; Tobias Trippel; Carmen Scheibenbogen; Annetine Staff; Peter R Mertens; Madlen Löbel; Justin Mastroianni; Corinna Plattfaut; Frank Gieseler; Duska Dragun; Barbara Elizabeth Engelhardt; Maria J Fernandez-Cabezudo; Hans D Ochs; Basel K Al-Ramadi; Peter Lamprecht; Antje Mueller; Harald Heidecke; Gabriela Riemekasten Journal: Nat Commun Date: 2018-12-06 Impact factor: 14.919
Authors: Otavio Cabral-Marques; Lena F Schimke; Edgar Borges de Oliveira; Nadia El Khawanky; Rodrigo Nalio Ramos; Basel K Al-Ramadi; Gesmar Rodrigues Silva Segundo; Hans D Ochs; Antonio Condino-Neto Journal: Front Immunol Date: 2019-11-26 Impact factor: 7.561