Pathogenesis Of Thyroid-associated Ophthalmopathy Research Articles

Single-cell BCR and transcriptome analysis reveals peripheral immune signatures in patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is the most prevalent orbital disease in adults caused by an autoimmune disorder, which can lead to disfigurement and vision impairment. Developing effective treatments for this condition presents challenges due to our limited understanding of its underlying immune aberrations. In this study, we profiled the immune components in the peripheral blood of patients with TAO as well as healthy individuals, utilizing single-cell RNA sequencing and B-cell receptor repertoires (BCR) analysis. We observed a significant reduction in the proportions of regulatory B cells (Bregs) and type 2 conventional dendritic cells (DCs) in patients with TAO during the active phase. Conversely, there was a significant increase in the proportion of type 1 DCs. Further analysis of cell differentiation trajectory revealed potential impairment in the transition of B cells towards Breg phenotype during the active phase of TAO. Besides, the activation process of TAO appeared to involve inflammation and immune dysfunction, as indicated by the dynamic changes in the activities of key regulators. The abnormalities in the peripheral immune system, such as the reduced capacity of Bregs to suppress inflammation, were primarily driven by the enhanced interaction among Breg, DCs, and monocytes (i.e., CD22-PTPRC and BTLA-TNFRSF14). Collectively, our findings offer a comprehensive insight into the molecular regulation and cellular reconfiguration during the active phase of TAO at the single-cell level, in order to explore the pathogenesis of TAO and provide new ideas for the future treatment of TAO.

Early diagnosis of thyroid-associated ophthalmopathy using label-free Raman spectroscopy and multivariate analysis

Thyroid-associated ophthalmopathy (TAO) is the most common orbital disease in adults, with complex clinical manifestations and significant impacts on the life quality of patients. The current diagnosis of TAO lacks reliable biomarkers for early and non-invasive screening and detection, easily leading to poor prognosis. Therefore, it is essential to explore new methods for accurately predicting TAO development in its early stage. In this study, Raman spectroscopy, with non-destructive, label-free, and high-sensitivity characteristics, was used to analyze the differences in biochemical components of orbital adipocyte and tear samples between TAO and control groups. Furthermore, a multivariate analysis method (i.e., Principal Component Analysis-Linear Discriminant Analysis (PCA-LDA)) was applied for data processing and analysis. Compared with controls, PCA-LDA yielded TAO diagnostic accuracies of 72.7% and 75.0% using orbital adipocytes and tears, respectively. Our proof-of-concept results suggest that Raman spectroscopy holds potential for exploring the underlying pathogenesis of TAO, and its potential application in early screening of other thyroid-associated diseases can be further expanded.

Gut microbiota and thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a multifactorial-mediated autoimmune orbital disease with the highest incidence of orbital disease in adults. Due to the complex clinical manifestations and prolonged course,TAO seriously affect the physical and mental health of patients.The pathogenesis of TAO has not been fully elucidated and the treatment lacks specificity. Therefore, in-depth research on the pathogenesis of TAO is to find effective treatments. In recent years, studies have suggested that there is gut microbiota disorder in TAO, and the risk factors of TAO can promote gut microbiota disorder. Disordered gut microbiota can participate in the occurrence and development of TAO via influencing T cell differentiation, mimicking autoantigens, and influencing host non-coding RNA expression. Modulating the gut microbiota also has therapeutic effects on TAO and is a promising therapeutic approach.

Identification of optimal feature genes in patients with thyroid associated ophthalmopathy and their relationship with immune infiltration: a bioinformatics analysis.

Thyroid associated ophthalmopathy (TAO) is an organ-specific autoimmune disease that has a significant impact on individuals and society. The etiology of TAO is complicated and poorly understood. Thus, the goal of this study was to use bioinformatics to look into the pathogenesis of TAO and to identify the optimum feature genes (OFGs) and immune infiltration patterns of TAO. Firstly, the GSE58331 microarray data set was utilized to find 366 differentially expressed genes (DEGs). To find important modular genes, the dataset was evaluated using weighted gene coexpression network analysis (WGCNA). Then, the overlap genes of major module genes and DEGs were further assessed by applying three machine learning techniques to find the OFGs. The CIBERSORT approach was utilized to examine immune cell infiltration in normal and TAO samples, as well as the link between optimum characteristic genes and immune cells. Finally, the related pathways of the OFGs were predicted using single gene set enrichment analysis (ssGSEA). KLB, TBC1D2B, LINC01140, SGCG, TMEM37, and LINC01697 were the six best feature genes that were employed to create a nomogram with high predictive performance. The immune cell infiltration investigation revealed that the development of TAO may include memory B cells, T cell follicular helper cells, resting NK cells, macrophages of type M0, macrophages of type M1, resting dendritic cells, active mast cells, and neutrophils. In addition, ssGSEA results found that these characteristic genes were closely associated with lipid metabolism pathways. In this research, we found that KLB, TBC1D2B, LINC01140, SGCG, TMEM37, and LINC01697 are intimately associated with the development and progression of TAO, as well as with lipid metabolism pathways.

Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy.

To evaluate the clinical significance of detecting serum IgG4 and the IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy (TAO) and to explore whether high serum IgG4 levels and the IgG4/IgG ratio are associated with the severity and activity of TAO, we retrospectively assessed the records of 78 TAO patients and 32 controls collected in our hospital from July 2020 to July 2022. The TAO patients were divided into TAO inactive and TAO active phase groups according to the clinical activity score (CAS), and we evaluated the association between the serum IgG4 levels, the IgG4/IgG ratio, and the clinical data of the participants. The levels of IgG4 significantly increased in the TAO active group compared to those in the inactive and control groups (P < 0.05). Additionally, the number of patients with increased IgG4 levels (≥135 mg/dL) in the TAO active group was markedly higher than that in the inactive and control groups (P < 0.05). The IgG4/IgG ratio was also significantly enhanced in the TAO active group compared to the inactive and control groups (P < 0.05). CAS was identified as an independent factor influencing IgG4 levels in patients with TAO. The levels of serum IgG4, as well as the IgG4/IgG ratio, were significantly increased in some patients with active TAO, and they were related to the CAS, suggesting that the pathogenesis of TAO may be heterogeneous.

MicroRNA-376b is involved in the pathogenesis of thyroid-associated ophthalmopathy by regulating HAS2.

The aim of this study was to investigate the microRNA (miRNA) expression profile in peripheral blood mononuclear cells (PBMC) of thyroid-associated ophthalmopathy (TAO) patients and to explore the molecular mechanisms of MicroRNA-376b (miR-376b) in the pathogenesis of TAO. PBMCs from TAO patients and healthy controls were analyzed by miRNA microarray to screen for the significantly differentially expressed miRNAs. The miR-376b expression in PBMCs were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). The downstream target of miR-376b was screened by online bioinformatics, and detected by qRT-PCR and Western blotting. Compared with normal controls, 26 miRNAs were significantly different in PBMCs of TAO patients (14 miRNAs were down-regulated and 12 miRNAs were up-regulated). Among them, miR-376b expression was significantly decreased in PBMCs from TAO patients compared to healthy controls. Spearman correlation analysis revealed that miR-376b expression in PBMCs was significantly negatively correlated with free triiodothyronine (FT3), and positively correlated with thyroid-stimulating hormone (TSH). MiR-376b expression was obviously reduced in 6T-CEM cells after triiodothyronine (T3) stimulation compared to controls. MiR-376b mimics significantly decreased hyaluronan synthase 2 (HAS2) protein expression and the mRNA expression of intercellular cell adhesion molecule-1 (ICAM1) and tumor necrosis factor-α (TNF-α) in 6T-CEM cells, whereas miR-376b inhibitors markedly elevated HAS2 protein expression and gene expression of ICAM1 and TNF-α. MiR-376b expression in PBMCs was significantly decreased in PBMCs from TAO patients compared with the healthy controls. MiR-376b, regulated by T3, could modulate the expression of HAS2 and inflammatory factors. We speculate that miR-376b may be involved in the pathogenesis of TAO patients by regulating the expression of HAS2 and inflammatory factors.

Disrupted dynamic amplitude of low-frequency fluctuations in patients with active thyroid-associated ophthalmopathy.

Purpose: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease that affects the orbit and is the most prevalent extra-thyroidal complication of Graves' disease. Previous neuroimaging studies have focused on abnormal static regional activity and functional connectivity in patients with TAO. However, the characteristics of local brain activity over time are poorly understood. This study aimed to investigate alterations in the dynamic amplitude of low-frequency fluctuation (dALFF) in patients with active TAO and to distinguish patients with TAO from healthy controls (HCs) using a support vector machine (SVM) classifier. Methods: A total of 21 patients with TAO and 21 HCs underwent resting-state functional magnetic resonance imaging scans. dALFFs were calculated in conjunction with sliding window approaches to assess dynamic regional brain activity and to compare the groups. Then, we used SVM, a machine learning algorithm, to determine whether dALFF maps may be used as diagnostic indicators for TAO. Results: Compared with HCs, patients with active TAO showed decreased dALFF in the right calcarine, lingual gyrus, superior parietal lobule, and precuneus. The SVM model showed an accuracy of 45.24%-47.62% and area under the curve of 0.35-0.44 in distinguishing TAO from HCs. No correlation was found between clinical variables and regional dALFF. Conclusion: Patients with active TAO showed altered dALFF in the visual cortex and the ventral and dorsal visual pathways, providing further details on the pathogenesis of TAO.

Identification and validation of ferroptosis-related genes and immune cell infiltration in thyroid associated ophthalmopathy.

Thyroid associated ophthalmopathy (TAO) is an orbital autoimmune inflammatory disease that is commonly associated with thyroid dysfunction. Although the etiology of TAO is unclear, ROS accumulation and oxidative stress have been closely linked to the pathogenesis of TAO. Ferroptosis is an iron-dependent programmed cell death characterized by intracellular labile iron levels, excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation. Currently, there are few reports regarding the role of ferroptosis in TAO. This article aimed to identify ferroptosis-related genes (FRGs) with diagnostic and therapeutic potential in TAO and explore their relationship with immune cells and lncRNAs. GSE58331 was downloaded from Gene Expression Omnibus (GEO) database. A total of 162 DEGs were identified between 27 TAO samples and 22 health samples from GSE58331, among which six FRGs (CYBB, CTSB, SLC38A1, TLR4, PEX3, and ABCC1) were obtained. The AUC of SLC38A1, TLR4, PEX3 in lacrimal gland tissues was greater than 80 which suggested high diagnostic value in TAO. The result of immune cell infiltrate analysis indicated increased infiltration of monocytes (p < 0.001), macrophages M0(p = 0.039), mast cells activated (p = 0.008), and neutrophils (p = 0.045) in orbital tissues from TAO patients. Meanwhile, mast cells resting (p = 0.043) and macrophages M2 (p = 0.02) showed reduced infiltration in TAO samples. There were no gender differences in immune cell infiltration in the TAO patients. Two differentially expressed lncRNAs, LINC01140 and ZFHX4-AS1, in TAO groups were identified as ferroptosis-related lncRNAs. CYBB-LINC01140-TLR4, CYBB- LINC01140- SLC38A1, TLR4- LINC01140- SLC38A1, and CTSB- ZFHX4-AS1- CYBB may be potential RNA regulatory pathways in TAO. Targeted drugs and transcription factors for differential expressed FRGs were also screened out in our study. In vitro, experiments revealed that CTSB, PEX3, ABCC1 and ZFHX4-AS1(lncRNA) were differentially expressed in orbital fibroblasts (OFs) between TAO groups and healthy controls at the transcriptional level.

The effect of acromegaly on thyroid disease.

Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.

Metformin Attenuates Inflammation and Fibrosis in Thyroid-Associated Ophthalmopathy

The pathogenesis of thyroid-associated ophthalmopathy (TAO) is still unclear, and therapeutic drugs have great limitations. As metformin has multiple therapeutic effects in many autoimmune diseases, we explored the effects of metformin on TAO in an in vitro fibroblast model. We used orbital connective tissues and fibroblasts that were obtained from TAO patients and normal controls. The activity of adenosine monophosphate-activated protein kinase (AMPK) and the levels of inflammatory or fibrotic factors were examined by immunofluorescence (IF) and immunohistochemistry (IHC). Quantitative real-time polymerase chain reaction (qPCR), cytokine quantification by enzyme-linked immunosorbent sssay (ELISA), IF, and western blotting (WB) were used to measure the expression of factors related to inflammation, fibrosis, and autophagy. To determine the anti-inflammatory and antifibrotic mechanisms of metformin, we pretreated cells with metformin, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, an AMPK activator) or compound C (CC, an AMPK inhibitor) for 24 h and used WB to verify the changes in protein levels in the AMPK/mammalian target of rapamycin (mTOR) pathway. We determined that the low activity of AMPK in the periorbital tissue of TAO patients may be closely related to the occurrence and development of inflammation and fibrosis, and metformin exerts multiple effects by activating AMPK in TAO. Furthermore, we suggest that AMPK may be a potential target of TAO therapy.

