Autophagy in graves' ophthalmopathy.
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ABSTRACT:
SUBMITTER: Chen YQ
PROVIDER: S-EPMC10140433 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
Publications
Autophagy in graves' ophthalmopathy.
Chen Yu-Qing YQ Gao Lian-Di LD Liu Yi-Lin YL Shen Ya Y Diao Jia-Le JL Yang Wei-Hua WH Wei Rui-Li RL
Frontiers in cell and developmental biology 20230414
Graves' ophthalmopathy (GO) is an inflammatory autoimmune disease that affects the eyes. It can significantly alter the quality of life in patients because of its distinctive pathological appearance and the effect on vision. To date, the exact pathological mechanism of GO has not been explicitly discovered. However, several studies have associated autophagy with this disease. Autophagy is a catabolic process that helps maintain homeostasis in all organisms by protecting the cells and tissues fro ...[more]
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Project description:Graves' disease (GD) is the most common cause of thyrotoxicosis and often involves the orbits. Graves' ophthalmopathy (GO), also known as Thyroid Eye Disease (TED), can be clinically significant and advance to sight-threatening stages. Our knowledge of the immunogenetic pathophysiology of GO is rapidly expanding. The present review is an attempt to summarize the current state of knowledge on the immunogenetics of GO. First we briefly review the epidemiology and clinical importance of GO, and then we describe in detail the macromolecular pathogenesis and finally immunogenetics of GO. Discrepancies between the results from various reports and the limitations of the available data are discussed. In particular, there is a scarcity of data from non-Asian populations. While several studies have demonstrated significant associations between polymorphisms in certain genes (especially CTLA-4, HLA-DRB-1, and TNF-?), there is a need for studies that investigate the relationship between polymorphisms and both serum and local concentrations of the resulting proteins. A complete understanding of GO susceptibility and pathogenesis has not been yet possible due to a number of important knowledge gaps that need to be filled by future research.
| S-EPMC3271309 | biostudies-literature
Project description:BackgroundA large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms.MethodsWe used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians).ResultsThe allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP.ConclusionsThese results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.
| S-EPMC2857451 | biostudies-literature
Project description:BackgroundGraves' ophthalmopathy (GO) significantly impairs the quality of life of affected individuals and the most severe cases can be sight threatening. Given the limited therapeutic options, a strong emphasis should be placed on disease prevention to diminish the significant morbidity associated with this disease.SummaryGO is most prevalent in women and most severe in men. Although some genetic differences between GO patients and Graves' disease patients without ophthalmopathy have been identified, none of the polymorphisms identified to date impart a high enough risk of GO to justify genetic testing to guide therapy or preventive strategies. Poorly defined mechanical factors that appear also to play a role in GO susceptibility will likely be better elucidated with advances in imaging techniques. Tobacco smoking has been consistently linked to development or deterioration of GO. Smokers who receive radioactive iodine have the highest incidence of unfavorable GO outcome, which is proportional to the number of cigarettes smoked per day. Several studies have reported an association between radioactive iodine treatment for Graves' disease and worsening or development of GO. Observational studies suggest that the same appears to be true for thyroid dysfunction, including both hyper- and hypothyroidism. While thyrotropin receptor antibody levels appear to be useful in predicting the course of disease and response to therapy, it is not known whether they are predictive of GO development. The puzzling scenarios of euthyroid or clinically unilateral GO, the large number of nonsmoking GO patients, and the occasional development of GO years after thyroid dysfunction has been treated all underline the multifactorial etiology of this disorder in which no single factor determines the clinical outcome.ConclusionsGO appears to have a complex genetic basis with multiple susceptibility alleles that act in combination with nongenetic factors to contribute to disease expression.
| S-EPMC3357079 | biostudies-literature
Project description:BackgroundGraves' ophthalmopathy (GO) is a complicated autoimmune disease. Various therapies have been used to manage GO; however the optimum therapy is not clear. Glucocorticoids (GCs) therapy is the mainstay of treatment especially for active moderate to severe patients, which needs evidence-based support.MethodWe searched all the randomized controlled trials (RCTs) involving corticosteroid treatment for patients diagnosed with GO from EMBASE, Medline, and the Cochrane library and then conducted a system review and meta-analysis. The electronic search covered the period from April 1966 to March 2018.ResultTwenty-nine trials were included. GCs were proved to be beneficial for GO patients [response rate, risk ratio (RR) = 1.72, 95% confidence interval (CI): 1.28~2.31, P=0.0003], and intravenous corticosteroids worked significantly better than oral corticosteroids as ever reported. When compared with the single treatment of GCs, the combination of radiotherapy and GCs showed similar effects on response rate (RR=1.25, 95%CI: 0.91~1.73). A study proved the advantage of mycophenolate mofetil over GCs in three outcomes (response rate, RR=0.74, 95%CI: 0.63~0.88). Additional treatments such as technetium-99 methylene diphosphate (99Tc-MDP) or cyclosporine enhanced the effect of GCs on proptosis reduction, respectively (P<0.00001 and P=0.02).ConclusionOur meta-analysis confirmed the effects of GCs in the management of GO and intravenous GCs are proved to be better than oral GCs as ever reported. Combination of radiotherapy and GCs did not enhance the effects of GCs. However, if proptosis is the main issue, combination of 99Tc-MDP or cyclosporine with GCs may be taken into consideration. The reported advantages of mycophenolate mofetil over GCs are noteworthy and need more RCTs to confirm.
| S-EPMC6282115 | biostudies-literature
Project description:Graves' disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves' ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism per se, but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO.
