Microarray Data of Lacrimal Gland Implicates Dysregulated Protein Processing in Endoplasmic Reticulum in Graves' Ophthalmopathy.

Wenling Tu,Zhanjun Mei,Xue Jiang,Yuhong Shi,Jia Yao

doi:10.3389/fendo.2020.571151

Abstract

Graves’ ophthalmopathy (GO) has become one of the most common orbital diseases. Although some evidences announced the potential mechanism of pathological changes in extraocular muscle and orbital adipose tissue, little is known about that in lacrimal enlargement of GO patients. Thus, gene expression profiles of lacrimal gland derived from GO patients and normal controls were investigated using the microarray datasets of GSE105149 and GSE58331. The raw data and annotation files of GSE105149 and GSE58331 were downloaded from Gene Expression Omnibus (GEO) database. Bioinformatics including differentially expressed genes (DEGs), Gene Ontology, Kyoto Encyclopedia of Gene and Genome (KEGG) pathway, protein-protein interaction (PPI) network construction, hub gene identification, and gene set variation analysis (GSVA) were successively performed. A total of 173 overlapping DEGs in GSE105149 and GSE58331 were screened out, including 20 up-regulated and 153 down-regulated genes. Gene Ontology, KEGG and GSVA analyses of these DEGs showed that the most significant mechanism was closely associated with endoplasmic reticulum (ER). Moreover, we identified 40 module genes and 13 hub genes which were also enriched in the ER-associated terms and pathways. Among the hub genes, five genes including HSP90AA1, HSP90B1, DNAJC10, HSPA5, and CANX may be involved in the dysfunction of protein processing in ER. Taken together, our observations revealed a dysregulated gene network which is essential for protein processing in ER in GO patients. These findings provided a potential mechanism in the progression of lacrimal enlargement in GO patients, as a new insight into GO pathogenesis.

Highlights

Graves’ ophthalmopathy (GO), known as thyroid eye disease (TED), is an orbital disease that is uniquely linked to Graves’ disease (GD), generally present in 25%–50% of GD patients [1]
The overlapping differentially expressed genes (DEGs) were further measured through Gene Ontology and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses to explore the possible functions and pathways in the pathogenesis of GO lacrimal enlargement
In the biological process (BP) category, most DEGs were involved in RNA splicing, protein folding in endoplasmic reticulum (ER), cell-cell adhesion, mRNA processing and ER to Golgi vesicle-mediated transport

Summary

Introduction

Graves’ ophthalmopathy (GO), known as thyroid eye disease (TED), is an orbital disease that is uniquely linked to Graves’ disease (GD), generally present in 25%–50% of GD patients [1]. It is generally agreed that GO is an autoimmune disease that results in orbital remodeling, enlargement and fibrosis [3]. These pathological changes involves three distinct but related immune processes: inflammation, adipogenesis and glycosaminoglycan accumulation [4]. Activated orbital fibroblasts could secrete many cytokines, such as interleukins 1b, 6, 8, 16, TNF-a, RANTES and CD154 [6]. These cytokines promote orbital trafficking of monocytes and macrophages, facilitate differentiation of orbital fibroblasts and stimulate accumulation of hyaluronic acid-rich stroma, leading to uncontrolled immune responses [4,5,6]. Several mechanisms have been proposed for the development of GO, the exact pathogenesis of GO has not yet been illustrated

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