Pathogenesis of Graves' Ophthalmopathy: The Role of Autoantibodies

Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Thyroid (Impact Factor: 4.49). 11/2007; 17(10):1013-8. DOI: 10.1089/thy.2007.0185
Source: PubMed


The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within orbital tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage.

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    • "The observed increase of IP-10/CXCL10 was also more pronounced in the early phase of TAO with active inflammation as compared with the late phase. These results showing increased levels of IP-10/CXCL10 induced by IFN-γ in orbital fibroblasts from TAO patients are in agreement with a previous report of TH1 cytokine involvement in both Graves' disease and TAO.29 "
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    ABSTRACT: The aim of the present study was to identify a new candidate anti-inflammatory compound for use in the active stage of thyroid-associated ophthalmopathy (TAO). Benzylideneacetophenone compound JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] was synthesized based on a structural modification of yakuchinone B, a constituent of the seeds of Alpinia oxyphylla, which belongs to the ginger family (Zingiberaceae), has been widely used in folk medicine as an anti-inflammatory phytochemical. Orbital fibroblasts were primarily cultured from patients with TAO, and the potential of JC3 to suppress the interferon (IFN)-γ-induced protein (IP)-10/CXCL10 production in these cells was determined. IFN-γ strongly increased the level of IP-10/CXCL10 in orbital fibroblasts from patients with TAO. JC3 exerted a significant inhibitory effect on the IFN-γ-induced increase in IP-10/CXCL10 in a dose-dependent manner; its potency was greater than that of an identical concentration of yakuchinone B with no toxicity to cells at the concentration range used. Moreover, the constructed dimer and trimer polystructures of JC3, showed greater potency than JC3 in suppressing the IFN-γ-induced production of IP-10/CXCL10. JC3 significantly attenuated the IP-10/CXCL10 mRNA expression induced by IFN-γ, and a gel-shift assay showed that JC3 suppressed IFN-γ-induced DNA binding of signal transducer and activator of transcription-1 (STAT-1) in TAO orbital fibroblasts. Our results provide initial evidence that the JC3 compound reduces the levels of IP-10/CXCL10 protein and mRNA induced by IFN-γ in orbital fibroblasts of TAO patients. Therefore, JC3 might be considered as a future candidate for therapeutic application in TAO that exerts its effects by modulating the pathogenic mechanisms in orbital fibroblasts.
    Experimental and Molecular Medicine 06/2014; 46(6):e100. DOI:10.1038/emm.2014.26 · 3.45 Impact Factor
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    • "The pathogenesis of the ocular involvement of GD is explained by the expression of TSH-R not only in the thyroid follicular cells but also in adipocytes, fibroblasts, and lymphocytes in the orbit.1,10 Although the link between GD and GO is still unclear,11,12 the close association between onset of GD and the development of GO suggests that GD and GO may have common pathogenic mechanisms.1 Thus, the idea that TRAb detection may be of clinical benefit in the assessment of thyroid eye disease makes the elucidation of the relationship between the autoantibodies and GO clinically valuable.11-15 "
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    ABSTRACT: Purpose To investigate an association between the levels of serum thyroid-stimulating hormone (TSH)-receptor autoantibodies (TRAbs) and Graves' orbitopathy (GO) activity/severity scores, and compare the performance of three different TRAb assays in assessing the clinical manifestations of GO. Materials and Methods Cross-sectional study. Medical records of 155 patients diagnosed with GO between January 2008 and December 2010 were reviewed. GO activity was assessed by clinical activity score (CAS) and severity graded with the modified NOSPECS score by a single observer. Serum TRAb was measured by three different methods: 1st generation thyrotropin-binding inhibitor immunoglobulin (TBII) assay (TRAb1st); 3rd generation TBII assay (TRAb3rd); and biological quantitative assay of thyroid-stimulating immunoglobulin (TSI) using Mc4-CHO cells (Mc4-CHO TSI assay). Results were correlated with scores of activity/severity of thyroid eye disease. Results All three assays (TRAb1st, TRAb3rd, and Mc4-CHO TSI) yielded results that were significantly positively correlated with CAS (β=0.21, 0.21, and 0.46, respectively; p<0.05) and proptosis (β=0.38, 0.34, and 0.33, respectively; p<0.05). Mc4-CHO TSI bioassay results were significantly positively correlated with all GO severity indices (soft tissue involvement, proptosis, extraocular muscle involvement, and total eye score; β=0.31, 0.33, 0.25, and 0.39, respectively; p<0.05). Conclusion Mc4-CHO TSI bioassay was superior over the two TBIIs in assessing active inflammation and muscle restriction due to GO, whereas TBII assay would be sufficient for evaluation of patients with proptosis.
    Yonsei medical journal 07/2013; 54(4):1033-1039. DOI:10.3349/ymj.2013.54.4.1033 · 1.29 Impact Factor
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    • "Besides this tissutal morphogenetic function FBs actively participate in the inflammatory response by producing chemokines and cytokines, and in the antigen presentation by acting as non-professional antigen presenting cells [7-12]. Moreover, in the autoimmune processes, FBs are frequently targeted by autoantibodies, leading to a biological dysfunction [9,13,14]. Based on the above characteristics, FBs are involved in diseases characterized by tissue architectural alterations, inflammation and autoimmunity. "
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    ABSTRACT: Background Celiac disease (CD) is mainly characterised by villous atrophy and mucosal architectural rearrangement. The fibroblasts (FBs) are the most abundant mesenchymal cell type in the intestinal mucosa and are responsible for both the architectural arrangement of the villi and the formation of the extracellular matrix (ECM). This study aimed at the evaluation of both the intracellular distribution of different proteins involved in ECM and FBs characterisation, and the cellular displacement of primary FBs obtained from duodenal endoscopic biopsies of healthy subjects and celiac patients. Methods Primary healthy and celiac duodenal FBs were evaluated by means of immuno-fluorescence assay for collagen type I and IV, fibronectin, actin, alpha-Smooth Muscle Actin (alpha-SMA), Fibroblast Surface Protein (FSP) and transglutaminase type 2 (TG2). The geometric indexes of the fluorescence signals were investigated by image analysis software (Image J, NIH). Both morphology and kinetic were evaluated during a 72 hours time course movie. TG2 medium activity was evaluated by means of ELISA. Results All the cells examined were immunopositive for FSP, alpha-SMA, actin, collagen I, collagen IV and TG2. CD cells showed a signet collagen-I and collagen-IV pattern, as compared to the controls being characterised by a spindle geometry. Moreover, the collagen signals in CD FBs showed a significantly higher circularity index (major orthogonal diameter ratio) than the controls (p < 0.0001), whereas the perimeter and area ratio were significantly lower (p < 0.0001). The TG2 signal had a decreased area (p < 0.05), but a two-fold increased medium activity. The time course highlighted a reduction of the displacement of CD FBs. Conclusions The isolated primary CD FBs showed a different collagen and TG2 pattern of distribution associated with a different cellular displacement. The reasons for such CD cell peculiar characteristics are yet unknown but they might represent a factor in the progression of the intestinal damage.
    Journal of Translational Medicine 04/2013; 11(1):91. DOI:10.1186/1479-5876-11-91 · 3.93 Impact Factor
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