Cutaneous drug-induced reactions are immune-mediated responses that can lead to life-threatening diseases such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome, and toxic epidermal necrolysis, collectively known as severe cutaneous adverse reactions (SCARs). Unfortunately, they cannot be predicted during drug development, and, at present, a prognostic biomarker is not available nor are validated in vitro assays for diagnosis. Thus, by using proteomic and microarray miRNA analysis, the cargo of extracellular vesicles obtained from SCARs patients was analyzed and correlated with the severity of the reaction. Confirmatory assays using Western blot and qRT-PCR were performed to validate findings, and bioinformatic tools were used to establish the correlation between protein and miRNAs expression between groups. The proteomic analysis showed an increase in the amount of pro-inflammatory proteins, von Willebrand factor, and C-reactive protein and a decrease in anti-inflammatory and protective proteins in the SCARs group compared with the control group. Additionally, histone protein H2A was enriched in DRESS patients. APO1 and SERPINA4 proteins, highly increased in the control group but absent in the SCARs group, are the target of several overexpressed miRNAs, suggesting that the regulation of these proteins might involve gene silencing and protein repressing mechanisms in the severe patients. According with previous reports showing its presence in plasma and T-cells, microRNA miR-18 was upregulated in extracellular vesicles obtained from the most severe patients. Determination of the unique cargo associated with different disease conditions will help to understand the pathophysiology of these complex reactions and might help to develop novel biomarkers for life-threatening iatrogenic cutaneous disease.

中文翻译：

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来自人血浆的细胞外囊泡在患有严重皮肤不良反应的患者中显示出独特的蛋白质组和 miRNA 谱

皮肤药物诱发反应是免疫介导的反应，可导致危及生命的疾病，如嗜酸性粒细胞增多和全身症状的药物反应 (DRESS)、史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症，统称为严重皮肤不良反应 (SCARs) ）。不幸的是，它们在药物开发过程中无法预测，目前，预后生物标志物不可用，也无法在体外进行验证用于诊断的化验。因此，通过使用蛋白质组学和微阵列 miRNA 分析，分析了从 SCAR 患者获得的细胞外囊泡的货物，并将其与反应的严重程度相关联。使用蛋白质印迹和 qRT-PCR 进行确认性分析以验证结果，并使用生物信息学工具建立组间蛋白质和 miRNA 表达之间的相关性。蛋白质组学分析显示，与对照组相比，SCARs 组的促炎蛋白、血管性血友病因子和 C 反应蛋白的数量增加，抗炎和保护蛋白的数量减少。此外，组蛋白 H2A 在 DRESS 患者中富集。APO1 和 SERPINA4 蛋白，在对照组中高度增加，但在 SCARs 组中不存在，是几种过表达miRNA的靶标，表明这些蛋白质的调节可能涉及重症患者的基因沉默和蛋白质抑制机制。根据之前的报告显示其存在于血浆和 T 细胞中，microRNA miR-18 在从最严重的患者获得的细胞外囊泡中上调。确定与不同疾病状况相关的独特货物将有助于了解这些复杂反应的病理生理学，并可能有助于开发威胁生命的医源性皮肤病的新型生物标志物。microRNA miR-18 在从最严重的患者获得的细胞外囊泡中上调。确定与不同疾病状况相关的独特货物将有助于了解这些复杂反应的病理生理学，并可能有助于开发威胁生命的医源性皮肤病的新型生物标志物。microRNA miR-18 在从最严重的患者获得的细胞外囊泡中上调。确定与不同疾病状况相关的独特货物将有助于了解这些复杂反应的病理生理学，并可能有助于开发威胁生命的医源性皮肤病的新型生物标志物。