Karen Put1, Anneleen Avau1, Ellen Brisse1, Tania Mitera1, Stéphanie Put1, Paul Proost2, Brigitte Bader-Meunier3, René Westhovens4, Benoit J Van den Eynde5, Ciriana Orabona6, Francesca Fallarino6, Lien De Somer7, Thomas Tousseyn8, Pierre Quartier3, Carine Wouters9, Patrick Matthys10. 1. Laboratory of Immunobiology. 2. Laboratory of Molecular Immunology, Rega Institute, University of Leuven, Leuven, Belgium. 3. IMAGINE Institute, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris-Descartes, Paris, France. 4. Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, University of Leuven, Department of Rheumatology, University Hospital Leuven, Leuven, Belgium. 5. Ludwig Institute for Cancer Research and de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 6. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy. 7. Laboratory of Pediatric Immunology, University Hospital Leuven, University of Leuven and. 8. Department of Imaging and Pathology, University of Leuven, Leuven, Belgium. 9. 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. 10. Laboratory of Immunobiology, patrick.matthys@rega.kuleuven.be.
Abstract
OBJECTIVES: 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. CONCLUSION: 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.
OBJECTIVES: 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. CONCLUSION: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.
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