Inflammation Of Orbital Tissue Research Articles

IL-17 and IL-38 gene polymorphisms in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune condition commonly linked with Graves' disease (GD), characterized by orbital tissue inflammation and fibrosis. It is hypothesized that gene polymorphisms may influence production of the IL-17 and IL-38 cytokines, thereby impacting TAO development and progression. This study focused on investigating the gene polymorphisms of IL-17 (rs9463772 C/T in IL17F) and IL-38 (rs3811058 C/T, rs7570267 A/G in IL1F10) in patients with GD. A case-control study was conducted on 132 patients with TAO and 153 patients without TAO according to eligibility criteria. After clinical examination blood samples were collected for further investigations. Genotyping was performed with the TaqMan™ Master Mix kit. Allele and genotype frequencies were compared between studied groups and subgroups. No significant differences were found in age, duration of GD, or thyroid hormone between patients with and without TAO. However, a higher predisposition to develop TAO was observed among smokers (OR = 1.682, p = 0.03). Overall, no significant associations between gene polymorphisms and TAO development were identified in GD patients. Further analysis revealed that the CC genotype in IL1F10 rs3811058 polymorphism among Caucasians was associated with an increased risk of TAO (OR = 2.7, p = 0.02), as well as allele differences were also significant (OR = 2.8, p = 0.001). These findings shed light on TAO genetic predispositions in Kazakhstani GD patients, notably among Caucasians, underscoring the need for further research. These results may offer valuable targets for the development of novel treatments for TAO.

Differential diagnosis of thyroid orbitopathy - diseases mimicking the presentation or activity of thyroid orbitopathy.

Thyroid orbitopathy (TO) is the most common cause of orbital tissue inflammation, accounting for about 60% of all orbital inflammations. The inflammatory activity and severity of TO should be diagnosed based on personal experience and according to standard diagnostic criteria. Magnetic resonance imaging (MRI) of the orbit is used not only to identify swelling and to differentiate inflammatory active from non-active TO, but also to exclude other pathologies, such as orbital tumours or vascular lesions. However, a group of diseases can mimic the clinical manifestations of TO, leading to serious diagnostic difficulties, especially when the patient has previously been diagnosed with a thyroid disorder. Diagnostic problems can be presented by cases of unilateral TO, unilateral or bilateral TO in patients with no previous or concomitant symptoms of thyroid disorders, lack of symptoms of eyelid retraction, divergent strabismus, diplopia as the only symptom of the disease, and history of increasing diplopia at the end of the day. The lack of visible efficacy of ongoing immunosuppressive treatment should also raise caution and lead to a differential diagnosis of TO. Differential diagnosis of TO and evaluation of its activity includes conditions leading to redness and/or swelling of the conjunctiva and/or eyelids, and other causes of ocular motility disorders and eye-setting disorders. In this paper, the authors review the most common diseases that can mimic TO or falsify the assessment of inflammatory activity of TO.

Orbital Inflammation in Thyroid Eye Disease: Stress Responses and Their Implications

Thyroid Eye Disease (TED) is a debilitating autoimmune condition characterized by significant inflammation of orbital tissues, including the extraocular muscles and adipose tissues. The pathological mechanisms underlying this inflammation involve a complex interplay of stress responses at the cellular and molecular level. This review aims to critically evaluate and synthesize existing literature on the mechanisms of orbital inflammation in TED. We discuss the role of autoantibodies, cytokines, and reactive oxygen species (ROS) in the initiation and propagation of the inflammatory process. Additionally, we explore how stress responses triggered by these elements affect the integrity of orbital tissues and contribute to its remodeling. Our review underscores the need for continued research in this field, which may pave the way for novel therapeutic strategies for TED.

Factors affecting the course of Graves’ Orbitopathy and poor response to glucocorticoid treatment followed by orbital radiotherapy.

