Abstract
Systemic juvenile idiopathic arthritis (sJIA) is an immune disorder characterized by fever, skin rash, arthritis and splenomegaly. Recently, increasing number of sJIA patients were reported having lung disease. Here, we explored lung abnormalities in a mouse model for sJIA relying on injection of IFN-γ deficient (IFN-γ KO) mice with complete Freund's adjuvant (CFA). Monitoring of lung changes during development of sJIA using microcomputer tomography revealed a moderate enlargement of lungs, a decrease in aerated and increase in non-aerated lung density. When lung function and airway reactivity to methacholine was assessed, gender differences were seen. While male mice showed an increased tissue hysteresivity, female animals were characterized by an increased airway hyperactivity, mirroring ongoing inflammation. Histologically, lungs of sJIA-like mice showed subpleural and parenchymal cellular infiltrates and formation of small granulomas. Flow cytometric analysis identified immature and mature neutrophils, and activated macrophages as major cell infiltrates. Lung inflammation in sJIA-like mice was accompanied by augmented expression of IL-1β and IL-6, two target cytokines in the treatment of sJIA. The increased expression of granulocyte colony stimulating factor, a potent inducer of granulopoiesis, in lungs of mice was striking considering the observed neutrophilia in patients. We conclude that development of sJIA in a mouse model is associated with lung inflammation which is distinct to the lung manifestations seen in sJIA patients. Our observations however underscore the importance of monitoring lung disease during systemic inflammation and the model provides a tool to explore the underlying mechanism of lung pathology in an autoinflammatory disease context.
Highlights
Systemic juvenile idiopathic arthritis is a childhood auto-inflammatory immune disorder, characterized by growth retardation, spiking fever, skin rash, arthritis, splenomegaly and polyserositis
While the inflammation is mild in WT animals, IFN-γ KO mice develop a more severe disease with symptoms and blood abnormalities that are similar to those reported in Systemic juvenile idiopathic arthritis (sJIA) patients (Supplementary Table 1) [22]
To identify potential lung disease during development of systemic inflammation, mice were monitored by high-resolution low-dose in vivo μCT before and after immunization with complete Freund’s adjuvant (CFA), that is, at day 12 when sJIA symptoms started to appear and at day 21 when blood abnormalities are maximal in both groups of mice [22]
Summary
Systemic juvenile idiopathic arthritis (sJIA) is a childhood auto-inflammatory immune disorder, characterized by growth retardation, spiking fever, skin rash, arthritis, splenomegaly and polyserositis. Hematological changes, such as leucocytosis, neutrophilia, anemia and thrombocytosis are typically seen. High levels of interleukin-6 (IL-6), IL-18, C-reactive protein (CRP) and S100 acute phase proteins are present in plasma of sJIA patients [1,2,3,4,5,6]. Around 10–15% of patients develop a live-threatening complication, called macrophage activation syndrome (MAS) which is associated with pancytopenia, increased liver enzymes, high ferritin levels, and coagulopathy [1, 7,8,9]. Part of sJIA patients can successfully be treated with biologics targeting IL-1β or IL-6, which replaced chronic high dose treatment with corticosteroids [11,12,13,14]
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