Wang Shuya, Sun Xianlei, Xin Qingxuan, Shi Jianxiang, Li Jin, Zhang Huilin, Xue Mengjiao, Yin Fanxiang, Qiu Zan, Wang Xiaoqian, Sun Nannan, Li Yingmei, Chen Yaoyao, Fu Liyan, Li Chaoqi, Yan Shaohua, Zhao Xian, Jue Bolin, Gao Yanxia, Yue Baohong, Qin Bo, Jiang Yong, Guo Rongqun
Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
iScience. 2025 Apr 17;28(5):112450. doi: 10.1016/j.isci.2025.112450. eCollection 2025 May 16.
Wilson disease (WD) is caused by mutations of the copper-transporting gene, , leading to abnormal copper metabolism. A better characterization of WD is essential in understanding the effects of excess copper and how it disrupts immune regulation and hematopoietic development. Furthermore, the exploration of the relationship between copper-mediated proliferation or cuproptosis and immune regulation is critical for developing new immune therapies. Therefore, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) to develop an atlas of the immune landscape. Cells were clustered into several immune subsets, and cuproptosis-associated genes were assessed. Differential expression analysis was performed to identify WD-specific signatures by comparing transcriptome profiles of patients with WD with HDs. Excess copper impaired immune homeostasis and hematopoietic development. Then, we developed a map of the immune landscape of patients with WD. Excess copper is involved in the metabolic reprogramming of immune cells, such as glycolysis in CD14 monocytes. We found that the antigen processing-related pathway is dysregulated in immune cells of patients with WD. Our study revealed that abnormal copper concentration influences the expression of HLA-I and HLA-II molecules. It is noteworthy that a high concentration of intracellular copper differs significantly from the high concentration of extracellular copper. We have also identified a gene set of neurologic abnormalities, which were dysregulated in PBMCs of patients with WD. We also observed abnormal expression of cuproptosis-associated genes in proliferating or malignant cells, providing new insights into the application of cuproptosis in cancer treatment.
威尔逊病（WD）由铜转运基因的突变引起，导致铜代谢异常。更好地描述WD对于理解过量铜的影响以及它如何破坏免疫调节和造血发育至关重要。此外，探索铜介导的增殖或铜死亡与免疫调节之间的关系对于开发新的免疫疗法至关重要。因此，我们对外周血单个核细胞（PBMC）进行了单细胞RNA测序（scRNA-seq），以构建免疫图谱。细胞被聚类为几个免疫亚群，并评估了与铜死亡相关的基因。通过比较WD患者与健康对照（HD）的转录组谱进行差异表达分析，以确定WD特异性特征。过量铜损害了免疫稳态和造血发育。然后，我们绘制了WD患者的免疫图谱。过量铜参与免疫细胞的代谢重编程，如CD14单核细胞中的糖酵解。我们发现抗原加工相关途径在WD患者的免疫细胞中失调。我们的研究表明，异常的铜浓度会影响HLA-I和HLA-II分子的表达。值得注意的是，细胞内高浓度铜与细胞外高浓度铜有显著差异。我们还确定了一组神经学异常相关基因，这些基因在WD患者的PBMC中失调。我们还观察到与铜死亡相关基因在增殖或恶性细胞中的异常表达，为铜死亡在癌症治疗中的应用提供了新的见解。
