Mechanisms That Underly T Cell Immunity in Graves' Orbitopathy.
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ABSTRACT:
SUBMITTER: Fang S
PROVIDER: S-EPMC8049604 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Mechanisms That Underly T Cell Immunity in Graves' Orbitopathy.
Fang Sijie S Lu Yi Y Huang Yazhuo Y Zhou Huifang H Fan Xianqun X
Frontiers in endocrinology 20210401
Graves' orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is the most common ocular abnormality of Graves' disease. It is a disfiguring, invalidating, and potentially blinding orbital disease mediated by an interlocking and complicated immune network. Self-reactive T cells directly against thyroid-stimulating hormone receptor-bearing orbital fibroblasts contribute to autoimmune inflammation and tissue remodeling in GO orbital connective tissues. To date, T helper (Th) 1 (cytotox ...[more]
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Project description:PurposeGraves' orbitopathy (GO) is a sight-threatening autoimmune disorder causing extraocular muscle fibrosis, upper lid retraction and eye bulging due to orbital fat expansion. These clinical features are mediated by aspects of orbital fibroblasts differentiation, including adipogenesis and fibrosis. Our previous work suggested that this dual phenotype might be a manifestation of mixed cell populations, partially linked to the expression of mesenchymal stem cell (MSC) marker CD90. Thus, we set out to determine whether GO orbital fibroblasts displayed MSC properties.MethodsControl and GO orbital fibroblasts previously characterized for CD90 and CD45 expression were analyzed by flow cytometry for classical MSC positive (CD73, CD105) and negative (CD14, CD19, HLA-DR, and CD34) markers. Graves' orbitopathy fibroblasts were tested further for their ability to undergo lineage specific differentiation following standard protocols.ResultsControl and GO fibroblasts strongly expressed CD73 and CD105, with a higher percentage of positive cells and stronger expression levels in GO. Neither cell type expresses CD14, CD19, and HLA-DR. Protein CD34 was expressed at low levels by 45% to 70% of the cells, with its expression significantly lower in GO cells. Graves' orbitopathy fibroblasts displayed features of osteogenesis (calcium deposits, and osteocalcin [BGLAP] and osteonectin [SPARC] expression), chondrogenesis (glycosaminoglycan production; SOX9 and aggrecan [ACAN] expression), myogenesis (α-smooth muscle actin expression), and neurogenesis (β-III tubulin expression) upon differentiation.ConclusionsOur findings suggest that orbital fibroblasts contain a population of cells that fulfil the criteria defining MSC. This subpopulation may be increased in GO, possibly underlying the complex differentiation phenotype of the disease.
| S-EPMC4559215 | biostudies-literature
Project description:The most important of the extra-thyroidal manifestations of Graves' disease, Graves' orbitopathy (GO), remains a vexing clinical problem. Treatment of severe active disease has been limited to steroids or radiotherapy. In the relatively rare case where vision is threatened, emergent decompression surgery can be performed. The proptosis, motility, or cosmetic concerns associated with stable GO are commonly remedied with surgical intervention. Substantial obstacles have prevented the development of specific medical therapies for GO, in large part resulting from poor understanding of disease pathogenesis and the absence of preclinical animal models. Fundamental aspects of GO's etiology have been uncovered from studies based in cell culture, extensive analysis of blood constituents, and detailed examination of orbital contents collected at the time of surgical intervention. Many of the published reports resulting from these studies are descriptive and all have failed to yield unifying concepts that integrate the anatomically divergent manifestations of Graves' disease. This brief review covers recent findings of several research groups. While major breakthroughs continue to occur in closely related autoimmune diseases, progress in identifying the pathogenic mechanisms relevant to GO has been limited. As emerging insights into human autoimmunity becomes applied to the study of Graves' disease, we anticipate that improved therapeutic strategies will find their way to our patients with GO.
