The limited role of interferon‐γ in systemic juvenile idiopathic arthritis cannot be explained by cellular hyporesponsiveness

Abstract

Objective Systemic juvenile idiopathic arthritis (JIA) is an autoinflammatory syndrome in which the myelomonocytic lineage appears to play a pivotal role. Inflammatory macrophages are driven by interferon‐γ (IFNγ), but studies have failed to demonstrate an IFN‐ induced gene signature in active systemic JIA. This study sought to characterize the status of an IFN‐induced signature within affected tissue and to gauge the integrity of IFN signaling pathways within peripheral monocytes from patients with systemic JIA. Methods Synovial tissue from 12 patients with active systemic JIA and 9 with active extended oligoarticular JIA was assessed by real‐time polymerase chain reaction to quantify IFN‐induced chemokine gene expression. Peripheral monocytes from 3 patients with inactive systemic JIA receiving anti–interleukin‐1β (anti–IL‐1β) therapy, 5 patients with active systemic JIA, and 8 healthy controls were incubated with or without IFNγ to gauge changes in gene expression and to measure phosphorylated STAT‐1 (pSTAT‐1) levels. Results IFN‐induced chemokine gene expression in synovium was constrained in active systemic JIA compared to the known IFN‐mediated extended oligoarticular subtype. In unstimulated peripheral monocytes, IFN‐induced gene expression was similar between the groups, except that lower levels of STAT1, MIG, and PIAS were observed in patients with active disease, while higher levels of PIAS1 were observed in patients with inactive disease. Basal pSTAT‐1 levels in monocytes tended to be higher in systemic JIA patients compared to healthy controls, with the highest levels seen in those with inactive disease. Upon stimulation of monocytes, the fold increase in gene expression was roughly equal between groups, except for a greater increase in STAT1 in patients with inactive systemic JIA compared to controls, and a greater increase in IRF1 in those with active compared to inactive disease. Upon stimulation, the fold increase in pSTAT‐1 was highest in monocytes from patients with inactive systemic JIA. Conclusion Monocytes in patients with active systemic JIA retain the ability to respond to IFNγ, suggesting that the lack of an IFN‐induced gene signature in patients with active disease reflects a limited in vivo exposure to IFNγ. In patients with inactive systemic JIA who received treatment with anti–IL‐1β, hyperresponsiveness to IFNγ was observed.

Altered signaling in systemic juvenile idiopathic arthritis monocytes

“…Our findings are similar to a study by Sikora et al [45], who showed that fresh, positively (CD14+) isolated, sJIA CD14+ monocytes from 4 active and 3 inactive sJIA patients did not exhibit hyporesponsiveness to IFNγ, as assessed by levels of pSTAT1. All the inactive sJIA patients were on IL-1 blockade and showed a higher fold increase in IFNγ-induced pSTAT1 than active patients or controls [45]. Interestingly, defective phosphorylation in response to IL-18 in sJIA NK cells was also restored following successful treatment with an IL-1 inihibitor [46].…”

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

“…However, other studies of unstimulated autoimmune patient PBMCs compared with controls have also not detected baseline differences in phosphorylation of signaling molecules, including p-STAT1 and p-STAT2 in Addison's disease (30), p-ZAP70 in type 1 diabetes (31), and p-STAT1 in systemic JIA (32,33). The lack of differences in basal phosphorylation may be due to sample processing.…”

Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

“…Consistently, patients with both active and inactive sJIA do not exhibit increased serum or synovial fluid IFNγ levels 27. Supporting the limited role of IFNγ in the arthritis of sJIA, and differently from what found in oligoarticular or polyarticular JIA, CXCL9 and CXCL10 are almost undetectable in the synovial tissues of patients with sJIA 28. Additionally, stimulation of IFNγ knockout mice with Freund's complete adjuvant produces a systemic inflammatory syndrome that includes features of sJIA 29…”