Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Cells. 2023 Feb 21;12(5):676. doi: 10.3390/cells12050676.
Measure of drug-mediated immune reactions that are dependent on the patient's genotype determine individual medication protocols. Despite extensive clinical trials prior to the license of a specific drug, certain patient-specific immune reactions cannot be reliably predicted. The need for acknowledgement of the actual proteomic state for selected individuals under drug administration becomes obvious. The well-established association between certain HLA molecules and drugs or their metabolites has been analyzed in recent years, yet the polymorphic nature of HLA makes a broad prediction unfeasible. Dependent on the patient's genotype, carbamazepine (CBZ) hypersensitivities can cause diverse disease symptoms as maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms or the more severe diseases Stevens-Johnson-Syndrome or toxic epidermal necrolysis. Not only the association between HLA-B15:02 or HLA-A31:01 but also between HLA-B57:01 and CBZ administration could be demonstrated. This study aimed to illuminate the mechanism of HLA-B57:01-mediated CBZ hypersensitivity by full proteome analysis. The main CBZ metabolite EPX introduced drastic proteomic alterations as the induction of inflammatory processes through the upstream kinase ERBB2 and the upregulation of NFκB and JAK/STAT pathway implying a pro-apoptotic, pro-necrotic shift in the cellular response. Anti-inflammatory pathways and associated effector proteins were downregulated. This disequilibrium of pro- and anti-inflammatory processes clearly explain fatal immune reactions following CBZ administration.
衡量药物介导的免疫反应的指标取决于患者的基因型，从而决定了个体的用药方案。尽管在特定药物获得许可之前进行了广泛的临床试验，但某些特定于患者的免疫反应仍无法可靠预测。在药物给药时，需要承认选定个体的实际蛋白质组状态，这一点变得显而易见。近年来，已经分析了某些 HLA 分子与药物或其代谢物之间的明确关联，但 HLA 的多态性使得广泛的预测变得不可行。根据患者的基因型，卡马西平 (CBZ) 过敏会导致多种疾病症状，如斑丘疹性发疹、伴有嗜酸性粒细胞增多和全身症状的药物反应或更严重的史蒂文斯-约翰逊综合征或中毒性表皮坏死松解症。不仅可以证明 HLA-B15:02 或 HLA-A31:01 与 CBZ 给药之间存在关联，而且还可以证明 HLA-B57:01 与 CBZ 给药之间存在关联。本研究旨在通过全蛋白质组分析阐明 HLA-B57:01 介导的 CBZ 过敏反应的机制。主要的 CBZ 代谢物 EPX 通过上游激酶 ERBB2 诱导炎症过程，并上调 NFκB 和 JAK/STAT 途径，导致蛋白质组发生剧烈变化，这意味着细胞反应发生了促凋亡、促坏死的转变。抗炎途径和相关的效应蛋白下调。这种促炎和抗炎过程的失衡清楚地解释了 CBZ 给药后致命的免疫反应。
