Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ

• Published in: Rheumatology (Oxford, England) England), 2015-08, Vol.54 (8), p.1507-1517
• Main Authors: Put, Karen, Avau, Anneleen, Brisse, Ellen, Mitera, Tania, Put, Stéphanie, Proost, Paul, Bader-Meunier, Brigitte, Westhovens, René, Van den Eynde, Benoit J, Orabona, Ciriana, Fallarino, Francesca, De Somer, Lien, Tousseyn, Thomas, Quartier, Pierre, Wouters, Carine, Matthys, Patrick
• Format: Article
• Language: English
• Subjects: Adolescent; Arthritis, Juvenile - diagnosis; Arthritis, Juvenile - metabolism; Arthritis, Juvenile - pathology; Biopsy; Case-Control Studies; Child; Child, Preschool; Cytokines - metabolism; Diagnosis, Differential; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Infant; Interferon-gamma - metabolism; Interleukin-18 - metabolism; Interleukin-6 - metabolism; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphohistiocytosis, Hemophagocytic - diagnosis; Lymphohistiocytosis, Hemophagocytic - metabolism; Lymphohistiocytosis, Hemophagocytic - pathology; Macrophage Activation Syndrome - diagnosis; Macrophage Activation Syndrome - metabolism; Macrophage Activation Syndrome - pathology; Male; Young Adult
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/keu524

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. 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. 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. 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.