Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-gamma

Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-gamma

Author Cabral-Marques, Otavio Google Scholar
Ramos, Rodrigo Nalio Google Scholar
Schimke, Lena F. Google Scholar
Khan, Taj Ali Google Scholar
Amaral, Eduardo Pinheiro Google Scholar
Barbosa Bomfim, Caio Cesar Google Scholar
Reis Junior, Osvaldo Google Scholar
Franca, Tabata Takahashi Google Scholar
Arslanian, Christina Google Scholar
Carola Correia Lima, Joanna Darck Google Scholar
Weber, Cristina Worm Google Scholar
Ferreira, Janaira Fernandes Google Scholar
Tavares, Fabiola Scancetti Google Scholar
Sun, Jing Google Scholar
D'Imperio Lima, Maria Regina Google Scholar
Seelaender, Marilia Google Scholar
Garcia Calich, Vera Lucia Google Scholar
Marzagao Barbuto, Jose Alexandre Google Scholar
Costa-Carvalho, Beatriz Tavares Autor UNIFESP Google Scholar
Riemekasten, Gabriela Google Scholar
Seminario, Gisela Google Scholar
Bezrodnik, Liliana Google Scholar
Notarangelo, Luigi Google Scholar
Torgerson, Troy R. Google Scholar
Ochs, Hans D. Google Scholar
Condino-Neto, Antonio Google Scholar
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-gamma (rhIFN-gamma) 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-g and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-gamma 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-gamma but not sCD40L. In contrast, rhIFN-gamma and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-gamma reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-gamma. Additionally, rhIFN-gamma 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-gamma suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.
Keywords Macrophages
CD40 ligand
opportunistic infections
xmlui.dri2xhtml.METS-1.0.item-coverage New York
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
Jeffrey Modell Foundation
Grant number FAPESP: 2012/50515-4
FAPESP: 2012/51745-3
Date 2017
Published in Journal Of Allergy And Clinical Immunology. New York, v. 139, n. 3, p. 900-912, 2017.
ISSN 0091-6749 (Sherpa/Romeo, impact factor)
Publisher Mosby-Elsevier
Extent 900-912
Access rights Closed access
Type Article
Web of Science ID WOS:000397295800023

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