Pathways to fibrosis in Graves' orbitopathy
Lead Research Organisation:
University of Oxford
Department Name: Kennedy Institute
Abstract
Around a quarter of patients with the most common cause of thyroid gland overactivity (Graves' disease) develop a complication known as Graves' orbitopathy (GO). In GO, tissues in the space behind the eyeballs (the orbit) become inflamed, causing pressure to build up. This causes intense pain, restriction of eye movements, and in some cases permanent damage to sight. The pressure causes the eyeballs to bulge forward (proptosis), causing a startled, staring appearance which is disfiguring and a cause of great psychological harm (at least a third develop significant depression and anxiety). Following an initial highly active phase, patients with GO develop long lasting changes in the tissues of the orbit, which means the eyeballs remain projected forwards. Patients may be treated with high doses of steroids, and some require surgery to decompress the orbit, both to save sight and also to improve the appearance of the eyes.
It is well established that antibodies targeting a receptor which stimulates the thyroid gland are the cause of its overactivity in Graves' disease. Whilst this antibody is also important in GO, the majority of GD patients do not develop this complication. Why this might be is unknown. We also don't know if different antibodies are important in GO, and whether they are made by inflammatory cells local to the eye. The reason some patients develop long term disfigurement is also not understood.
In this project, we will use advanced techniques to analyse the makeup of the inflamed orbit, one cell at a time, from samples taken during decompression surgery. We will look at the antibody producing cells in the orbit and compare them to those in the blood, to see whether they are likely to be driving the disease. We will also look to see how the cells in the orbit are different between the initial and long term phases, and if there are subsets which may be responsible for this progression. Finally, we will perform experiments to see how antibodies and other inflammatory molecules cause changes in fibroblasts, important structural cells of the orbit.
It is well established that antibodies targeting a receptor which stimulates the thyroid gland are the cause of its overactivity in Graves' disease. Whilst this antibody is also important in GO, the majority of GD patients do not develop this complication. Why this might be is unknown. We also don't know if different antibodies are important in GO, and whether they are made by inflammatory cells local to the eye. The reason some patients develop long term disfigurement is also not understood.
In this project, we will use advanced techniques to analyse the makeup of the inflamed orbit, one cell at a time, from samples taken during decompression surgery. We will look at the antibody producing cells in the orbit and compare them to those in the blood, to see whether they are likely to be driving the disease. We will also look to see how the cells in the orbit are different between the initial and long term phases, and if there are subsets which may be responsible for this progression. Finally, we will perform experiments to see how antibodies and other inflammatory molecules cause changes in fibroblasts, important structural cells of the orbit.
Technical Summary
Graves' orbitopathy (GO) is a disfiguring and sight-threatening complication of Grave's disease, in which immune-mediated inflammation of the orbital contents progresses to tissue fibrosis. Whilst it is established that activating antibodies against the TSH receptor are central to GD, not all patients with GD develop GO, even in the presence of severe hyperthyroidism. We hypothesize that subsets of stromal cells and local antibody production drives GO, and mediates transition to tissue fibrosis.
To explore these hypotheses we will uncover the cellular landscape of the disease in its acute and fibrotic phases, using single-cell analysis of transcriptome, surface markers, and immune repertoire, in biopsy tissue and peripheral blood. We will study novel stromal cell subsets, and express pathogenic antibodies, determining their interactions with fibroblasts in functional experiments. This work will address fundamental mechanistic questions in immune-driven fibrotic disease, and has the potential to uncover new therapeutic targets for GO.
To explore these hypotheses we will uncover the cellular landscape of the disease in its acute and fibrotic phases, using single-cell analysis of transcriptome, surface markers, and immune repertoire, in biopsy tissue and peripheral blood. We will study novel stromal cell subsets, and express pathogenic antibodies, determining their interactions with fibroblasts in functional experiments. This work will address fundamental mechanistic questions in immune-driven fibrotic disease, and has the potential to uncover new therapeutic targets for GO.
