Abstract
BackgroundAlthough thyroid eye disease is a common complication of Graves’ disease, the pathogenesis of the orbital disease is poorly understood. Most authorities implicate the immune response as an important causal factor. We sought to clarify pathogenesis by using gene expression microarray.MethodsAn international consortium of ocular pathologists and orbital surgeons contributed formalin fixed orbital biopsies. RNA was extracted from orbital tissue from 20 healthy controls, 25 patients with thyroid eye disease (TED), 25 patients with nonspecific orbital inflammation (NSOI), 7 patients with sarcoidosis and 6 patients with granulomatosis with polyangiitis (GPA). Tissue was divided into a discovery set and a validation set. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays which include 54,000 probe sets.ResultsPrincipal component analysis showed that gene expression from tissue from patients with TED more closely resembled gene expression from healthy control tissue in comparison to gene expression characteristic of sarcoidosis, NSOI, or granulomatosis with polyangiitis. Unsupervised cluster dendrograms further indicated the similarity between TED and healthy controls. Heat maps based on gene expression for cytokines, chemokines, or their receptors showed that these inflammatory markers were associated with NSOI, sarcoidosis, or GPA much more frequently than with TED.ConclusionThis is the first study to compare gene expression in TED to gene expression associated with other causes of exophthalmos. The juxtaposition shows that inflammatory markers are far less characteristic of TED relative to other orbital inflammatory diseases.
Highlights
The rationale to classify Graves’ disease as an autoimmune disease is irrefutable
Principal component analysis showed that gene expression from tissue from patients with thyroid eye disease (TED) more closely resembled gene expression from healthy control tissue in comparison to gene expression characteristic of sarcoidosis, nonspecific orbital inflammation (NSOI), or granulomatosis with polyangiitis
Heat maps based on gene expression for cytokines, chemokines, or their receptors showed that these inflammatory markers were associated with NSOI, sarcoidosis, or granulomatosis with polyangiitis (GPA) much more frequently than with TED
Summary
Graves’ disease is characterized by an autoantibody to the thyroid stimulating hormone receptor. It is widely believed that thyroid eye disease (TED) is autoimmune. It frequently coexists with Graves’ disease, so there is “guilt by association”. Many patients with Graves’, do not develop TED, nor is it clear that the autoantibody responsible for hyperthyroidism plays a pathogenic role in orbital disease. Thyroid eye disease is associated with polymorphisms in HLA molecules [1] and polymorphisms in receptors that modulate the immune response [2]. An increase in cytokine mRNA expression has been noted in orbital tissue from patients with TED [3]. We sought to clarify pathogenesis by using gene expression microarray
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