A single-cell transcriptomic atlas of immune cells in Wilson disease identifies copper-specific immune regulation.

Wilson disease (WD) is caused by mutations of the copper-transporting gene, ATP7B, 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.