Distinct Fibroblast Phenotypes in Active and Inactive Thyroid Eye Disease Revealed by Single-Cell Transcriptomic Profiling
Author: Anne Xuan-Lan Nguyen
Base Hospital / Institution: Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
ePoster presentation
Abstract ID: 25-354
Purpose
Thyroid Eye Disease (TED) is a sight-threatening complication in up to 50% of Graves’ disease patients. The immune-to-fibrosis shift in TED remains poorly understood. We characterize distinct cellular landscapes in acute versus fibrotic phases of thyroid eye disease (TED), emphasizing pathogenic fibroblast subsets.
Methods
We collected clinical data, laboratory results, orbital tissue, and blood samples from TED patients undergoing decompression surgery and non-inflammatory controls at the Oxford Eye Hospital (Oxford, United Kingdom). TED patients were classified as active (Clinical Activity Score≥3) or inactive (CAS<3). Single-cell RNA sequencing on orbital samples was performed to characterize gene expression profiles, with analyses of fibroblast subpopulations.
Results
Eleven participants were included: 4 orbital samples from active TED patients (mean age of 66, all female, all White, 1/3 active smoker, mean TSH receptor antibody (TRAb) levels of 10.6), 6 orbital samples from inactive patients (mean age of 54, 4/6 female, 4/6 White & 2/6 Asian, 2/6 smokers, mean TrAb of 3.9), and 2 orbital samples from controls (mean age of 55, both male, White and non-smoker).
Single-cell analysis revealed distinct fibroblast phenotypes associated with disease activity. Active TED was characterized by inflammatory-adipogenic PLIN2+/TNFSF8+ fibroblasts expressing KYNU and S100A9, corresponding to clinical proptosis and inflammation. Inactive TED demonstrated a transition toward fibrotic (SPARC, GPX3, BAMBI) and contractile (TAGLN, NDUFA4L2, COLEC11) phenotypes, associated to restricted motility and fibrosis. RORA+ fibroblasts marked a TSHR+/IGF1R+ cluster that may modulate these disease-stage transitions through ELL2 expression.
Conclusion
This study reveals fibroblast heterogeneity in TED, identifying distinct transcriptomic signatures and subsets driving inflammatory-adipogenic versus fibrotic-contractile pathways. These findings hint to potential therapeutic targets for stage-specific intervention, with future work focusing on predictive models for personalized treatment.
Additional Authors
| First name | Last name | Base Hospital / Institution |
|---|---|---|
| Hana F. | Andrew | Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom. |
| Julia C. | Johnstone | Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom. |
| Jonathan | Norris | Oxford Eye Hospital, John Radcliffe Hospital, Oxford, United Kingdom. |
| Alexander | Clarke | Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom. |
