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-␥ (IFN␥) in immune regulation, we challenged wild-type (WT) and IFN␥-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␥, these symptoms were more pro-

Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders

“…IL-17, produced by both adaptive CD4 + T cells and innate gd T cells, was shown to play a key proinflammatory role, as early treatment with either anti-IL-12/IL23p40 or anti-IL-17 antibodies prevented the emergence of the full sJIA/HLH-like syndrome. Interestingly, the observed defect in NK cell cytotoxicity might explain the susceptibility of CFA-challenged IFN-g À/À mice to the development of sJIA/HLH-like features, as CFA treatment of NK cell-depleted WT mice partially resulted in a syndrome similar to that seen in the IFN-g À/À mice [122]. Together with the reports on CpG-treated mice [114], this study highlights that HLH-like symptoms, including anemia and hemophagocytosis, can arise in the absence of IFN-g, questioning its role in secondary HLH as opposed to primary HLH [27].…”

“…Likewise, IL-6 is increased in the TLR9-induced MAS model [112], both Trypanosoma-induced animal models [103,106], in CFA-treated IFN-g À/À mice [122] and in three primary HLH models [17,23,39]. Tocilizumab, an anti-IL-6 receptor antibody, has been successfully administered to a patient who developed MAS in adult-onset Still's disease [148] but has also been associated with the onset of MAS in other patients [142,149].…”

“…IFN-g levels also vary significantly between different animal models, being generally higher in the models for primary HLH. Keeping the conditional effect of IFN-g in the TLR9-induced MAS model in mind [114], together with the emergence of HLH-like symptoms in CFA-challenged mice lacking IFN-g [122], this cytokine may not play the same dominant pathogenic role in secondary HLH as it does in most types of primary HLH. Data on IFN-g neutralization in various secondary HLH models are greatly needed to verify this possible discrepancy and its potential therapeutic relevance.…”

“…Another mouse model for sJIA was recently developed by Avau et al [122], generating a systemic inflammatory syndrome in IFNg À/À BALB/c mice by means of a single injection with complete Freund's adjuvant (CFA). In IFN-g À/À mice, compared to wild-type controls, this challenge triggered a persistent innate immune response with distinct sJIA-like features such as arthritis, occasional skin rash, neutrophilia, thrombocytosis and an increase in immature blood cell populations.…”

From bench to bedside and back again: translational research in autoinflammation

“…104,105 Thus, the challenge is to obtain an exact diagnosis and categorization of patients with sJIA in order to assess the value of this promising therapeutic approach (Figure 4).…”