Dataset Information

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy.

ABSTRACT: Thyroid-associated ophthalmopathy (TAO), the most common and severe manifestation of Graves' disease (GD), is a disfiguring and potentially blinding autoimmune disease. The high relapse rate (up to 20%) and substantial side effects of glucocorticoid treatment further decrease the life quality of TAO patients. To develop novel therapies, we amid to explore the immunopathogenesis of TAO. To identify the key immune-related genes (IRGs) in TAO, we integrated the IRG expression profiles in thyrocytes from a GD patient set (GD vs healthy control) and a TAO patient set (TAO vs GD). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) and receiver operating characteristic (ROC) curve analyses identified the leptin receptor (LEPR) gene as the key IRG in TAO immunopathogenesis. Gene set enrichment analysis (GSEA) suggested enrichment of the antigen presentation pathway in TAO patients with higher LEPR. Increased LEPR expression was validated in TAO orbital tissues, and weighted gene co-expression network analysis (WGCNA) showed that cell adhesion processes were positively correlated with LEPR. Our study revealed that LEPR is a key gene in TAO immunopathogenesis and plays different roles in thyrocytes and orbital tissues. Our findings provide new insights into diagnostic and therapeutic biomarkers for TAO.

SUBMITTER: Chen Z

PROVIDER: S-EPMC8184729 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy.

Chen Ziyi Z Chen Zhe Z Wang Jingya J Zhang Meng M Wang Xiaofei X Cuomu Deji D Shi Bingyin B Wang Yue Y

Journal of cellular and molecular medicine 20210514 12

Thyroid-associated ophthalmopathy (TAO), the most common and severe manifestation of Graves' disease (GD), is a disfiguring and potentially blinding autoimmune disease. The high relapse rate (up to 20%) and substantial side effects of glucocorticoid treatment further decrease the life quality of TAO patients. To develop novel therapies, we amid to explore the immunopathogenesis of TAO. To identify the key immune-related genes (IRGs) in TAO, we integrated the IRG expression profiles in thyrocytes ...[more]

PMID: 33988300

Similar Datasets

Project description:BackgroundThyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.MethodsWe conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed.ResultsIn the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes.ConclusionsIn patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).

Project description:BackgroundThyroid-associated ophthalmopathy (TAO) is a common and organ-specific autoimmune disease. Early diagnosis and novel treatments are essential to improve the prognosis of TAO patients. Therefore, the current work was performed to identify the key genes and pathways for the biological and clinical implications of TAO through comprehensive bioinformatics analysis and a series of clinical validations.MethodsGSE105149 and GSE185952 were obtained from the Gene Expression Omnibus (GEO) database for analysis. The data were normalized to identify the common differentially expressed genes (DEGs) between the two datasets, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to assess key pathways in TAO. Protein-protein interaction (PPI) networks and hub genes among the common DEGs were identified. Furthermore, we collected the general information and blood samples from 50 TAO patients and 20 healthy controls (HCs), and the expression levels of the proteins encoded by hub genes in serum were detected by enzyme-linked immunosorbent assay (ELISA). Then we further assessed the relationship between the ELISA data and the TAO development.ResultsSeveral common pathways, including neuroactive ligand-receptor interaction, the IL-17 signaling pathway, and the TNF signaling pathway, were identified in both datasets. In parallel, 52 common DEGs were identified. The KEGG analysis showed that these common DEGs are mainly enriched in long-term depression, the VEGF signaling pathway, the IL-17 signaling pathway, the TNF signaling pathway, and cytokine-cytokine receptor interactions. The key hub genes PRKCG, OSM, DPP4, LRRTM1, CXCL6, and CSF3R were screened out through the PPI network. As confirmation, the ELISA results indicated that protein expression levels of PRKCG, OSM, CSF3R, and DPP4 were significantly upregulated in TAO patients compared with HCs. In addition, PRKCG and DPP4 were verified to show value in diagnosing TAO, and CSF3R was found to be a valuable diagnostic marker in distinguishing active TAO from inactive TAO.ConclusionsInflammation- and neuromodulation-related pathways might be closely associated with TAO. Based on the clinical verification, OSM, CSF3R, CXCL6, DPP4, and PRKCG may serve as inflammation- or neuromodulation-related biomarkers for TAO, providing novel insights for the diagnosis and treatment of TAO.

Project description:ContextThe molecular basis for anatomically dispersed clinical manifestations in Graves' disease (GD) eludes our understanding. Bone marrow-derived, pluripotent fibrocytes represent a subset of peripheral blood mononuclear cells and infiltrate the orbital and thyroid tissues in GD. These cells may be involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO).ObjectiveThe objective of the study was to quantify fibrocyte display of functional cell surface TSH receptor (TSHR), identify the profile of chemokines they express after TSHR activation, and determine whether circulating TSHR(+) peripheral blood fibrocytes are more frequent in situ in patients with TAO.Design/setting/participantsUsing a newly developed technique, fibrocytes were directly identified in peripheral blood from 31 patients with TAO and 19 healthy subjects receiving care at a multidisciplinary academic center.Main outcome measuresThe frequency in situ of fibrocytes (collagen 1(+), CD45(+), CD34(+), CD14(+), CD86(+) peripheral blood mononuclear cells) was assessed by multiparameter flow cytometry and correlated to clinical disease activity and smoking status. Levels of TSHR-displaying fibrocytes and their response to TSH and TSHR-activating antibody, M22, were measured by flow cytometry, Luminex, and real-time PCR.ResultsThe levels of TSHR expression by fibrocytes are substantially higher than those found in orbital fibroblasts. Moreover, the frequency of TSHR(+) fibrocytes in patients with TAO was greater than that in healthy subjects in situ. Their abundance is not influenced by disease activity or smoking history. These cells produce high levels of several cytokines and chemokines including IL-8, regulated upon activation, normal T cell expressed and secreted, and monocyte chemoattractant protein-1 when treated with TSH or M22. TSH induces IL-8 production at the pretranslational level. This induced cytokine can be detected in intact fibrocytes ex vivo.ConclusionsFrequency of circulating TSHR(+) fibrocytes is markedly increased in patients with TAO, and they express proinflammatory chemokines in response to TSH. Because they infiltrate both orbit and thyroid in GD, they may represent the link between systemic immunoreactivity and organ-specific autoimmunity.

Dataset Information

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy.

Publications

Leptin receptor is a key gene involved in the immunopathogenesis of thyroid-associated ophthalmopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets