Shared and Distinctive Transcriptomic and Proteomic Pathways in Adult and Juvenile Dermatomyositis

Abstract

ObjectiveTranscript and protein expression were interrogated to examine gene locus and pathway regulation in the peripheral blood of active adult dermatomyositis (DM) and juvenile DM patients receiving immunosuppressive therapies.MethodsExpression data from 14 DM and 12 juvenile DM patients were compared to matched healthy controls. Regulatory effects at the transcript and protein level were analyzed by multi‐enrichment analysis for assessment of affected pathways within DM and juvenile DM.ResultsExpression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or juvenile DM, with 70 genes shared. A subset of interferon‐stimulated genes was elevated, including CXCL10, ISG15, OAS1, CLEC4A, and STAT1. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up‐regulated in both DM and juvenile DM, including BPI, CTSG, ELANE, LTF, MPO, and MMP8. Pathway analysis revealed up‐regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up‐regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and juvenile DM. Up‐regulated components shared by DM and juvenile DM included cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR, several Bcl‐2 components, and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling.ConclusionThe combination of proteomics and transcript expression by multi‐enrichment analysis broadened the identification of up‐ and down‐regulated pathways among active DM and juvenile DM patients. These pathways, particularly those which feed into PI3K/AKT and MAPK signaling and neutrophil degranulation, may be potential therapeutic targets. image