| S-EPMC6779038 | biostudies-literature
Project description:BackgroundOn 21st January 2020, the FDA approved Tepezza (teprotumumab-trbw) for the treatment of active Graves' orbitopathy (GO) in adults. This approval was based on positive results from two multinational randomised double-blind placebo-controlled clinical trials.DiscussionThis article discusses the outcomes of those trials and the potential role of teprotumumab in altering current treatment paradigms in Graves' orbitopathy. Future challenges are explored, including the need to confirm its disease-modifying effect, to establish its optimal position in the treatment pathway, and to define the appropriate subset of patients who would benefit from its use.ConclusionsThe results from these two large clinical trials have shown teprotumumab to have remarkable effects on multiple clinical outcomes in GO, particularly in its ability to reverse proptosis. It may herald a new era in the treatment of thyroid eye disease and could offer an alternative to surgery and its associated complications. Additional studies will continue to shape the treatment of GO and define the role of teprotumumab within the treatment paradigm.
| S-EPMC7334856 | biostudies-literature
Project description:ObjectivesA beneficial effect of sirolimus in Graves' orbitopathy (GO) was reported, suggesting a possible use in clinical practice. We conducted an observational, single-centre, no-profit, clinical study to investigate the efficacy of sirolimus as a second-line treatment for moderate-to-severe, active GO compared with methylprednisolone.MethodsData from consecutive patients given sirolimus (2 mg orally on first day, followed by 0.5 mg/day for 12 weeks) or methylprednisolone [500 mg iv/weekly (6 weeks), 250 mg/weekly (6 weeks)] as a second-line treatment were collected and compared.Primary objectiveoverall GO outcome at 24 weeks, based on a composite evaluation. Secondary objectives at 24 weeks: (1) improvement in quality of life, evaluated using a specific uestionnaire (GO-QoL); (2) reduction in proptosis; (3) reduction in the clinical activity score (CAS); (4) improvement of eye ductions; and (5) reduction in eyelid aperture.ResultsData from 30 patients (15 per group) treated between January 15, 2020, and June 15, 2021, were analysed. Proportion of GO responders (primary outcome) at 24 weeks was significantly greater in sirolimus group compared with methylprednisolone group (86.6% vs 26.6%; OR: 17.8; 95% CI from 2.7 to 116.8; P = 0.0026). GO-quality of life (GO-QoL) score was greater in sirolimus group. Proportion of proptosis responders was greater in sirolimus group, as well as proportion of clinical activity score (CAS) responders. No serious adverse events were observed, with no differences between groups.ConclusionsSirolimus seems to be an effective second-line treatment for GO. Further randomized clinical trials are needed to confirm our observations.
| S-EPMC9525329 | biostudies-literature
Project description:Graves' disease (GD), similarly to most autoimmune disease, is triggered by environmental factors in genetically predisposed individuals. Particular HLA alleles increase or decrease GD risk. No such correlation was demonstrated for Graves' orbitopathy (GO) in Caucasian population. HLA-A, -B, -C, -DQB1 and -DRB1 genotyping was performed using a high-resolution method in a total number of 2378 persons including 70 patients with GO, 91 patients with non-GO GD and 2217 healthy controls to compare allele frequencies between GO, non-GO and controls. Significant associations between GO and HLA profile were demonstrated, with HLA-A*01:01, -A*32:01, -B*37:01, -B*39:01, -B*42:01, -C*08:02, C*03:02, DRB1*03:01, DRB1*14:01 and DQB1*02:01 being genetic markers of increased risk of GO, and HLA-C*04:01, -C*03:04, -C*07:02 and -DRB1*15:02 being protective alleles. Moreover, correlations between HLA alleles and increased or decreased risk of non-GO GD, but with no impact on risk of GO development, were revealed. Identification of these groups of GO-related and GO-protective alleles, as well as the alleles strongly related to non-GO GD, constitutes an important step in a development of personalized medicine, with individual risk assessment and patient-tailored treatment.
