title: Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Rheumatology, University Lübeck, Lübeck, Germany.
authors.forename: Otavio
authors.initials: O
authors.lastname: Cabral-Marques
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo Nalio
authors.initials: RN
authors.lastname: Ramos
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Rheumatology, University Lübeck, Lübeck, Germany.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Schimke
authors.affiliation: 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.
authors.forename: Taj Ali
authors.initials: TA
authors.lastname: Khan
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Eduardo Pinheiro
authors.initials: EP
authors.lastname: Amaral
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Caio César
authors.initials: CC
authors.lastname: Barbosa Bomfim
authors.affiliation: Central Laboratory of High Performance Technologies (LaCTAD), State University of Campinas, São Paulo, Brazil.
authors.forename: Osvaldo Reis
authors.initials: OR
authors.lastname: Junior
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Tabata Takahashi
authors.initials: TT
authors.lastname: França
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Christina
authors.initials: C
authors.lastname: Arslanian
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Joanna Darck
authors.initials: JD
authors.lastname: Carola Correia Lima
authors.affiliation: Pediatric Allergy & Immunology Clinic, Caxias do Sul, Brazil.
authors.forename: Cristina Worm
authors.initials: CW
authors.lastname: Weber
authors.affiliation: Albert Sabin Hospital, Fortaleza, Brazil.
authors.forename: Janaíra Fernandes
authors.initials: JF
authors.lastname: Ferreira
authors.affiliation: Pediatric Immunology Clínic, Unit of Pediatrics, Hopital de Base do Distrito Federal Brasilia, Brasilia, Brazil.
authors.forename: Fabiola Scancetti
authors.initials: FS
authors.lastname: Tavares
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Regina
authors.initials: MR
authors.lastname: D'Imperio Lima
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Marília
authors.initials: M
authors.lastname: Seelaender
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Garcia Calich
authors.affiliation: 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.
authors.forename: José Alexandre
authors.initials: JA
authors.lastname: Marzagão Barbuto
authors.affiliation: Division of Allergy-Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Beatriz Tavares
authors.initials: BT
authors.lastname: Costa-Carvalho
authors.affiliation: Department of Rheumatology, University Lübeck, Lübeck, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.affiliation: Dr Ricardo Gutierrez Children's Hospital, Immunology, Buenos Aires, Argentina.
authors.forename: Gisela
authors.initials: G
authors.lastname: Seminario
authors.affiliation: Dr Ricardo Gutierrez Children's Hospital, Immunology, Buenos Aires, Argentina.
authors.forename: Liliana
authors.initials: L
authors.lastname: Bezrodnik
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Luigi
authors.initials: L
authors.lastname: Notarangelo
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Wash.
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Wash.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: condino@icb.usp.br.
authors.forename: Antonio
authors.initials: A
authors.lastname: Condino-Neto
mesh_terms: D000293:Adolescent; D000328:Adult; D023201:CD40 Ligand / Q000172:deficiency*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000166:cytology; D009169:Mycobacterium tuberculosis; D010587:Phagocytosis; D059467:Transcriptome / Q000187:drug effects; D055815:Young Adult
chemical_list: D023201:CD40 Ligand; D007371:Interferon-gamma
keywords: CD40 ligand; IFN-γ; Macrophages; opportunistic infections