Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, NIH, Bethesda, Maryland and Research Triangle, Park, North Carolina.
Arthritis Rheumatol. 2023 Nov;75(11):2014-2026. doi: 10.1002/art.42615. Epub 2023 Aug 13.
Transcript 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.
Expression 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.
Expression 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.
The 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.
通过转录组和蛋白表达分析，研究接受免疫抑制治疗的成人活动期皮肌炎（DM）和青少年 DM 患者外周血中的基因座和通路调控。
将 14 名 DM 患者和 12 名青少年 DM 患者的表达数据与匹配的健康对照进行比较。通过多富集分析评估 DM 和青少年 DM 中受影响的通路，分析转录组和蛋白水平的调控效应。
在 DM 或青少年 DM 中，有 1124 个基因座的转录本或蛋白水平发生显著改变，其中 70 个基因是共同的。一组干扰素刺激基因升高，包括 CXCL10、ISG15、OAS1、CLEC4A 和 STAT1。DM 和青少年 DM 中均上调了中性粒细胞颗粒和中性粒细胞细胞外陷阱的固有免疫标志物，包括 BPI、CTSG、ELANE、LTF、MPO 和 MMP8。通路分析显示 PI3K/AKT、ERK 和 p38 MAPK 信号通路上调，这些通路的核心成分在 DM 中广泛上调，而 DM 和青少年 DM 中，上游和下游的外周成分则存在差异调节。DM 和青少年 DM 共同上调的成分包括细胞因子：受体对 LGALS9：HAVCR2、LTF/NAMPT/S100A8/HSPA1A：TLR4、CSF2：CSF2RA、EPO：EPOR、FGF2/FGF8：FGFR、几个 Bcl-2 成分和许多糖酵解酶。DM 特有的通路包括沉默调节蛋白信号通路、芳烃受体信号通路、蛋白质泛素化和颗粒酶 B 信号通路。
多富集分析的蛋白质组学和转录组表达相结合，扩大了对活动期 DM 和青少年 DM 患者中上调和下调通路的识别。这些通路，特别是那些与 PI3K/AKT 和 MAPK 信号通路以及中性粒细胞脱颗粒有关的通路，可能是潜在的治疗靶点。
