Altered signaling in systemic juvenile idiopathic arthritis monocytes

Abstract

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002-2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011-2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

Response to: ‘Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease: case report’ by Bader-Meunier et al

“…The patient in this report showed increased expression of interferon (IFN)-stimulated genes during anti-IL-1 treatment, consistent with evidence that a subset of patients on cytokine inhibition for sJIA developed an IFN signature/heightened response 5 6. Together with the observation of elevated circulating Th1 cells, the findings raise the possibility that IFN-γ signalling is a target of ruxolitinib in this patient.…”

Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis

“…It is unknown whether cytokine‐directed treatment with biologic agents, by targeting only a subset of pathways dysregulated in systemic JIA, could impact other immune signaling pathways. There is report of upregulated IFN‐induced pathways in patients treated with anakinra , and report that monocytes from patients treated with IL‐1 blocking agents show hyperresponsiveness to IFNγ . While the findings of this retrospective study cannot address these molecular mechanisms, they do support continued risk for MAS in patients treated with biologic agents during acute infections.…”

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.…”