| S-EPMC8085526 | biostudies-literature
Project description:BackgroundSeveral immunosuppressive therapeutic regimens are widely used to treat Graves' ophthalmopathy (GO), including oral glucocorticoids (OGC), intravenous glucocorticoids (IVGC), retrobulbar injections of glucocorticoids (ROGC) and orbital radiotherapy (OR). The priority among these is unknown. This meta-analysis investigated the efficacy and tolerability of the above regimens.MethodsThe PubMed, EMBASE, and Cochrane Library databases and the Chinese Biomedicine Database were searched up to November 18, 2014. Randomized controlled trials (RCTs) comparing monotherapies (OGC, IVGC, ROGC and OR) in patients with moderate-to-severe active GO were selected. The main efficacy measures were the response rate, the standard mean difference (SMD) in the reduction in the clinical activity score (CAS) and the mean difference (MD) in proptosis from baseline to the end of treatment. The main tolerability measure was the risk ratio (RR) for adverse events. The pooled estimates and 95% confidence intervals (95% CIs) were calculated using the RevMan software, version 5.1.ResultsSeven published RCTs involving 328 participants were included in the present meta-analysis, including IVGC versus OGC (3 trials), ROGC versus OGC (3 trials) and OR versus OGC (1 trial). IVGC was more effective than OGC in response rate (RR = 1.48, 95% CI = 1.18-1.87) and had an obvious CAS reduction (SMD = 0.69, 95% CI = 0.13-1.25). IVGC caused fewer adverse events than OGC. ROGC and OGC had no statistically significant difference in response rate (RR = 1.16, 95% CI = 0.94-1.42). OR also did not differ significantly compared with OGC (RR = 0.93, 95% CI = 0.54-1.60). ROGC and OR had fewer adverse events, such as weight gain, compared with OGC.ConclusionsFor patients with GO in the moderate-to-severe active phase, current evidence gave priority to IVGC, which had a statistically significant advantage over OGC and caused fewer adverse events. ROGC and OR did not provide greater efficacy than OGC, although better tolerability and fewer adverse events were shown.
| S-EPMC4607493 | biostudies-literature
Project description:Diagnosis of Graves ophthalmopathy is based on the typical eye signs and symptoms, the exclusion of other orbital pathologies and evidence of thyroid autoimmunity. We report the case of a non-smoker 61 years old woman, known with Graves disease, which performed a 3T MRI examination in order to evaluate the orbits. The MRI exam revealed eye protrusion, increased orbital fat with compression on the optic nerve and increased volume of the extraocular muscles. We concluded that MRI, using high-field 3T imaging techniques, is very important for diagnosis of these anomalies, making the differential diagnosis with other pathology and also providing additional information in the decision for therapy.
| S-EPMC6246998 | biostudies-other
Project description:BACKGROUND: Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation. METHODS: In this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined. RESULTS: Haplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10-14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients. CONCLUSIONS: These results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.
| S-EPMC3582428 | biostudies-literature
Project description:ContextThe TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role.ObjectiveWe previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies.Design/setting/participantsImmunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor.Main outcome measuresHyaluronan (hyaluronic acid [HA]) secretion was measured as a major biological response for GOF stimulation. IGF-1R autophosphorylation was used as a measure of direct IGF-1R activation. TSHR activation was determined through cAMP production.ResultsA total of 42 out of 57 GO-Ig samples stimulated HA secretion. None of the GO-Ig samples exhibited evidence for IGF-1R autophosphorylation. Both anti-IGF-1R antibodies completely inhibited IGF-1 stimulation of HA secretion. By contrast, only 1 IGF-1R antibody partially blocked HA secretion stimulated by M22 or GO-Igs in a manner similar to linsitinib, whereas the other IGF-1R antibody had no effect on M22 or GO-Ig stimulation. These findings show that the IGF-1R is involved in GO-Igs stimulation of HA secretion without direct activation of IGF-1R.ConclusionsIGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO.
| S-EPMC4891793 | biostudies-literature
Project description:BackgroundGraves' disease is the most common form of autoimmune thyroid disorder, characterized by hyperthyroidism due to circulating autoantibodies. To address the pathological features and establish a therapeutic approach of this disease, an animal model carrying the phenotype of Graves' disease (GD) in concert with Graves' Ophthalmopathy (GO) will be very important. However, there are no ideal animal models that are currently available. The aim of the present study is to establish an animal model of GD and GO disease, and its pathological features were further characterized.MethodsA recombinant plasmid pcDNA3.1- T289 was constructed by inserting the TSHR A-subunit gene into the expression vector pcDNA3.1, and genetic immunization was successfully performed by intramuscular injection of the plasmid pcDNA3.1-T289 on female 8-week-old BALB/c mice. Each injection was immediately followed by in vivo electroporation using ECM830 square wave electroporator. Morphological changes of the eyes were examined using 7.0T MRI scanner. Levels of serum T4 and TSHR antibodies (TRAb) were assessed by ELISA. The pathological changes of the thyroid and orbital tissues were examined by histological staining such as H&E staining and Alcian blue staining.ResultsMore than 90% of the immunized mice spontaneously developed goiter, and about 80% of the immunized mice manifested increased serum T4 and TRAb levels, combined with hypertrophy and hyperplasia of thyroid follicles. A significantly increased synthesis of hyaluronic acid was detected in in the immunized mice compared with the control groups.ConclusionWe have successfully established an animal model manifesting Graves' hyperthyroidism and ophthalmopathy, which provides a useful tool for future study of the pathological features and the development of novel therapies of the diseases.
| S-EPMC5358867 | biostudies-literature