title: Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ.
abstract: OBJECTIVE
  To study the role of IFN-γ in the pathogenesis of systemic JIA (sJIA) and haemophagocytic lymphohistiocytosis (HLH) by searching for an IFN-γ profile, and to assess its relationship with other cytokines.
  
  
  METHODS
  Patients with inactive (n = 10) and active sJIA (n = 10), HLH [n = 5; of which 3 had sJIA-associated macrophage activation syndrome (MAS)] and healthy controls (n = 16) were enrolled in the study. Cytokines and IFN-γ-induced genes and proteins were determined in plasma, in patient peripheral blood mononuclear cells (PBMCs) and in lymph node biopsies of one patient during both sJIA and MAS episodes. IFN-γ responses were investigated in healthy donor PBMCs, primary fibroblasts and endothelial cells.
  
  
  RESULTS
  Plasma IFN-γ, IL-6 and IL-18 were elevated in active sJIA and HLH. Levels of IFN-γ and IFN-γ-induced proteins (IP-10/CXCL-10, IL-18BP and indoleamine 2,3-dioxygenase) in HLH were much higher than levels in active sJIA. Free IL-18 and ratios of IL-18/IFN-γ were higher in active sJIA compared with HLH. HLH PBMCs showed hyporesponsiveness to IFN-γ in vitro when compared with control and sJIA PBMCs. Endothelial cells and fibroblasts expressed IFN-γ-induced proteins in situ in lymph node staining of a MAS patient and in vitro upon stimulation with IFN-γ.
  
  
  CONCLUSIONS
  Patients with active sJIA and HLH/MAS show distinct cytokine profiles, with highly elevated plasma levels of IFN-γ and IFN-γ-induced proteins typically found in HLH/MAS. In addition to PBMCs, histiocytes, endothelial cells and fibroblasts may contribute to an IFN-γ profile in plasma. Increasing levels of IFN-γ compared with IL-18 may raise suspicion about the development of MAS in sJIA.
authors.affiliation: Laboratory of Immunobiology.
authors.forename: Karen
authors.initials: K
authors.lastname: Put
authors.affiliation: Laboratory of Immunobiology.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Avau
authors.affiliation: Laboratory of Immunobiology.
authors.forename: Ellen
authors.initials: E
authors.lastname: Brisse
authors.affiliation: Laboratory of Immunobiology.
authors.forename: Tania
authors.initials: T
authors.lastname: Mitera
authors.affiliation: Laboratory of Immunobiology.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Put
authors.affiliation: Laboratory of Molecular Immunology, Rega Institute, University of Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.affiliation: IMAGINE Institute, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris-Descartes, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader-Meunier
authors.affiliation: Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, University of Leuven, Department of Rheumatology, University Hospital Leuven, Leuven, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Westhovens
authors.affiliation: Ludwig Institute for Cancer Research and de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Van den Eynde
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Laboratory of Pediatric Immunology, University Hospital Leuven, University of Leuven and.
authors.forename: Lien
authors.initials: L
authors.lastname: De Somer
authors.affiliation: Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.affiliation: IMAGINE Institute, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris-Descartes, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.affiliation: IMAGINE Institute, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris-Descartes, Paris, France, Laboratory of Pediatric Immunology, University Hospital Leuven, University of Leuven and.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Laboratory of Immunobiology, patrick.matthys@rega.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism*; D003937:Diagnosis, Differential; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D055501:Macrophage Activation Syndrome / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055815:Young Adult
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D015850:Interleukin-6; D007371:Interferon-gamma
keywords: IFN-γ; IL-18; cytokine; haemophagocytic lymphohistiocytosis; macrophage activation syndrome; peripheral blood mononuclear cells; plasma; systemic juvenile idiopathic arthritis