Cytokines in Thyroid-Associated Ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), also known as thyroid eye disease (TED) or Graves' orbitopathy (GO), is a complex autoimmune condition causing visual impairment, disfigurement, and harm to patients' physical and mental health. The pathogenesis of TAO has not been fully elucidated, and the mainstream view is that coantigens shared by the thyroid and orbit trigger remodeling of extraocular muscles and orbital connective tissues through an inflammatory response. In recent years, cytokines and the immune responses they mediate have been crucial in disease progression, and currently, common evidence has shown that drugs targeting cytokines, such as tocilizumab, infliximab, and adalimumab, may be novel targets for therapy. In this review, we summarize the research development of different cytokines in TAO pathogenesis in the hope of discovering new therapeutic targets.

Single-cell RNA sequencing depicts the local cell landscape in thyroid-associated ophthalmopathy

SummaryThere is a specific reactivity and characteristic remodeling of the periocular tissue in thyroid-associated ophthalmopathy (TAO). However, local cell changes responsible for these pathological processes have not been sufficiently identified. Here, single-cell RNA sequencing is performed to characterize the transcriptional changes of cellular components in the orbital connective tissue in individuals with TAO. Our study shows that lipofibroblasts with RASD1 expression are highly involved in inflammation and adipogenesis during TAO. ACKR1+ endothelial cells and adipose tissue macrophages may engage in TAO pathogenesis. We find CD8+CD57+ cytotoxic T lymphocytes with the terminal differentiation phenotype to be another source of interferon-γ, a molecule actively engaging in TAO pathogenesis. Cell-cell communication analysis reveals increased activity of CXCL8/ACKR1 and TNFSF4/TNFRSF4 interactions in TAO. This study provides a comprehensive local cell landscape of TAO and may be valuable for future therapy investigation.

PD-L1 Inhibits T Cell-Induced Cytokines and Hyaluronan Expression via the CD40-CD40L Pathway in Orbital Fibroblasts From Patients With Thyroid Associated Ophthalmopathy

Thyroid associated ophthalmopathy (TAO), characterized by T cell infiltration and orbital fibroblast activation, is an organ-specific autoimmune disease which is still short of effective and safety therapeutic drugs. The PD-1/PD-L1 pathway has been reported hindering the progression of Graves’ disease to some extent by inhibiting T cell activity, and tumor therapy with a PD-1 inhibitor caused some adverse effects similar to the symptoms of TAO. These findings suggest that the PD-1/PD-L1 pathway may be associated with the pathogenesis of TAO. However, it remains unknown whether the PD-1/PD-L1 pathway is involved in orbital fibroblast activation. Here, we show that orbital fibroblasts from patients with TAO do not express PD-L1. Based on in vitro OF-T cell co-culture system, exogenous PD-L1 weakens T cell-induced orbital fibroblast activation by inhibiting T cell activity, resulting in reduced production of sICAM-1, IL-6, IL-8, and hyaluronan. Additionally, exogenous PD-L1 treatment also inhibits the expression of CD40 and the phosphorylation levels of MAPK and NF-κB pathways in orbital fibroblasts of the OF-T cell co-culture system. Knocking down CD40 with CD40 siRNA or down-regulating the phosphorylation levels of MAPK and NF-κB pathways with SB203580, PD98059, SP600125, and PDTC can both reduce the expression of these cytokines and hyaluronan. Our study demonstrates that the orbital immune tolerance deficiency caused by the lack of PD-L1 in orbital fibroblasts may be one of the causes for the active orbital inflammation in TAO patients, and the utilization of exogenous PD-L1 to reconstruct the orbital immune tolerance microenvironment may be a potential treatment strategy for TAO.

Identification of tRNA-Related Fragments and Their Potential Regulatory Effects in Thyroid-Associated Ophthalmopathy.

