Abstract
The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.
Highlights
Human immune responses arise as the result of complex molecular and cellular interactions upon exposure to environmental and internal triggers
Oligonucleotides that stimulate TLR8 (ORN-8L) and TLR9 (CpG-C) induced an IFN response in PBMCs (Guiducci et al, 2013), this was not demonstrated in whole blood, where the response was predominantly proinflammatory (IL-1 and NF-κB pathways; Fig. S1 B).This may be caused by conformational or interaction alterations of oligonucleotides in plasma, because low-molecular-weight compounds that activate TLR7 (R837) and TLR8 (R848) induce IFN signatures in blood (Coch et al, 2013)
Of the 19 modules identified by weighted gene coexpression network analysis (WGCNA) (Fig. 5 A), we focused on the ones that strongly correlated with protein markers and that displayed transcriptional differences between systemic juvenile idiopathic arthritis (sJIA) inactive untreated (sIU) patients and healthy controls in response to any stimulus (Fig. 5 B)
Summary
Human immune responses arise as the result of complex molecular and cellular interactions upon exposure to environmental and internal triggers. Comprehensive examination of these networks in health and disease has been facilitated by systems biology, a discipline that employs high-throughput assays to evaluate thousands of parameters simultaneously (Chuang et al, 2010; Kidd et al, 2014). Immune cells are commonly profiled ex vivo, which represents a snapshot of their in vivo phenotype. Well suited to characterize effector responses during active disease, ex vivo profiling often fails to reveal the underlying molecular phenotypes and events predispos-.
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