T-cell exhaustion-related genes in Graves' disease: a comprehensive genome mapping analysis

Front Endocrinol (Lausanne). 2024 Aug 22:15:1364782. doi: 10.3389/fendo.2024.1364782. eCollection 2024.

Abstract

Background: T-cell exhaustion (Tex) can be beneficial in autoimmune diseases, but its role in Graves' disease (GD), an autoimmune disorder of the thyroid, remains unknown. This study investigated Tex-related gene expression in GD patients to discern the potential contributions of these genes to GD pathogenesis and immune regulation.

Methods: Through gene landscape analysis, a protein-protein interaction network of 40 Tex-related genes was constructed. mRNA expression levels were compared between GD patients and healthy control (HCs). Unsupervised clustering categorized GD cases into subtypes, revealing distinctions in gene expression, immune cell infiltration, and immune responses. Weighted gene co-expression network analysis and differential gene expression profiling identified potential therapeutic targets. RT-qPCR validation of candidate gene expression was performed using blood samples from 112 GD patients. Correlations between Tex-related gene expression and clinical indicators were analyzed.

Results: Extensive Tex-related gene interactions were observed, with six genes displaying aberrant expression in GD patients. This was associated with atypical immune cell infiltration and regulation. Cluster analysis delineated two GD subtypes, revealing notable variations in gene expression and immune responses. Screening efforts identified diverse drug candidates for GD treatment. The Tex-related gene CBL was identified for further validation and showed reduced mRNA expression in GD patients, especially in cases of relapse. CBL mRNA expression was significantly lower in patients with moderate-to-severe thyroid enlargement than in those without such enlargement. Additionally, CBL mRNA expression was negatively correlated with the disease-specific indicator thyrotropin receptor antibodies.

Conclusion: Tex-related genes modulate GD pathogenesis, and their grouping aids subtype differentiation and exploration of therapeutic targets. CBL represents a potential marker for GD recurrence.

Keywords: CBL; Graves’ disease; T-cell exhaustion; enlargement of thyroid gland; weighted gene co-expression network analysis.

MeSH terms

  • Adult
  • Case-Control Studies
  • Chromosome Mapping
  • Female
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Graves Disease* / genetics
  • Graves Disease* / immunology
  • Humans
  • Male
  • Middle Aged
  • Protein Interaction Maps
  • Proto-Oncogene Proteins c-cbl / genetics
  • T-Cell Exhaustion
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Proto-Oncogene Proteins c-cbl

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Startup Fund for scientific research, Fujian Medical University (Grant number: 2021QH1117), the Quanzhou Guiding Science and Technology Programme projects in the field of medical and health care (Grant number: 2021N019S) and the Fujian Natural Science Foundation Project (Grant number: 2021J01252).