Graves’ orbitopathy is a rare autoimmune disorder characterized by the inflammation of orbital tissues. The course of disease can be described in terms of its activity and severity.
 Aim: The aim of our study was to determine the factors affecting the activity and severity of Graves’ orbitopathy, as well as to identify the predictive factors of poor response to glucocorticoid treatment followed by orbital irradiation.
 Methods: We performed a prospective observational study of 214 patients with Graves’ orbitopathy who were divided into two groups depending on the treatment they had previously obtained for their Graves’ disease. They received i.v. methylprednisolone pulses followed by orbital radiotherapy. They were examined and had their TSH, TRAb and FT4 levels evaluated prior to treatment and after 1, 6 and 12 months.
 Results: A pre-treatment TRAb concentration higher by one unit (U/L) implied a mean increase in the relative risk of active orbitopathy by 4.7% (p = 0.0362). A TRAb concentration higher by one U/L 1 month after treatment implied a mean increase in the relative risk of moderate-to-severe and severe GO by 8.7% (p = 0.0167) 6 months after treatment. As regards poor response to treatment, patients with moderate-to-severe and severe Graves’ orbitopathy on admission carried a higher risk of being non-responders. Each point scored on the NOSPECS scale prior to treatment increased the relative risk of the patient being a non-responder by 30%.
 Conclusions: Patients with higher TRAb levels have a higher risk of active Graves’ orbitopathy and moderate-to-severe and severe Graves’ orbitopathy. Monitoring TRAb serum concentration in those patients is of great importance. Patients with more severe Graves’ orbitopathy carry a higher risk of being poor responders to immunosuppressive treatment. Therefore, careful monitoring of patients with Graves’ orbitopathy and their early referral to specialized centers is essential.

Integrative Analysis of Proteomics and DNA Methylation in Orbital Fibroblasts From Graves' Ophthalmopathy.

BackgroundGraves’ ophthalmopathy (GO) is a frequent extrathyroidal complication of Graves’ hyperthyroidism. Orbital fibroblasts contribute to both orbital tissue inflammation and remodeling in GO, and as such are crucial cellular elements in active GO and inactive GO. However, so far it is largely unknown whether GO disease progression is associated with functional reprogramming of the orbital fibroblast effector function. Therefore, the aim of this study was to compare both the proteome and global DNA methylation patterns between orbital fibroblasts isolated from active GO, inactive GO and healthy controls.MethodsOrbital fibroblasts from inactive GO (n=5), active GO (n=4) and controls (n=5) were cultured and total protein and DNA was isolated. Labelled and fractionated proteins were analyzed with a liquid chromatography tandem-mass spectrometer (LC-MS/MS). Data are available via ProteomeXchange with identifier PXD022257. Furthermore, bisulphite-treated DNA was analyzed for methylation pattern with the Illumina Infinium Human Methylation 450K beadchip. In addition, RNA was isolated from the orbital fibroblasts for real-time quantitative (RQ)-PCR. Network and pathway analyses were performed.ResultsOrbital fibroblasts from active GO displayed overexpression of proteins that are typically involved in inflammation, cellular proliferation, hyaluronan synthesis and adipogenesis, while various proteins associated with extracellular matrix (ECM) biology and fibrotic disease, were typically overexpressed in orbital fibroblasts from inactive GO. Moreover, orbital fibroblasts from active GO displayed hypermethylation of genes that linked to inflammation and hypomethylated genes that linked to adipogenesis and autoimmunity. Further analysis revealed networks that contained molecules to which both hypermethylated and hypomethylated genes were linked, including NF-κB, ERK1/2, Alp, RNA polymerase II, Akt and IFNα. In addition, NF-κB, Akt and IFNα were also identified in networks that were derived from the differentially expressed proteins. Generally, poor correlation between protein expression, DNA methylation and mRNA expression was observed.ConclusionsBoth the proteomics and DNA methylation data support that orbital fibroblasts from active GO are involved in inflammation, adipogenesis, and glycosaminoglycan production, while orbital fibroblasts from inactive disease are more skewed towards an active role in extracellular matrix remodeling. This switch in orbital fibroblast effector function may have therapeutic implications and further studies into the underlying mechanism are thus warranted.

