TY - JOUR
T1 - Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ
AU - Cabral-Marques, Otavio
AU - Ramos, Rodrigo Nalio
AU - Schimke, Lena F.
AU - Khan, Taj Ali
AU - Amaral, Eduardo Pinheiro
AU - Barbosa Bomfim, Caio César
AU - Junior, Osvaldo Reis
AU - França, Tabata Takahashi
AU - Arslanian, Christina
AU - Carola Correia Lima, Joanna Darck
AU - Weber, Cristina Worm
AU - Ferreira, Janaíra Fernandes
AU - Tavares, Fabiola Scancetti
AU - Sun, Jing
AU - D'Imperio Lima, Maria Regina
AU - Seelaender, Marília
AU - Garcia Calich, Vera Lucia
AU - Marzagão Barbuto, José Alexandre
AU - Costa-Carvalho, Beatriz Tavares
AU - Riemekasten, Gabriela
AU - Seminario, Gisela
AU - Bezrodnik, Liliana
AU - Notarangelo, Luigi
AU - Torgerson, Troy R.
AU - Ochs, Hans D.
AU - Condino-Neto, Antonio
N1 - Funding Information:
Supported by Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (grant 2012/50515-4 to O.C.-M. and grant 2012/51745-3 to A.C.-N.) and the Jeffrey Modell Foundation.
Publisher Copyright:
© 2016 American Academy of Allergy, Asthma & Immunology
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84994430036&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2016.07.018
DO - 10.1016/j.jaci.2016.07.018
M3 - Journal articles
C2 - 27554817
AN - SCOPUS:84994430036
SN - 0091-6749
VL - 139
SP - 900-912.e7
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 3
ER -
