Journal
RHEUMATOLOGY
Volume 57, Issue 3, Pages 488-498Publisher
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/kex441
Keywords
juvenile idiopathic arthritis; low-density granulocytes; neutrophils; microarray; transcriptomics
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Funding
- Alder Hey Charity
- Arthritis Research UK
- University of Liverpool MRes Clinical Sciences Research Support Fund
- University of Liverpool, Alder Hey Children's NHS Foundation Trust
- Experimental Arthritis Treatment Centre for Children
- Medical Research Council [MR/P020941/1, MR/M01665X/1] Funding Source: researchfish
- MRC [MR/P020941/1, MR/M01665X/1] Funding Source: UKRI
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JIA is an autoimmune, inflammatory disease with involvement of innate and adaptive immune responses. However, the role of neutrophils in JIA pathogenesis remains unclear. This study aimed to identify and validate neutrophil gene expression signatures in JIA using public microarray datasets and new clinical samples. Three suitable datasets were analysed by significance analysis of microarray and Ingenuity. Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from a new cohort of JIA patients and healthy paediatric controls (HCs). Gene expression was validated using quantitative PCR. Serum concentrations of proteins were measured using ELISA. Low-density granulocytes (LDGs) in JIA and HC PBMCs were quantified by flow cytometry using forward/side-scatter properties. Ingenuity identified transcriptional regulation (false discovery rate < 0.05) by G-CSF, GM-CSF and IL-8 along with expression of neutrophil granule protein genes including ELANE, MPO, MMP8 and MMP9 in datasets from JIA PBMCs. LDG counts were elevated in JIA compared with HCs (2.5% vs 1.4%; P = 0.007). Transcripts for MMP8 (P = 0.005), MPO (P = 0.0124) and Fc gamma Receptor 1B (FC gamma R1B) (P = 0.0417) were significantly higher in JIA compared with HC neutrophils. MMP9 protein levels were lower in systemic JIA patient sera [355.95 ng/ml (s.d. 250.03)] compared with HCs [675.41 ng/ml (s.d. 181.17); P = 0.007], but levels of elastase, MPO and MMP8 were not significantly different. LDGs are elevated in JIA and contribute to the transcriptomic profile of JIA PBMCs. JIA neutrophils express higher levels of MMP8 and FCGR1B, which may be implicated in disease pathology through the release of proteases and reactive oxygen metabolites, causing systemic inflammation and damage to joints.
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