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Healthy adult and sJIA blood stimulation with innate immune ligands

ABSTRACT: The goal of this study was to characterize altered inducible immune networks in Systemic onset juvenile idiopathic arthritis (sJIA), an IL-1-driven autoinflammatory disease of unknown etiology. To this end, we developed a high-throughput assay that quantifies the transcriptional and protein-level responses of blood leukocytes to innate stimuli. Herein, we report transcriptional data from healthy adult blood stimulated with 16 different conditions, including TLR ligands, cytosolic receptor ligands and inflammatory cytokines. We further report blood transcriptional profiles from sJIA patients with various disease activity and treatment statuses, both ex vivo (baseline) and after in vitro stimulation with a subset of innate stimuli including heat-killed bacterial pathogens.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103500 | GEO | 2017/09/19

SECONDARY ACCESSION(S): PRJNA401767

REPOSITORIES: GEO

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Project description:Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation. Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown. The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity. Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release. Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID. Results: Patients with SJIA and active systemic features demonstrated a higher number of CD16+CD62Llo neutrophil population compared to controls. This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features. Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils. Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts. Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils. Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes compared to neutrophils from healthy controls. The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4. Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation. Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8. Conclusion: We identify features of neutrophil activation in SJIA patients with active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation. Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.

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Healthy adult and sJIA blood stimulation with innate immune ligands

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