Journal Article

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

Karen Put, Anneleen Avau, Ellen Brisse, Tania Mitera, Stéphanie Put, Paul Proost, Brigitte Bader-Meunier, René Westhovens, Benoit J. Van den Eynde, Ciriana Orabona, Francesca Fallarino, Lien De Somer, Thomas Tousseyn, Pierre Quartier, Carine Wouters and Patrick Matthys

in Rheumatology

Volume 54, issue 8, pages 1507-1517
Published in print August 2015 | ISSN: 1462-0324
Published online March 2015 | e-ISSN: 1462-0332 | DOI: https://dx.doi.org/10.1093/rheumatology/keu524
Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ

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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.

Keywords: systemic juvenile idiopathic arthritis; macrophage activation syndrome; haemophagocytic lymphohistiocytosis; IFN-γ; IL-18; cytokine; plasma; peripheral blood mononuclear cells

Journal Article.  5724 words.  Illustrated.

Subjects: Rheumatology

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