Systemic Juvenile Idiopathic Arthritis-like Syndrome in Mice Following Stimulation of the Immune System With Freund's Complete Adjuvant Regulation by Interferon-γ

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-gamma (IFN gamma) in immune regulation, we challenged wild-type (WT) and IFN gamma-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 IFN gamma, 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 IFN gamma-KO mice showed increased expression of IL-17 by CD4+ T cells and by innate gamma/delta 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 IFN gamma-KO mice with CFA produces a systemic inflammatory syndrome reflecting the clinical, biologic, and histopathologic picture of systemic JIA. The protective function of IFN gamma 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.