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

Area of Science:

• * Genetics and Immunology
• * Cellular Metabolism

Background:

• * Wilson disease (WD) results from ATP7B gene mutations, causing abnormal copper metabolism and accumulation.
• * Understanding copper's impact on immune regulation and hematopoietic development is crucial for WD management and therapy.
• * Cuproptosis, a copper-dependent cell death, and its link to immune responses require further investigation.

Purpose of the Study:

• * To characterize the immune landscape in Wilson disease using single-cell RNA sequencing.
• * To investigate the effects of excess copper on immune cell function and metabolism.
• * To identify WD-specific immune signatures and explore the role of cuproptosis.

Main Methods:

• * Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from WD patients and healthy donors (HDs).
• * Immune cell subset clustering and assessment of cuproptosis-associated genes.
• * Differential gene expression analysis to identify WD-specific transcriptomic profiles.

Main Results:

• * Excess copper impairs immune homeostasis and hematopoietic development in WD patients.
• * A detailed immune landscape map for WD revealed metabolic reprogramming in immune cells, including glycolysis in CD14+ monocytes.
• * Antigen processing pathways and HLA molecule expression (HLA-I and HLA-II) are dysregulated; neurologic abnormality gene sets are altered in WD PBMCs.
• * Abnormal cuproptosis-associated gene expression observed in proliferating/malignant cells.

Conclusions:

• * Excess copper significantly disrupts immune homeostasis and hematopoietic development in Wilson disease.
• * scRNA-seq provides a comprehensive immune atlas of WD, highlighting metabolic shifts and pathway dysregulation.
• * Findings offer insights into WD pathogenesis and potential therapeutic targets, including cuproptosis in cancer treatment.