# Transcriptomic Profiling of Orbital Fat Tissue and Ocular Surface Wash in Active Thyroid Eye Disease Requiring Urgent Orbital Decompression

## TL;DR

This study explores the molecular changes in orbital fat and eye surface samples from patients with severe thyroid eye disease, revealing immune system involvement and potential new treatments.

## Contribution

The study provides a molecular atlas of active TED and identifies neutrophils, noninvasive biomarkers, and candidate therapeutics.

## Key findings

- Retro-orbital fat showed upregulated immune genes with a strong neutrophilic signature.
- Ocular surface wash samples had downregulated immune signatures and potential biomarkers like CD151, MAST4, and HPCAL1.
- JAK and BTK inhibitors were identified as candidate therapeutics for TED.

## Abstract

Thyroid eye disease (TED) is an autoimmune disorder characterized by orbital inflammation and tissue remodeling. Although most patients with active TED respond to medical therapy, a subset develops sight-threatening complications which require urgent orbital decompression when conservative treatment fails. This study aimed to elucidate the molecular mechanisms underlying active, moderate-to-severe TED in patients requiring urgent orbital decompression during the active disease stage.

Transcriptomic profiling was performed on retro-orbital fat samples from 13 patients and ocular surface wash samples from 9 patients undergoing urgent orbital decompression, as well as on samples from control subjects. Differential gene expression, pathway enrichment, cell-type composition, and drug-gene interactions were analyzed.

In retro-orbital fat, the majority of differentially expressed genes were upregulated, predominantly mapping to immune system, with a pronounced neutrophilic signature including degranulation and extracellular trap formation. Increased infiltration of neutrophils, B cells, and T cells was observed, whereas ocular surface wash samples exhibited a largely downregulated immune signature, reflecting compartment-specific immune responses. Expression of several transcripts from ocular surface wash correlated with patients’ disease activity, suggesting potential use as noninvasive biomarkers with CD151, MAST4, and HPCAL1 genes correlating best. Drug-gene interaction analysis nominated JAK and BTK inhibitors as candidate therapeutics in TED.

This study provides a unique molecular atlas of active, moderate-to-severe TED environment, uncovers the active role of neutrophils in TED pathogenesis, and identifies candidate therapeutic targets and noninvasive biomarkers that may inform future clinical strategies.