期刊
RHEUMATOLOGY
卷 54, 期 8, 页码 1507-1517出版社
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keu524
关键词
systemic juvenile idiopathic arthritis; macrophage activation syndrome; haemophagocytic lymphohistiocytosis; IFN-gamma; IL-18; cytokine; plasma; peripheral blood mononuclear cells
类别
资金
- Fund for Scientific Research - Flanders
- Regional Government of Flanders
- Interuniversity Attraction Poles Program
- Institute for the Promotion of Innovation through Science and Technology
Objectives. To study the role of IFN-gamma in the pathogenesis of systemic JIA (sJIA) and haemophagocytic lymphohistiocytosis (HLH) by searching for an IFN-gamma 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-gamma-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-gamma responses were investigated in healthy donor PBMCs, primary fibroblasts and endothelial cells. Results. Plasma IFN-gamma, IL-6 and IL-18 were elevated in active sJIA and HLH. Levels of IFN-gamma and IFN-gamma-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-gamma were higher in active sJIA compared with HLH. HLH PBMCs showed hyporesponsiveness to IFN-gamma in vitro when compared with control and sJIA PBMCs. Endothelial cells and fibroblasts expressed IFN-gamma-induced proteins in situ in lymph node staining of a MAS patient and in vitro upon stimulation with IFN-gamma. Conclusion. Patients with active sJIA and HLH/MAS show distinct cytokine profiles, with highly elevated plasma levels of IFN-gamma and IFN-gamma-induced proteins typically found in HLH/MAS. In addition to PBMCs, histiocytes, endothelial cells and fibroblasts may contribute to an IFN-gamma profile in plasma. Increasing levels of IFN-gamma compared with IL-18 may raise suspicion about the development of MAS in sJIA.
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