Recently, the potential role of tRNA-related fragments (tRFs) in ophthalmic diseases has been extensively researched. However, systematic studies on the potential regulatory effects of tRFs in thyroid-associated ophthalmopathy (TAO) are lacking. We used high-throughput sequencing techniques to measure expression levels of mRNAs and tRFs in patients with TAO, and the results were verified by real-time quantitative reverse transcription polymerase chain reaction (q-PCR). Next, the potential biological regulatory effect of differentially expressed tRFs was analyzed, and potential downstream target RNAs of differentially expressed tRFs were predicted to explore the potential role of tRFs as therapeutic targets and biomarkers of TAO. A total of 50 tRFs and 361 mRNAs were dysregulated in the TAO group, and tRF5-GluCTC, PMAIP1, HSD17B2 and ATF3 were verified to be significantly differentially expressed in TAO. Our research reveals that several associated pathways likely play a role in the pathogenesis of TAO. By targeting ATF3, HSD17B2 and PMAIP1, tRF5-GluCTC may play a potential role in regulating the orbital fibroblast adipogenic response and fibrotic hyperplasia in patients with TAO.

Correlation between Peripheral T Cell Subsets and the Activity of Thyroid-Associated Ophthalmopathy.

Introduction Thyroid-associated ophthalmopathy (TAO) is the most common orbital immunological disease in adults. T cells play an important role in the pathogenesis of TAO. However, our knowledge of the circulating T cell subsets in TAO is limited. Objective To investigate the circulating T cell subsets in TAO and the correlations between them and the activity of TAO. Methods Thirty-eight TAO patients (19 active and 19 nonactive) were enrolled. The absolute number and percentage of total lymphocytes, CD3+T cells, CD4+T cells, CD8+ T cells, CD3+CD4-CD8-T cells (DNT cells), and CD3+CD4+CD8+ T cells (DPT cells) in peripheral blood were measured by flow cytometer. Results TAO patients were divided into the active group and the nonactive group by the clinical activity score (CAS). The mean CAS was 4 ± 1.11 in the active group and 1.47 ± 0.61 in the nonactive group. No statistical differences were found in gender, age, and the levels of FT3, FT4, TSH, and TRAb between the two groups. The percentage of DNT cells was lower in the active group than in the non-active group, and it was negatively correlated with CAS (r = −0.349, P=0.032), but not the absolute number. The CD4/CD8 ratio, the absolute number and percentage of CD3+ T cells, CD4+ T cells, CD8+ T cells, and DPT cells did not differ between the two groups. ConclusionIn the present study, we found the percentage of DNT cells was significantly lesser in the active TAO than in the nonactive TAO, and it was negatively correlated with the activity of the TAO. It suggests that DNT cells may involve in the immunopathogenesis of TAO and can serve as a clinical biomarker of the disease activity.

Epigenetics effect on pathogenesis of thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease. Recent studies have found the aberrant epigenetics in TAO, including DNA methylation, non-coding RNAs, and histone modification. Many genes have an aberrant level of methylation in TAO. For example, higher levels are found in CD14, MBP, ANGLE1, LYAR and lower levels in DRD4 and BOLL. Non-coding RNAs are involved in the immune response (miR-146a, miR-155, miR-96, miR-183), fibrosis regulation (miR-146a, miR-21, miR-29), adipogenesis (miR-27) and are thought to play roles in TAO. MicroRNA is also related to the clinical activity score (miR-Let7d-5p) and may be a predictor of glucocorticoid therapy (miR-224-5p). The quantities of H4 in TAO are increased compared with euthyroid control subjects, and the role of histone modifications in Graves' disease may lead to better understanding of its role in TAO. More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.

Single-Cell RNA Sequencing Depicts the Local Cell Landscape in Thyroid-Associated Ophthalmopathy

There is a specific reactivity and characteristic remodeling of the periocular tissue in thyroid-associated ophthalmopathy (TAO). However, the cellular components responsible for these changes have not been sufficiently identified. Here, single-cell RNA sequencing was performed to characterize the transcriptional properties of cellular components in the orbital connective tissue in TAO patients. RASD1 expression in orbital fibroblasts defines lipofibroblastic phenotypes. These celltypes specifically expresses adipogenic differentiation associated genes. ACKR1+ Endothelial cells and adipose tissue macrophages are also involved in the disease process. Our study then highlights CD8+CD57+KLRG1+ cytotoxic T lymphoid cells with terminal differentiation phenotype as sources of sustained interferon-γ secretion. Moreover, cell–cell communication analysis revealed evidence of increased activity of the ACKR1/CXCL8 and TNFSF4/TNFRSF4 systems in TAO, which is consistent with stronger inflammatory cell infiltrating and fibrosis response. These cells in the orbital connective tissue constitute an orbital fibroblast-based cell-cell interaction network that regulates the pathogenesis of TAO.

