Understanding the tissue biology of thyroid eye disease

Project No: NC-20
Intake: 2024 KIR Non Clinical

PROJECT OVERVIEW

Thyroid eye disease (also known as Graves’ orbitopathy, GO) is a potentially sight-threatening and disfiguring complication of Graves’ disease (GD), an inflammatory syndrome characterised by hyperthyroidism, orbital inflammation, and dermopathy, associated with activating antibodies against the TSH receptor. GD is one of the most common autoimmune diseases.

It is well established that the presence of activating autoantibodies directed against the thyroid-stimulating hormone receptor (TSHR) is central to GD pathogenesis. Although it may be inferred that GO is a result of a similar underlying process, the TSHR is expressed on many other tissues which are not clinically involved in GD. In addition, ophthalmopathy may develop before or many years after the onset of hyperthyroidism. GO is a highly inflammatory process, with orbital infiltration of B and T cells, monocytes and macrophages. Activation of fibroblasts increases hyaluronan production and enhances their differentiation into either myofibroblasts or adipocytes. This process causes extraocular muscle and orbital adipose tissue enlargement, and the excess volume of intraorbital tissue accounts for the clinical features of GO Strikingly, it still remains unknown why some patients with GD develop eye disease.

Treatment options for GO are limited, and responses are often poor – frequently surgical decompression is required to avert sight loss or correct cosmetic appearances.

In this project, you will use cutting edge methodologies to investigate the cellular basis for GO in orbital tissue obtained during surgery, and to understand how the immune system determines disease, and so prioritise potential new therapeutic targets.

KEYWORDS (5 WORDS)

Thyroid eye disease

Graves’ orbitopathy

Immunology

Single cell genomics

TRAINING OPPORTUNITIES

This project provides a broad training in cell biology, immunology, and genomics, with a focus on single cell genomics, high dimensional immune profiling, and computational biology. There will be substantial clinical contact throughout at Oxford Eye Hospital.

KEY PUBLICATIONS (5 MAXIMUM)

Bahn, R. S. Graves' ophthalmopathy. N. Engl. J. Med. 362, 726–738 (2010).

Bashford-Rogers, R. J. M. et al. Analysis of the B cell receptor repertoire in six immune-mediated diseases. Nature 1–29 (2019). doi:10.1038/s41586-019-1595-3

Khong, J. J., McNab, A. A., Ebeling, P. R., Craig, J. E. & Selva, D. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol 100, 142–150 (2016).