The role of oxidative stress in the pathogenesis of Graves’ orbitopathy

Graves' disease (GD) is a chronic autoimmune condition, in which the anti-thyroid stimulating hormone receptor antibodies (TRAb) activate the thyrotropin receptor (TSHR) located on thyrocytes, leading to excessive thyroid hormone production. TSHR is also expressed in extrathyroidal tissues, in particular, within the orbit. The serum levels of TRAb corelate with severity and activity of thyroid orbitopathy (TO). TO is the most common extrathyroidal manifestation of GD. It is an autoimmune inflammation of orbital tissues, that is, extraocular muscles, orbital adipose tissue or a lacrimal gland. Increased orbital fibroblast and adipocyte proliferation, overproduction of glycosaminoglycans, as well as extraocular muscle oedema result in an increased orbital tissue volume and trigger the onset of TO symptoms. The pathophysiology of TO is complex and has not been fully unexplained to date. Orbital fibroblasts show expression of the TSHR, which is the main target of autoimmunity. It has been hypothesised that T-cell activation induced by orbital receptor stimulation by the target antibody results in orbital tissue infiltration, triggering a cascade of events which leads to the production of cytokines, growth factors and reactive oxygen species (ROS). ROS cause damage to many components of the cell: the cell membrane through the peroxidation of lipids and proteins leading to a loss of their function and enzymatic activity. Oxidative stress leads to activation of the antioxidant system which operates through two mechanisms: enzymatic and non-enzymatic. Assessment of the concentration of oxidative stress markers and the concentration or activity of antioxidative system parameters enables evaluation of oxidative stress severity, which in the future may be utilized for assessment of treatment efficacy and prognosis in patients with active OT.

Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves' Ophthalmopathy through the Regulation of FoxO3a Signaling.

Graves' ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves' disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue (n = 4) and serum specimens (n = 6) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

Rola stresu oksydacyjnego w patogenezie orbitopatii Gravesa

Streszczenie Choroba Gravesa-Basedowa (chGB) jest przewlekłą chorobą autoimmunologiczną, której auto-antygenem jest receptor TSH (TSHR) umiejscowiony na tyreocytach, a jego pobudzenie przez przeciwciała przeciwko TSHR (TRAb) powoduje nadmierne wytwarzanie hormonów tarczycy. TSHR wykazuje także ekspresję w tkankach pozatarczycowych, przede wszystkim w tkankach oczodołu, a stężenie TRAb w surowicy krwi dodatnio koreluje z ciężkością oraz aktywnością orbitopatii tarczycowej (OT). OT jest najczęstszym pozatarczycowym objawem chGB. Jest to choroba autoimmunologiczna, w której dochodzi do zmian zapalnych w obrębie tkanek oczodołów, tj.: mięśniach okoruchowych, tkance tłuszczowej oczodołu czy gruczole łzowym. Wzrost proliferacji fibroblastów oczodołowych i adipocytów oraz nadmierne wytwarzanie glikozaminoglikanów, obrzęk mięśni okoruchowych zwiększają objętość tkanek oczodołu i powodują powstanie objawów klinicznych choroby. Patogeneza OT jest złożona i nadal pozostaje niewyjaśniona. Fibroblasty oczodołów wykazują ekspresję TSHR, który jest głównym miejscem ataku autoimmunologicznego. Zgodnie z szeroko akceptowaną hipotezą po pobudzeniu receptorów dochodzi do aktywacji limfocytów T, które naciekając tkanki oczodołu stymulują je do wytwarzania cytokin, czynników wzrostu oraz wolnych rodników tlenowych (WRT). WRT powodują uszkodzenie wielu składowych komórki m.in. błony komórkowej przez peroksydację lipidów oraz białek doprowadzając do utraty ich funkcji i aktywności enzymatycznej. Stres oksydacyjny uaktywnia układ antyoksydacyjny działający poprzez dwa mechanizmy: enzymatyczny oraz nieenzymatyczny. Ocena stężenia markerów stresu oksydacyjnego oraz stężenia lub aktywności parametrów układu antyoksydacyjnego umożliwia ocenę nasilenia stresu oksydacyjnego, co w przyszłości może być wykorzystywane do oceny skuteczności leczenia i rokowania u chorych z aktywną OT.

Orbital diseases mimicking graves' orbitopathy: a long-standing challenge in differential diagnosis.

