Pathogenesis of orbital adipose tissue hypertrophy in Graves’ ophthalmopathy
Date Issued
2008
Date
2008
Author(s)
Chen, Mei-Hsiu
Abstract
Graves’ ophthalmopathy (GO) or thyroid eye disease (TED) is associated with manifestations of proptosis, lid retraction, lid edema and extraocular muscles restriction related diplopia, which may influence patients’ cosmetics and visual acuity. Causes of proptosis included hypertrophy of extraocular muscle and orbital fat。 We are interested in orbital fat pathology as we know more about the new conepts of adipose tissue in its role in encocrine and inflammatory physiology as well as adipogensis in the recent 10 years. The only treatment for proptosis now is surgery. We hope the study about the molecular mechanism of Graves’ ophthalmoapthy will help to find out the possible medical treatment or the way to prevent it. In contrast to the understanding of the patholgenesis of hyperthyroidism in Graves’ disease, the pathogeneis of Graves’ ophthalmopathy is not so clear. Since Graves’ disease is an autoimmune disease, earlier studies focused in the release of cytokines (or chemokines) from lymphocytes and fibroblasts. However, in recent 10 years, we know that adipocytes could secret adipokines which will influence metabolism and inflammatory process and the preadipocytes which reside in adipose tissue have the ability to differentiate to adipocyte. After knowing that, studies began with adipogenesis in orbital fat using isolated orbital fibroblasts. We know that adipose tissue is a heterogenous tissue with multiple cell types, the studies using isolate orbital fibroblast would see only part of the mecahnism. For us to understand the whole tissue pathology, we need cDNA microassay to generate the hypothesis about the molecular mechanism of orbital fat hypertrophy. However, the large number of genes tested, the high variability between individuals, and the limited samples sizes in human studies have made it difficult to distinguish true differences from noise. The Gene Sets Enrichment Analysis (GSEA) is a powerful method to avoid the noise. By using the GSEA method, we found the expressions of specific gene sets related to lytic vacuoles, lysosomes and vacuoles, which we termed lysosome-related genes, were substantially different between orbital adipose tissues obtained from patients with and without Graves’ ophthalmopathy. We also use real-time quantitative PCR (QPCR) to validate single gene under those gene sets, which revealed the expression of CLN2, CLN3, and HEXB were down-regulated in orbital fat of patients with Graves’ ophthalmopathy. We also noticed that the macrophage marker, CD68, is a member of the lysosome-related gene set. We tried to elucidate the infiltration macrophage in orbital fat and its associated mechanism. We demonstrated macrophage infiltration is increased in orbital fat of patients with Graves’ ophthalmopathy and the mechanism is similar to the mechanism of macrophage infiltration in adipose tissue of obese subjects, to be associated with C-C motif chemokine family 2 (CCL2), or monocyte chemoattratant protein-1 (MCP-1). We understood that what we have done is not sufficient for generating medical treatment or way to prevent Graves’ ophthalmopathy, but our work provided a workable way to it.
Subjects
Graves'' ophthalmopathy
adipose tissue
microarray
Gene Sets Enrichemnt Analysis (GSEA)
lysosome
macrophage
SDGs
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