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Lung Functioning and Inflammation in a Mouse Model of Systemic Juvenile Idiopathic Arthritis.

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.

SUBMITTER: Malengier-Devlies B

PROVIDER: S-EPMC7996094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveAccumulating evidence links juvenile idiopathic arthritis (JIA) to nonhost factors such as gut microbes. We hypothesize that children with new-onset JIA have increased intestinal bacterial translocation and circulating lipopolysaccharide (LPS).MethodsWe studied systemic treatment-naive patients with JIA [polyarticular JIA, n = 22, oligoarticular JIA, n = 31, and spondyloarthropathies (SpA), n = 16], patients with established inflammatory bowel disease-related arthritis (IBD-RA, n = 11), and 34 healthy controls. We determined circulating IgG reactivity against LPS, LPS-binding protein (LBP), α-1-acid glycoprotein (α-1AGP), and C-reactive protein (CRP) in plasma or serum from these patients and controls. Juvenile Arthritis Disease Activity Score (JADAS-27) was calculated for patients with JIA.ResultsCirculating anticore LPS antibody concentrations in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.024), and SpA (p = 0.001) were significantly greater than in controls, but there were no significant intergroup differences. Circulating LBP concentrations were also significantly greater in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.002), and SpA (p = 0.006) than controls, as were α-1AGP concentrations (p = 0.001, 0.001, and 0.003, respectively). No differences were observed between controls and patients with IBD-RA in any of the assays. Circulating concentrations of LBP and α-1AGP correlated strongly with CRP concentrations (r = 0.78 and r = 0.66, respectively). Anticore LPS antibody levels and CRP (r = 0.26), LBP (r = 0.24), and α-AGP (r = 0.22) concentrations had weaker correlations. JADAS-27 scores correlated with LBP (r = 0.66) and α-1AGP concentrations (r = 0.58).ConclusionChildren with polyarticular JIA, oligoarticular JIA, and SpA have evidence of increased exposure to gut bacterial products. These data reinforce the concept that the intestine is a source of immune stimulation in JIA.

Project description:OBJECTIVE:Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD). METHODS:Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. RESULTS:Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-?-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD. CONCLUSION:Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.

Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Project description:Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation. Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown. The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity. Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release. Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID. Results: Patients with SJIA and active systemic features demonstrated a higher number of CD16+CD62Llo neutrophil population compared to controls. This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features. Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils. Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts. Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils. Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes compared to neutrophils from healthy controls. The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4. Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation. Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8. Conclusion: We identify features of neutrophil activation in SJIA patients with active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation. Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.

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Lung Functioning and Inflammation in a Mouse Model of Systemic Juvenile Idiopathic Arthritis.

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