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Neutrophil and mononuclear leukocyte pathways and upstream regulators revealed by serum proteomics of adult and juvenile dermatomyositis
Arthritis Research & Therapy ( IF 4.4 ) Pub Date : 2024-11-11 , DOI: 10.1186/s13075-024-03421-7
A. Clare Sparling, James M. Ward, Kakali Sarkar, Adam Schiffenbauer, Payam Noroozi Farhadi, Michael A. Smith, Saifur Rahman, Kamelia Zerrouki, Frederick W. Miller, Jian-Liang Li, Kerry A. Casey, Lisa G. Rider

Serum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers. Serum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures. Seventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM. Coordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.

中文翻译:


成人和青少年皮肌炎的血清蛋白质组学揭示的中性粒细胞和单核白细胞通路以及上游调节因子



评估成人和青少年皮肌炎 (DM 和 JDM) 患者的血清蛋白丰度,以确定差异调节的蛋白质、改变的通路和候选疾病活动生物标志物。通过多重免疫测定将 17 名活动性成年 DM 和 JDM 患者的血清蛋白表达与匹配的健康对照受试者进行比较。检查差异调节蛋白的通路分析和蛋白质聚类以评估潜在机制。通过将蛋白质表达与疾病活动度指标相关联来鉴定候选疾病活动生物标志物。与健康对照相比,DM 和 JDM 患者血清中 172 种蛋白中有 78 种在血清中差异表达。48 个蛋白在 DM 中差异表达,32 个蛋白在 JDM 中差异表达,14 个蛋白在 DM 和 JDM 中差异表达。结合 DM 和 JDM 队列后,鉴定出 12 种额外的差异表达蛋白。C-X-C 基序趋化因子配体 10 (CXCL10) 是 DM 和 JDM 血清中上调最强的蛋白。DM 中其他高度上调的蛋白质包括 S100 钙结合蛋白 A12 (S100A12)、CXCL9 和烟酰胺磷酸核糖转移酶 (NAMPT),而 JDM 中高度上调的蛋白质包括基质金属肽酶 3 (MMP3) 、生长分化因子 15 (GDF15) 和血管性血友病因子 (vWF)。通路分析表明,磷酸肌醇 3-激酶 (PI3K) 、 p38 丝裂原活化蛋白激酶 (MAPK) 和 toll 样受体 7 (TLR7) 信号在 DM 和 JDM 中被激活。确定了 DM 或 JDM 特异性的其他途径。在 DM 和 JDM 中观察到与中性粒细胞和单核白细胞相关的蛋白质簇以及干扰素相关蛋白簇。 DM 中的 22 种蛋白质和 JDM 血清中的 24 种蛋白质与整体、肌肉和/或皮肤病活动相关。7 种蛋白质与 DM 和 JDM 血清中的疾病活动指标相关。IL-1 受体样 1 (IL1RL1) 成为 DM 和 JDM 的候选整体疾病活动生物标志物。通过多重免疫测定协调分析 DM 和 JDM 患者血清中的蛋白质表达,验证了先前的基因表达研究,并确定了新的失调蛋白、改变的信号通路和候选疾病活动生物标志物。这些发现可能进一步为 DM 和 JDM 患者的评估提供信息,并有助于确定潜在的治疗靶点。
更新日期:2024-11-11
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