Session Title: Pediatric Rheumatology – Pathogenesis and Genetics Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Although type I interferon (IFN1) and endoplasmic reticulum (ER) stress have been implicated in pathogenesis of juvenile dermatomyositis (JDM), little else is known about additional biological processes that may be involved and perhaps upstream of these pathways, or about processes that remain abnormal even when inflammation is controlled. To identify novel pathways dysregulated in JDM, we performed RNASeq on sorted immune subtypes from JDM patients and healthy controls.
Peripheral blood samples were obtained from patients enrolled in the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS) at pre-treatment (n=13) and 11.8 [11.3-13.2] months follow-up, (n=13) including n=10 matched samples, and age/sex-matched healthy controls (n=8). CD4+, CD8+, CD14+ and CD19+ cells were flow-sorted from PBMCs by flow cytometry and RNA was extracted and sequenced. Gene set enrichment analysis (GSEA) and gene ontology (GO) term enrichment analysis were performed.
A strong IFN1 signature was identified: “IFNα signaling” was the most strongly enriched gene set identified by GSEA in all cell types (normalized enrichment scores of 2.39 (p<0.001), 2.84 (p<0.001), 2.88 (p<0.001) and 3.41 (p<0.001) for CD4, CD8, CD19 and CD14 cells, respectively). Overall, a higher proportion of differentially expressed (DE) genes were identified in CD14+ monocytes compared to other cell subtypes. Interestingly, 1,594 genes were DE in on-treatment monocytes compared to controls when IFN1 was no longer abnormal, suggesting on-going abnormal function even after a year of treatment. GO analysis of these genes identified over-representation of GO terms involved in mitochondrial function. A mitochondrial score (comprising all 13 protein-coding mitochondrial genes) correlates negatively with an IFN1 score (15 representative IFN-stimulated genes) in baseline monocytes (R=-0.87, p=0.003), indicating reduced expression of mitochondrially-encoded genes is associated with increased IFN1 signature. Analysis of the 343 genes annotated by the “Mitochondrion” Gene Ontology term GO:0005739 showed 54 were DE in baseline monocytes compared to follow-up, 51 were DE in baseline monocytes compared to controls, and 59 were DE in follow-up monocytes compared to controls. Notably, a set of genes involved in mitochondrial function were abnormally expressed in both baseline and follow-up monocytes compared to controls, indicating that mitochondrial dysfunction is not fully corrected by current treatment. Functional studies to characterise dysfunctions of monocytes and mitochondria are ongoing.
This transcriptomic study has identified abnormal gene expression in the monocyte compartment in particular, and a striking dysregulation of genes involved in mitochondrial function. Ongoing functional work to characterize these dysfunctions will explore the potential of mitochondrial dysfunction as a novel treatment target.
To cite this abstract in AMA style:Deakin C, Rosser E, Marshall L, Wilkinson M, Khabbush A, Simou S, Otto G, Dowle S, Kelberman D, Yona S, Eaton S, Wedderburn LR. Transcriptomic Analysis Reveals Mitochondrial and Monocyte Dysfunctions Are Linked to the Interferonopathy of Juvenile Dermatomyositis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/transcriptomic-analysis-reveals-mitochondrial-and-monocyte-dysfunctions-are-linked-to-the-interferonopathy-of-juvenile-dermatomyositis/. Accessed September 24, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptomic-analysis-reveals-mitochondrial-and-monocyte-dysfunctions-are-linked-to-the-interferonopathy-of-juvenile-dermatomyositis/