Systemic Juvenile Idiopathic Arthritis–like Syndrome in Mice Following Stimulation of the Immune System With Freund's Complete Adjuvant: Regulation by Interferon‐γ
Abstract
Objective: Systemic juvenile idiopathic arthritis (JIA) is unique among the rheumatic diseases of childhood, given its distinctive systemic inflammatory character. Inappropriate control of innate immune responses following an initially harmless trigger is thought to account for the excessive inflammatory reaction. The aim of this study was to generate a similar systemic inflammatory syndrome in mice by injecting a relatively innocuous, yet persistent, immune system trigger: Freund's complete adjuvant (CFA), containing heat‐killed mycobacteria. Methods: Given the central role of interferon‐γ (IFNγ) in immune regulation, we challenged wild‐type (WT) and IFNγ‐knockout (KO) BALB/c mice with CFA, and analyzed their clinical symptoms and biologic characteristics. The production of cytokines and the effects of anticytokine antibodies were investigated. Results: In WT mice, CFA injection resulted in splenomegaly, lymphadenopathy, neutrophilia, thrombocytosis, and increased cytokine expression. In the absence of IFNγ, these symptoms were more pronounced and were accompanied by weight loss, arthritis, anemia, hemophagocytosis, abundance of immature blood cells, and increased levels of interleukin‐6 (IL‐6), all of which are reminiscent of the symptoms of systemic JIA. CFA‐challenged IFNγ‐KO mice showed increased expression of IL‐17 by CD4+ T cells and by innate γ/δ T cells. Inflammatory and hematologic changes were prevented by treatment with anti–IL‐12/IL‐23p40 and anti–IL‐17 antibodies. Conclusion: Immune stimulation of IFNγ‐KO mice with CFA produces a systemic inflammatory syndrome reflecting the clinical, biologic, and histopathologic picture of systemic JIA. The protective function of IFNγ in preventing anemia and overall systemic inflammation is a striking observation. The finding that both adaptive and innate T cells are important sources of IL‐17 may be of relevance in the pathogenesis of systemic JIA.
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An experimental model of macrophage activation syndrome provides evidence that Th17 cells can be drivers of a cytokine storm that is independent of interferon-γ.
“An experimental model of macrophage activation syndrome (a form of secondary HLH) provides evidence that Th17 cells can be drivers of a cytokine storm that is independent of interferon-γ.”
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- Authors
- Avau, A., Mitera, T., Put, S., Put, K., Brisse, E., Filtjens, J., Uyttenhove, C., Van Snick, J., Liston, A., Leclercq, G., Billiau, A. D., Wouters, C. H., & Matthys, P.
- Affiliations
- KU Leuven (BE)
- Ghent University (BE)
- UCLouvain (BE)
- Université Catholique de Louvain Brussels Belgium
- Universitair Ziekenhuis Leuven (BE)
- ORCID
- Venue
- Arthritis & Rheumatology
- Publisher
- Wiley
- Published
- 2014-04-28
- Volume
- 66
- Issue
- 5
- Pages
- 1340-1351
- ISSN
- 2326-5191 (ISSN-L)
- 2326-5205
- OpenAlex
- W1784973049
- Cited by
- 90
- References
- 52
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 9 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 13 · 2018: 9 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 4
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arthritis & Rheumatology (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Belgian Federal Science Policy Office
- Vlaamse Overheid
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- systemic juvenile idiopathic arthritis, complete Freund's adjuvant, interferon-gamma, IL-17, anti-IL-17 antibody, innate immune regulation, mycobacterial adjuvant, CD4+ T cells, γδ T cells, hemophagocytosis, anemia, systemic inflammation, cytokine expression
- MeSH terms
- Anemia, Animals, Arthritis, Juvenile, Disease Models, Animal, Female, Freund's Adjuvant, Immune System, Immunity, Innate, Inflammation, Interferon-gamma, Male, Mice, Inbred BALB C, Syndrome, Interleukin-6, Cytokines, Mice, Knockout, Interleukin-17, Mice, Adaptive Immunity
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