Abstract:An increased accumulation of glycosaminoglycans (GAG) in the orbita has been reported in endocrine ophthalmopathy (EO). In this study we investigated whether antibodies directed against GAG are present in the sera of 52 EO patients and 47 healthy controls. Three out of 52 patients exhibited low titers of antinuclear antibodies and all patients were negative for antibodies against extractable nuclear antigens. Isotype IgG antibodies were detected by means of an ELISA using hyaluronic acid and dermatan sulfate a… Show more
“…The fibroblast activation is caused by pro-inflammatory cytokines derived from locally infiltrating T lymphocytes (CD4+, CD8+, CD45RO+, CD45RB+) [ 30 ] and macrophages [ 31 ]. Activation of TSHR-expressing orbital fibroblasts by stimulatory TSHR-Ab and pro-inflammatory cytokines causes production of collagen and hydrophilic mucopolysaccharides [ 28 , 32 ]. Fig.…”
Section: Graves’ Orbitopathy and The Thyrotropin Receptormentioning
Context and purpose
The thyrotropin receptor (TSHR) is the key autoantigen in Graves’ disease (GD) and associated orbitopathy (GO). Antibodies targeting the TSHR (TSHR-Ab) impact the pathogenesis and the course of GO. This review discusses the role and clinical relevance of TSHR-Ab in GO.
Methods
Review of the current and pertinent literature.
Results
GO is the most common extrathyroidal manifestation of GD and is caused by persistent, unregulated stimulation of TSHR-expressing orbital target cells (e.g. fibroblasts and pre-adipocytes). Serum TSHR-Ab and more specifically, the stimulatory Ab (TSAb) are observed in the vast majority of patients with GD and GO. TSHR-Ab are a sensitive serological parameter for the differential diagnosis of GO. TSHR-Ab can be detected either with conventional binding immunoassays that measure binding of Ab to the TSHR or with cell-based bioassays that provide information on their functional activity and potency. Knowledge of the biological activity and not simply the presence or absence of TSHR-Ab has relevant clinical implications e.g. predicting de-novo development or exacerbation of pre-existing GO. TSAb are specific biomarkers of GD/GO and responsible for many of its clinical manifestations. TSAb strongly correlate with the clinical activity and clinical severity of GO. Further, the magnitude of TSAb indicates the onset and acuity of sight-threatening GO (optic neuropathy). Baseline serum values of TSAb and especially dilution analysis of TSAb significantly differentiate between thyroidal GD only versus GD + GO.
Conclusion
Measurement of functional TSHR-Ab, especially TSAb, is clinically relevant for the differential diagnosis and management of GO.
“…The fibroblast activation is caused by pro-inflammatory cytokines derived from locally infiltrating T lymphocytes (CD4+, CD8+, CD45RO+, CD45RB+) [ 30 ] and macrophages [ 31 ]. Activation of TSHR-expressing orbital fibroblasts by stimulatory TSHR-Ab and pro-inflammatory cytokines causes production of collagen and hydrophilic mucopolysaccharides [ 28 , 32 ]. Fig.…”
Section: Graves’ Orbitopathy and The Thyrotropin Receptormentioning
Context and purpose
The thyrotropin receptor (TSHR) is the key autoantigen in Graves’ disease (GD) and associated orbitopathy (GO). Antibodies targeting the TSHR (TSHR-Ab) impact the pathogenesis and the course of GO. This review discusses the role and clinical relevance of TSHR-Ab in GO.
Methods
Review of the current and pertinent literature.
Results
GO is the most common extrathyroidal manifestation of GD and is caused by persistent, unregulated stimulation of TSHR-expressing orbital target cells (e.g. fibroblasts and pre-adipocytes). Serum TSHR-Ab and more specifically, the stimulatory Ab (TSAb) are observed in the vast majority of patients with GD and GO. TSHR-Ab are a sensitive serological parameter for the differential diagnosis of GO. TSHR-Ab can be detected either with conventional binding immunoassays that measure binding of Ab to the TSHR or with cell-based bioassays that provide information on their functional activity and potency. Knowledge of the biological activity and not simply the presence or absence of TSHR-Ab has relevant clinical implications e.g. predicting de-novo development or exacerbation of pre-existing GO. TSAb are specific biomarkers of GD/GO and responsible for many of its clinical manifestations. TSAb strongly correlate with the clinical activity and clinical severity of GO. Further, the magnitude of TSAb indicates the onset and acuity of sight-threatening GO (optic neuropathy). Baseline serum values of TSAb and especially dilution analysis of TSAb significantly differentiate between thyroidal GD only versus GD + GO.
Conclusion
Measurement of functional TSHR-Ab, especially TSAb, is clinically relevant for the differential diagnosis and management of GO.
