Otavio Cabral-Marques1, Rodrigo Nalio Ramos2, Lena F Schimke1, Taj Ali Khan3, Eduardo Pinheiro Amaral2, Caio César Barbosa Bomfim2, Osvaldo Reis Junior4, Tabata Takahashi França2, Christina Arslanian2, Joanna Darck Carola Correia Lima5, Cristina Worm Weber6, Janaíra Fernandes Ferreira7, Fabiola Scancetti Tavares8, Jing Sun9, Maria Regina D'Imperio Lima2, Marília Seelaender5, Vera Lucia Garcia Calich2, José Alexandre Marzagão Barbuto10, Beatriz Tavares Costa-Carvalho11, Gabriela Riemekasten12, Gisela Seminario13, Liliana Bezrodnik13, Luigi Notarangelo14, Troy R Torgerson15, Hans D Ochs15, Antonio Condino-Neto16. 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 Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan. 4. Central Laboratory of High Performance Technologies (LaCTAD), State University of Campinas, São Paulo, Brazil. 5. Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. 6. Pediatric Allergy & Immunology Clinic, Caxias do Sul, Brazil. 7. Albert Sabin Hospital, Fortaleza, Brazil. 8. Pediatric Immunology Clínic, Unit of Pediatrics, Hopital de Base do Distrito Federal Brasilia, Brasilia, Brazil. 9. University of Cincinnati College of Medicine, Cincinnati, Ohio. 10. 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. 11. Division of Allergy-Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil. 12. Department of Rheumatology, University Lübeck, Lübeck, Germany. 13. Dr Ricardo Gutierrez Children's Hospital, Immunology, Buenos Aires, Argentina. 14. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 15. Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Wash. 16. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: condino@icb.usp.br.
Abstract
BACKGROUND: CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. OBJECTIVES: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. METHODS: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. RESULTS: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. CONCLUSION: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.
BACKGROUND:CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficientpatients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. OBJECTIVES: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. METHODS: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficientpatient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficientpatients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. RESULTS: Macrophages from CD40L-deficientpatients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. CONCLUSION: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.
Authors: 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 Journal: J Allergy Clin Immunol Date: 2018-03-05 Impact factor: 10.793
Authors: Noor Ul Akbar; Shahid Niaz Khan; Muhammad Usman Amin; Muhammad Ishfaq; Otavio Cabral-Marques; Lena F Schimke; Asif Iqbal; Ikram Ullah; Mubashir Hussain; Ijaz Ali; Nasar Khan; Nadia El Khawanky; Hazir Rahman; Taj Ali Khan Journal: Immunol Res Date: 2019-10 Impact factor: 2.829
Authors: Junghee J Shin; Jason Catanzaro; Jennifer R Yonkof; Ottavia Delmonte; Keith Sacco; Min Sun Shin; Srikar Reddy; Paula J Whittington; Gary Soffer; Peter J Mustillo; Kathleen E Sullivan; Luigi D Notarangelo; Roshini S Abraham; Neil Romberg; Insoo Kang Journal: J Clin Immunol Date: 2021-01-26 Impact factor: 8.317
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