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

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.

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Regulatory Role for NK Cells in a Mouse Model of Systemic Juvenile Idiopathic Arthritis

The Journal of Immunology ◽

10.4049/jimmunol.1900510 ◽

2019 ◽

Vol 203 (12) ◽

pp. 3339-3348 ◽

Cited By ~ 3

Author(s):

Jessica Vandenhaute ◽

Anneleen Avau ◽

Jessica Filtjens ◽

Bert Malengier-Devlies ◽

Maya Imbrechts ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Mouse Model ◽

Nk Cells ◽

Systemic Juvenile Idiopathic Arthritis ◽

Regulatory Role

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Response to: ‘Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease’ by Sato et al

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-217426 ◽

2020 ◽

pp. annrheumdis-2020-217426

Author(s):

Vivian E Saper ◽

Guangbo Chen ◽

R Paul Guillerman ◽

Purvesh Khatri ◽

Randy Q Cron ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Lung Disease ◽

Plasma Exchange ◽

Successful Treatment ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Systemic Juvenile Idiopathic Arthritis ◽

Severe Lung Disease ◽

Activation Syndrome ◽

Severe Lung

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Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-217470 ◽

2020 ◽

pp. annrheumdis-2020-217470

Author(s):

Grant S Schulert ◽

Alex V Pickering ◽

Thuy Do ◽

Sanjeev Dhakal ◽

Ndate Fall ◽

...

Keyword(s):

Bone Marrow ◽

Juvenile Idiopathic Arthritis ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Systemic Juvenile Idiopathic Arthritis ◽

Rna Seq ◽

Bone Marrow Macrophage ◽

Ifn Γ ◽

Activation Syndrome

ObjectivesSystemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response.MethodsBulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling.ResultsBulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness.ConclusionsMacrophages with an ‘IFN-γ response’ phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.

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A defect in thymic tolerance causes T cell-mediated autoimmunity in a murine model of COPA syndrome

10.1101/2020.01.21.914440 ◽

2020 ◽

Author(s):

Zimu Deng ◽

Christopher S. Law ◽

Frances O. Ho ◽

Kristin M. Wang ◽

Kirk D. Jones ◽

...

Keyword(s):

T Cells ◽

Mouse Model ◽

Lung Disease ◽

Pulmonary Hemorrhage ◽

Autoimmune Disorder ◽

Cell Types ◽

Lung Pathology ◽

Missense Mutations ◽

Peripheral Tissues ◽

Copa Syndrome

AbstractCOPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the Coatomer protein complex subunit alpha (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis that requires life-saving measures such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. Here we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.One Sentence SummaryA new mouse model of COPA syndrome develops lung pathology that recapitulates patients and reveals that T cells are important drivers of the disease.

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A dysregulated interleukin-18–interferon-γ–CXCL9 axis impacts treatment response to canakinumab in systemic juvenile idiopathic arthritis

Rheumatology ◽

10.1093/rheumatology/keab113 ◽

2021 ◽

Author(s):

Tanja Hinze ◽

Christoph Kessel ◽

Claas H Hinze ◽

Julia Seibert ◽

Hermann Gram ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Systemic Juvenile Idiopathic Arthritis ◽

Complete Response ◽

Interferon Γ ◽

Response To Therapy ◽

Inactive Disease ◽

Serum Samples ◽

Open Label ◽

Baseline Serum ◽

Ifn Γ

Abstract Objectives The monoclonal IL-1β antibody canakinumab is approved for the treatment of systemic juvenile idiopathic arthritis (SJIA). Its efficacy has been proven in several trials, but not all patients show a complete and sustained response to therapy. We aimed to analyse the association of baseline serum biomarkers with treatment outcome in patients with SJIA treated with canakinumab. Methods Serum samples from 54 patients with active SJIA without recent macrophage activation syndrome (MAS) treated with canakinumab in an open-label response characterization study were subjected to a multiplexed bead array assay. Interesting targets from these analyses were validated by ELISA. Clinical treatment outcomes included modified paediatric ACR (pACR) 30 and 90 responses, clinically inactive disease (CID) within 15 days of treatment and sustained complete response, defined as pACR100 or CID within 15 days of treatment plus no future flare or MAS. Results In canakinumab-naïve patients most biomarkers were elevated when compared with healthy controls at baseline and some rapidly decreased by day 15 [IL-1 receptor antagonist (IL-1RA), IL-6, IL-18 and S100A12]. Responders had higher IL-18 and IFN-γ levels and lower chemokine (C-X-C motif) ligand 9 (CXCL9) levels at baseline, emphasized by the IL-18: CXCL9 and IFN-γ: CXCL9 ratios. These ratios had significant accuracy in predicting treatment responses. Conclusion Differential regulation of the IL-18–IFN-γ–CXCL9 axis is observed in patients with SJIA. Higher IL-18: CXCL9 and IFN-γ: CXCL9 ratios at baseline are associated with a better clinical response to canakinumab treatment in SJIA. Future studies are needed to validate these findings and determine their generalizability to patients with recent MAS.

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