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Type: Artigo
Title: Human Cd40 Ligand Deficiency Dysregulates The Macrophage Transcriptome Causing Functional Defects That Are Improved By Exogenous Ifn-gamma
Author: Cabral-Marques
Otavio; Ramos
Rodrigo Nalio; Schimke
Lena F.; Khan
Taj Ali; Amaral
Eduardo Pinheiro; Barbosa Bomfim
Caio Cesar; Reis Junior
Osvaldo; Franca
Tabata Takahashi; Arslanian
Christina; Carola Correia Lima
Joanna Darck; Weber
Cristina Worm; Ferreira
Janaira Fernandes; Tavares
Fabiola Scancetti; Sun
Jing; D'Imperio Lima
Maria Regina; Seelaender
Marilia; Garcia Calich
Vera Lucia; Marzagao Barbuto
Jose Alexandre; Costa-Carvalho
Beatriz Tavares; Riemekasten
Gabriela; Seminario
Gisela; Bezrodnik
Liliana; Notarangelo
Luigi; Torgerson
Troy R.; Ochs
Hans D.; Condino-Neto
Abstract: 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.
Subject: Macrophages
Cd40 Ligand
Opportunistic Infections
Editor: Mosby-Elsevier
New York
Citation: Journal Of Allergy And Clinical Immunology. Mosby-elsevier , v. 139, p. 900 - +, 2017.
Rights: fechado
Identifier DOI: 10.1016/j.jaci.2016.07.018
Date Issue: 2017
Appears in Collections:Unicamp - Artigos e Outros Documentos

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