| S-EPMC9935388 | biostudies-literature
Project description:ContextGraves' orbitopathy (GO) is a potentially sight-threatening disease for which available medical therapy is not uniformly successful. Multiple case series suggest that rituximab (RTX) may be effective therapy for GO patients.ObjectiveTo determine the efficacy of RTX in GO.DesignIt is a prospective, randomized, double-masked, placebo-controlled trial.SettingThe study was conducted at a large academic private practice.PatientsTwenty five patients with active moderate to severe GO were enrolled, and 21 completed the study to the primary endpoint.InterventionsTwo RTX infusions (1000 mg each) or two saline infusions were given 2 weeks apart.Main outcome measuresThe primary endpoint was a reduction in clinical activity score (CAS) assessed as a continuum and separately as improvement by ≥ 2 points at 24 weeks. Secondary endpoints included success and failure rates, proportions showing clinically significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos and disease severity, and changes in those parameters, orbital fat/ muscle volume and quality-of-life.ResultsThe treatment groups were similar in all parameters at baseline. The last observation was carried forward if the patient discontinued prematurely. No differences were found in the proportions of patients showing CAS improvement at 24 weeks (25% placebo; 31% RTX, P = .75) or in CAS decrease from baseline to 24 or 52 weeks [mean 1.5 points (1.8 SD) placebo; 1.2 (2 SD) RTX at 24 weeks, P = .73]. Similarly, there were no differences between groups in any of the secondary endpoints at either 24 or 52 weeks. There were four adverse events (AE) in 3/12 placebo patients and 11 AE in 8/13 RTX-treated patients; 5/6 moderate or severe AE occurred in the RTX group.ConclusionRTX offered no additional benefit over placebo to our patients with active and moderate to severe GO and carried with it non-negligible adverse effects.
| S-EPMC4318907 | biostudies-literature
Project description:Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.
| S-EPMC7730568 | biostudies-literature
Project description:BackgroundBoth Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders.SummaryImmunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy.Key messagesTherapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.
| S-EPMC7802437 | biostudies-literature
Project description:BackgroundGraves' orbitopathy (GO) as well as Graves' disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). GO phenotype is associated with environmental risk factors, mainly nicotinism, as well as genetic risk factors which initiate an immunologic reaction. In some patients GO is observed before diagnosis of GD hyperthyroidism, while it can also be observed far after diagnosis. The intensity of GO symptoms varies greatly in these patients. Thus, the pathogenesis of GD and GO may correlate with different genetic backgrounds, which has been confirmed by studies of correlations between GO and polymorphisms in cytokines involved in orbit inflammation. The aim of our analysis was to assess genetic predisposition to GO in young patients (age of diagnosis ≤30 years of age), for whom environmental effects had less time to influence outcomes than in adults.Methods768 GD patients were included in the study. 359 of them had clinically evident orbitopathy (NOSPECS ≥2). Patients were stratified by age at diagnosis. Association analyses were performed for genes with a known influence on development of GD - TSHR, HLA-DRB1, cytotoxic T-lymphocyte antigen 4 (CTLA4) and lymphoid protein tyrosine phosphatase (PTPN22).ResultsThe rs179247 TSHR polymorphism was associated with GO in young patients only. In young GO-free patients, allele A was statistically more frequent and homozygous carriers had a considerable lower risk of disease incidence than patients with AG or GG genotypes. Those differences were not found in either elderly patients or the group analyzed as a whole.ConclusionsAllele A of the rs179247 polymorphism in the TSHR gene is associated with lower risk of GO in young GD patients.
| S-EPMC4111286 | biostudies-literature
Project description:ObjectivesThere is a general belief that Graves' orbitopathy (GO) is a "chronic" disease, namely that patients' eyes do not return to how they were before GO appeared. Here, we investigate this issue from both the patient's and the physician's point of view.Study designWe studied the disappearance of GO, regardless of treatment, in all consecutive patients with a GO history of at least 10 years who came for a follow-up visit over a period of 5 years. Patients underwent an ophthalmological examination and were asked to answer a questionnaire on self-perception related to GO.ResultsWe studied 99 consecutive patients with a GO duration ≥10 years. Between the first and the last observation, patients received several types of treatment for their thyroid disease and/or for GO. At the end of follow-up, GO was considered disappeared based on objective criteria in 8 patients (∼8%) and based on subjective criteria in 24 patients (∼24%). When we considered both subjective and objective criteria, only 2 patients (∼2%) had all criteria fulfilled and could be considered as GO-free.ConclusionsGO is a chronic disease in the vast majority of patients. Even after a very long time since its onset, complete disappearance is rare, although a minority of patients believe they do not have GO anymore and an even lower proportion do not have relevant GO signs. Our findings have obvious implications in patient management and counseling.
| S-EPMC5649266 | biostudies-literature