Elevated IL-38 inhibits IL-23R expression and IL-17A production in thyroid-associated ophthalmopathy

IL-23/IL-23R and PGE2/EP2+EP4 have been recognized as crucial signals that promote Th17 differentiation in many autoimmune diseases, including thyroid-associated ophthalmopathy (TAO). However, the interactive role of IL-23R in IL-23/Th17 signaling and PGE2/Th17 signaling has not been clarified in TAO. Furthermore, the role of IL-38, a novel anti-inflammatory cytokine, has not been explored in TAO. Thus, we aimed to investigate the roles of IL-23R and IL-38 in the pathogenesis of TAO. Activated peripheral blood mononuclear cells (PBMCs) were cultured with or without IL-23 and PGE2. The results showed that IL-23R and IL-17A were upregulated to different degrees and reached the highest levels with both stimuli, indicating that IL-23 induced PBMCs to secrete PGE2, which further boosted the proportion of IL-23R+CD4+T cells to promote IL-17A secretion. Pretreatment with antagonists aimed at EP2/EP4 receptors diminished PGE2-induced upregulation of IL-23R and IL-17A. IL-38 in TAO patients was increased. Activated orbital fibroblasts (OFs) and PBMCs were pretreated with different concentrations of IL-38. IL-23R and IL-17A expression in circulating PBMCs and IL-6 and IL-8 in resident OFs were suppressed by IL-38 at relatively low concentrations. Our findings suggest that the feedback loop of IL-23/IL-23R/PGE2/EP2+EP4/IL-23R/IL-17A plays a significant role in the pathogenesis of TAO and that IL-23R is one of the key targets. Increased IL-38 in TAO could not only inhibit the expression of IL-23R and IL-17A in PBMCs but also suppress inflammation in OFs. Therapies targeting IL-23R may be effective, and IL-38 could be a potential therapeutic approach for TAO.

Teprotumumab as a Novel Therapy for Thyroid-Associated Ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) has remained a vexing and poorly managed autoimmune component of Graves’ disease where the tissues surrounding the eye and in the upper face become inflamed and undergo remodeling. This leads to substantial facial disfigurement while in its most severe forms, TAO can threaten eye sight. In this brief paper, I review some of the background investigation that has led to development of teprotumumab as the first and only US FDA approved medical therapy for TAO. This novel treatment was predicated on recognition that the insulin-like growth factor I receptor plays an important role in the pathogenesis of TAO. It is possible that a similar involvement of that receptor in other autoimmune disease may lead to additional indications for this and alternative insulin-like growth factor I receptor-inhibiting strategies.

PDK2-enhanced glycolysis promotes fibroblast proliferation in thyroid-associated ophthalmopathy.

The study aimed to investigate the role of pyruvate dehydrogenase kinase (PDK) in regulating glycolysis and proliferation of perimysial orbital fibroblasts (pOFs) during the pathogenesis of thyroid-associated ophthalmopathy (TAO). EdU and BrdU incorporation assays were performed to examine cell proliferation. Lactate production and oxygen consumption assays were conducted to evaluate glycolysis. Real-time PCR was adapted to quantify PDK mRNA levels. Capillary Western immunoassay was adapted to quantify PDK2, Akt, pAkt308 and GAPDH in protein samples. The TAO pOFs exhibited stronger proliferation activity, higher intracellular lactate concentration, and lower oxygen consumption rate than the control pOFs. The PDK inhibitor dichloroacetic acid (DCA) dose-dependently suppressed the proliferation of both TAO and control pOFs. DCA reduced lactate production and promoted oxygen consumption in the TAO pOFs but showed no significant effects on glycolysis in the control pOFs. Among four PDK isotypes, PDK2 was overexpressed in the TAO pOFs. The potential PDK signaling mediator, cytoplasmic Akt, was more abundant in TAO pOFs than control pOFs. Knockdown of PDK2 resulted in lower lactate production, stronger oxygen consumption, weaker proliferation activity, and less cytoplasmic Akt in the TAO pOFs but showed no significant effects in the control pOFs. The Akt inhibitor MK2206 suppressed proliferation in both TAO and control pOFs, and lactate production was inhibited by MK2206 in the TAO OFs but not the control pOFs. To conclude, PDK2 overexpression enhances glycolysis and promotes proliferation via Akt signaling in the TAO pOFs. These findings yield insights that PDK2 is a potential therapeutic target for TAO treatment.