Graves' orbitopathy (GO) is the most common cause of orbital tissue inflammation, accounting for ~ 60% of all orbital inflammatory conditions in the population aged 21-60years, and for ~ 40% in the population aged > 60year. GO is observed in 25-30% of patients with Graves' hyperthyroidism and more rarely in association with hypothyroid autoimmune thyroiditis. In addition, a small proportion of GO patients (1-2%) do not have a clinically overt thyroid dysfunction. Clinically, GO is characterized by proptosis, inflammation involving the eyelids and the conjunctiva, extraocular muscle hypertrophy, with consequent reduction of ocular motility and diplopia, and in the most severe cases, compression of the optic nerves at the orbital apex, with reduction of visual acuity. At CT scan or MRI, a muscle increase involving the superior, medial and inferior rectus is quite typical. In the most severe forms, compression of the optic nerves at the orbital apex can be observed. Euthyroid GO is usually an early sign of a full-blown Graves' disease; however, in some cases, the orbital disease can remain isolated. Moreover, euthyroid GO can rarely be unilateral, which makes the picture even more confusing. Under those circumstances, the diagnostic process becomes obviously quite difficult, having other conditions mimicking GO been excluded. A number of inflammatory conditions affecting orbital tissue can mimic GO, thereby requiring an accurate evaluation for a proper differential diagnosis. The majority of these conditions are immune mediated. Most of them are benign, but they can be rather aggressive and some can cause visual loss. The most common inflammatory condition affecting orbital tissues and mimicking GO is idiopathic orbital inflammation. Other, more rare, orbital diseases that should be considered in the differential diagnosis are infections, orbital manifestations of systemic diseases, primitive and secondary orbital neoplasms, and orbital vascular alterations. In most instances, when an orbitopathy occurs in the absence of hyperthyroidism, the diagnosis of the disease underlying the ocular symptoms and signs is based on exclusion of the other conditions. Here we review the conditions that can mimic GO and how to distinguish them from this obnoxious eye disease.

Knowledge of Thyroid Eye Disease in Graves' Disease Patients With and Without Orbitopathy.

Thyroid eye disease (TED) develops in around 25% of those with Graves' disease (GD). Patients with TED may present late to ophthalmologists, when debilitating orbital inflammatory changes have already occurred. The reasons for this are multifactorial, but poor knowledge of TED in GD patients may be contributory. This study aimed to assess the knowledge of TED in those with established TED, GD without orbitopathy, and control subjects. A validated, anonymized questionnaire, with 20 knowledge-based questions, was prospectively completed by 100 GD patients, 100 TED patients, and 100 age- and sex-matched controls (with no history of thyroid disease or TED) in two tertiary referral thyroid and orbital diseases clinics. Demographic data and details of highest educational level, disease duration, and follow-up were gained. Residence postcode was used to determine Index of Multiple Deprivation (2015) quintile. Knowledge score was established for each of the study groups of interest. Statistical analysis was undertaken with Kruskal-Wallis test, chi-square test, and multivariable logistic regression. There was no significant difference in median knowledge scores (out of 20) between GD (13.71, range 9-18) and TED (14.25, range 9-18) patients. However, both groups had significantly higher scores than controls (11.53, range 4-16; p < 0.001). Multivariable analysis determined no particular independent factor associated with lower knowledge score. There were a number of important areas in which patient knowledge of TED was poor. While almost all (99% TED, 89% GD) knew that TED involved orbital tissue inflammation, a large proportion (60% TED, 50% GD) were unaware that TED may develop in the absence of hyperthyroidism or did not know that cigarette smoking is associated with more severe TED (21%TED, 33% GD). TED patients had equivalent levels of TED knowledge compared to GD patients without orbitopathy. While subjects in both disease groups had greater knowledge than controls, each had significant misconceptions regarding aspects of TED diagnosis, management, and treatment. These findings should guide the future provision of patient information for TED, with educational materials being targeted to address existing gaps in knowledge.

Inne choroby pasożytnicze przedniego odcinka oka

Exotic tourism provides us with a lot of fun, but it can also be associated with serious eye complications. Parasites develop in the body for many months or even years before they cause specific symptoms of infection. Inflammation of the anterior segment may be associated with the consumption of contaminated food, bite by an infected insect or direct contact of the irritated eye with the parasite. Complications with parasites from the anterior segment of the eye include: orbital tissue inflammation (sometimes with the feeling of a foreign body resulting from the presence of a mature parasite), keratitis, hyperemia, pruritus and conjunctivitis, presence of a parasite under the conjunctiva or in the anterior chamber, uveitis, hypopyon, hyphema and iris atrophy. In differential diagnosis of clinically atypical anterior segment infection, parasite infections should be considered, even in the case where the patient was not in endemic areas, parasite infestation may occurr as a result of contact with the vector released after air or sea transport.

ORBITAL METASTASES OF SOLID TUMORS. DIAGNOSTIC PROBLEMS

Актуальность. Орбитальные метастазы составляют около 15% от всех злокачественных опухолей орбиты. При появлении у больных злокачественными опухолями образования в полости орбиты возникает подозрение на орбитальный метастаз. Тем не менее у онкологических больных возможно развитие неопухолевого процесса в орбите либо появление второй злокачественной опухоли по типу первично-множественного поражения.Цель – выявить отличительные признаки метастатической опухоли орбиты для проведения дифференциального диагноза с другими опухолевыми и неопухолевыми процессами в орбите и определить алгоритм действий для установления правильного диагноза и своевременного адекватного лечения заболевания орбиты.Материал и методы. Ретроспективно проанализированы истории болезни 81 пациента со злокачественными опухолями различных органов и патологическим процессом в орбите. Из них с метастазами в орбиту было 74 больных (64 женщины и 10 мужчин в возрасте 18–87 лет, медиана 45 лет); вторая злокачественная опухоль орбиты была представлена неходжкинской лимфомой у 5 пациентов (4 женщины и 1 мужчина 55–78 лет, медиана 61 год). У двоих мужчин 64 и 66 лет развился воспалительный процесс в орбите, который имитировал метастатическую опухоль. Всем больным кроме офтальмологического обследования, компьютерной томографии орбит было проведено обследование по органам для исключения рецидива первичной опухоли и метастатического поражения других органов. Результаты. Среди метастатического поражения орбиты наиболее часто встречалась очаговая форма роста одиночной опухоли с пристеночной локализацией преимущественно под верхней стенкой орбиты, с постепенным развитием безболезненного экзофтальма и нарушением подвижности глаза. Такая же клиническая картина была характерна и для неходжкинской лимфомы орбиты. Острое воспаление тканей орбиты у онкологических больных имело стертую клиническую картину и симулировало орбитальный метастаз.Заключение. Для своевременной диагностики орбитальных метастазов необходим комплексный анализ данных анамнеза, особенностей клинической картины и результатов морфологического анализа биоптата.

Human fibrocytes coexpress thyroglobulin and thyrotropin receptor

Thyroglobulin (Tg) is the macromolecular precursor of thyroid hormones and is thought to be uniquely expressed by thyroid epithelial cells. Tg and the thyroid-stimulating hormone receptor (TSHR) are targets for autoantibody generation in the autoimmune disorder Graves disease (GD). Fully expressed GD is characterized by thyroid overactivity and orbital tissue inflammation and remodeling. This process is known as thyroid-associated ophthalmopathy (TAO). Early reports suggested that in TAO, both Tg and TSHR become overexpressed in orbital tissues. Previously, we found that CD34(+) progenitor cells, known as fibrocytes, express functional TSHR, infiltrate the orbit, and comprise a large subset of orbital fibroblasts in TAO. We now report that fibrocytes also express Tg, which resolves as a 305-kDa protein on Western blots. It can be immunoprecipitated with anti-Tg Abs. Further, (125)iodine and [(35)S]methionine are incorporated into Tg expressed by fibrocytes. De novo Tg synthesis is attenuated with a specific small interfering RNA targeting the protein. A fragment of the Tg gene promoter fused to a luciferase reporter exhibits substantial activity when transfected into fibrocytes. Unlike fibrocytes, GD orbital fibroblasts, which comprise a mixture of CD34(+) and CD34(-) cells, express much lower levels of Tg and TSHR. When sorted into pure CD34(+) and CD34(-) subsets, Tg and TSHR mRNA levels become substantially higher in CD34(+) cells. These findings indicate that human fibrocytes express multiple "thyroid-specific" proteins, the levels of which are reduced after they infiltrate tissue. Our observations establish the basis for Tg accumulation in orbital GD.

Immunosuppressive treatment of Graves' ophthalmopathy.

Glucocorticoids and retrobulbar irradiation are the most employed immunosuppressive treatment modalities in Graves' ophthalmopathy. The response rate is approximately 60%. Efficacy is good for improvement of appearance and visual acuity, moderate for correction of extraocular muscle dysfunction, and poor for reduction of proptosis. Immunosuppression seldom cures the eye disease. Its main advantage is to stabilize the eye disease by inactivating the inflammation of orbital tissues, thereby permitting corrective eye surgery to be performed at an earlier time. Future developments in immunosuppression aim at reduction of side effects and enhancement of efficacy. Alternative treatment schedules (e.g., methylprednisolone pulses, intravenous immunoglobulin) may have equal efficacy but less side effects than classic high-dose oral steroids. Efficacy can be improved by restriction of immunosuppression to patients with active eye disease who are more likely to respond. Disease activity might well be the main determinant of therapeutic outcome of immunosuppression in Graves' ophthalmopathy.