“…We, therefore, suggest that serum antibodies against optic nerve head glycosaminoglycans, in part, may underlie the glaucomatous damage that occurs in patients in whom such antibodies are present, most often those with normalpressure glaucoma. This hypothesis is supported by findings [10][11][12]41,42 in which alterations in the distribution patterns, composition, and functional properties of the glycosaminoglycans secondary to cross-reactivity of serum autoantibodies with glycosaminoglycans mediate specific tissue injury in several autoimmune diseases. Negatively charged sulfate and carboxyl groups of glycosaminoglycans are thought to play a role in the immunodominant site.…”
Section: Commentmentioning
confidence: 68%
“…In several autoimmune-mediated diseases, including systemic lupus erythematosus, diabetes mellitus, thyroid disease, and scleroderma, elevated production and local accumulation of collagen and glycosaminoglycan in the affected tissues has been reported. 12,41,42 A similar cross-reactivity to optic nerve head glycosaminoglycans may occur in persons who have abnormal serum antibodies and may render an increased susceptibility for glaucomatous damage regardless of the intraocular pressure level. Therefore, our findings may not have only pathogenic significance but also may indicate an important serum marker for the increased susceptibility to glaucomatous optic neuropathy.…”
Background: Serum autoantibodies that cross-react with glycosaminoglycans have been proposed to play a significant role in specific tissue injury in patients with systemic autoimmune diseases. Objective: To investigate whether serum immunoreactivity to glycosaminoglycans is present in patients with glau-comawhohaveaberrantserumautoantibodiestoDNA,RNA, nuclear proteins, or retinal proteins, as proteoglycans and their glycosaminoglycan side chains are important components of the optic nerve head and its vasculature. Methods: We performed Western blotting using patient serum samples and human optic nerve head homogenates that were treated with or without specific glycosaminoglycan degrading enzymes. Monoclonal antibodies that recognize different determinants of glycosaminoglycans were used to identify specific substrate antigenicity. We compared the serum immunoreactivity to glycosaminoglycans in 60 age-matched patients with normal-pressure glaucoma, 36 patients with primary open-angle glaucoma, and 20 control subjects by enzyme-linked immunosorbent assay. In addition, immunohistochemistry was performed to compare the distribution patterns of glycosaminoglycans in the optic nerve head of postmortem eyes of agematched patients with normal-pressure glaucoma, primary open-angle glaucoma, and control subjects. Results: Western blotting demonstrated that serum samples from patients with glaucoma who have circulating autoantibodies can recognize optic nerve head proteoglycans, including chondroitin sulfate and heparan sulfate. The level of serum autoantibodies binding purified chondroitin sulfate and heparan sulfate glycosaminoglycans in an enzyme-linked immunosorbent assay was approximately 100% higher in patients with normal-pressure glaucoma than that in control subjects and approximately 50% higher than that in patients with primary open-angle glaucoma. We also observed increased immunostaining of glycosaminoglycans in the optic nerve head of eyes with glaucoma, particularly those with normal intraocular pressure, compared with control eyes. Conclusion: There are increased levels of autoantibodies recognizing glycosaminoglycans of the optic nerve head in the serum samples of some patients with glaucoma. Clinical Relevance: These autoantibodies may increase the susceptibility of the optic nerve head to damage in these patients by changing the functional properties of the lamina cribrosa, its vasculature, or both.
“…Specific HA, HS, and other polysulfated GAG antibodies were studied in sera of patients with TED (14). A GAG-stimulatory lymphokine that selectively increases GAG synthesis in normal human dermal fibroblasts has been demonstrated (15).…”
Orbital accumulation of hydrophilic, interstitial glycosaminoglycans (GAG) and subsequent expansion of retrobulbar tissue lead to the clinical manifestation of exophthalmos in patients with thyroid eye disease (TED). In order to analyze whether the alteration of distribution pattern and biochemical composition of GAG and proteoglycans play a role in the development of the disease, a highly specific high-pressure liquid chromatography (HPLC) method was developed. The concentration of total GAG, chondroitin sulfate A (CA), dermatan sulfate (DS), and hyaluronic acid (HA) was determined in patients and controls, revealing marked differences in urinary concentration of total GAG and HA, as well as an elevation of CA in patients versus controls. Method sensitivity was 0.86 for patients with active disease, and 0.87 for patients with untreated ophthalmopathy, whereas specificity was 1.0 for patients with inactive disease. Patients with increased GAG concentration responded well to steroids and/or orbital irradiation. Furthermore, distribution pattern of orbital extracellular matrix GAG exhibited a significant increase in the tissue fractions of CA and HA in patients with TED in comparison to controls. In conclusion, GAG polysaccharides not only play a major role in the pathogenesis of TED but have been successfully introduced as an activity marker of the disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
