NK Cell Exhaustion in Wilson’s Disease Revealed by Single-cell RNA Sequencing Predicts the Prognosis of Cholecystitis

  1. Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, P. R. China
  2. Department of Cadre Cardiology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, P. R. China
  3. Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, P. R. China
  4. Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230031, P. R. China
  5. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.

Read more about eLife’s peer review process.

Editors

  • Reviewing Editor
    Shiny Nair
    Yale University, New Haven, United States of America
  • Senior Editor
    Tadatsugu Taniguchi
    University of Tokyo, Tokyo, Japan

Reviewer #1 (Public Review):

Summary:

Wilson's Disease (WD) is an inherited rare pathological condition due to a mutation in ATP7B that alters mitochondrial structure and dysfunction. Additionally, WD results in dysregulated copper metabolism in patients. These metabolic abnormalities affect the functions of the liver and can result in cholecystitis. Understanding the immune component and its contribution to WD and cholecystitis has been challenging. In this work, the authors have performed single-cell RNA sequencing of mesenchymal tissue from three WD patients and three liver hemangioma patients.

Strengths:

The authors describe the transcriptomic alterations in myeloid and lymphoid compartments.

Weaknesses:

In brief, this manuscript lacks a clear focus, and the writing needs vast improvement. Figures lack details (or are misrepresented), the results section only catalogs observations, and the discussion needs to focus on their findings' mechanistic and functional relevance. The major weakness of this manuscript is that the authors do not provide a mechanistic link between the absence of ATP7B and NK cells' impaired/altered functions. While the work is of high clinical relevance, there are various areas that could be improved.

Reviewer #2 (Public Review):

Summary:

Wilson's disease is a rare genetic disorder caused by mutations in the ATP7B gene. Previous studies have documented that ATP7B mutations can disrupt copper metabolism, affecting brain and liver function. In this paper, the authors performed a retrospective clinical study and found that Wilson's disease has a high incidence of cholecystitis. Single-cell RNA-seq analysis revealed changes in the immune microenvironment, including the activation of immune responses and the exhaustion of natural killer cells.

Strengths:

A key finding of this study is that the predominant ATP7B gene mutation in the Chinese population is the 2333G>T (p. R778L) mutation. The authors reported associations between Wilson's disease and cholecystitis, as well as the exhaustion of natural killer cells.

Weaknesses:

The underlying mechanisms linking ATP7B mutations to cholecystitis and natural killer cell exhaustion remain unclear. Specifically, it is not yet determined whether copper metabolism alterations directly cause cholecystitis and natural killer cell exhaustion, or if these effects are secondary to liver dysfunction.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation