Cutting Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a Preclinical Female Mouse Model of Graves' Orbitopathy Induced by Thyrotropin Receptor Plasmid-in Vivo Electroporation

Moshkelgosha, Sajad; So, Po‐Wah; Deasy, Neil; Díaz‐Cano, Salvador; Banga, J. Paul

doi:10.1210/en.2013-1576

Cited by 104 publications

(119 citation statements)

References 28 publications

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“…In the first one, eye alterations resembling GO were observed [27], but the results were not reproduced by the same authors in a subsequent investigation, presumably because of environmental influences [28]. More recently, another model of GO was developed by genetic immunization of BALB/c mice with the human TSH-R A-subunit [29]. Although mice were hyporather than hyperthyroid, features of GO were observed at histology and by magnetic resonance imaging.…”

Section: Thyroid Autoantigens Possibly Involved In the Pathogenesis Omentioning

confidence: 99%

Total thyroid ablation in Graves’ orbitopathy

Menconi

Leo

Vitti

et al. 2015

J Endocrinol Invest

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Graves' orbitopathy (GO) is an autoimmune condition almost always associated with autoimmune thyroid disease, especially Graves' disease (GD). According to the most widely accepted model, the autoantigens responsible for GO would include molecules expressed by thyroid epithelial cells that are present also in orbital tissues. The high likelihood that the etiologies of GO and of the underlying autoimmune thyroid diseases are somehow linked is confirmed by the very close relationship between GO, the onset and the course of Graves' diseases, the size of the thyroid gland, and most importantly, thyroid function and thyroid treatment. Based on these considerations, it has been proposed that complete removal of thyroid antigens and of thyroid infiltrating lymphocytes, the so-called total thyroid ablation (TTA), may be followed by an attenuation of the immune reaction against orbital antigens, and ultimately by an amelioration of GO. The possibility that TTA, achieved by near total thyroidectomy followed by radioiodine, may be beneficial for GO was initially suggested by two retrospective studies and more recently by two prospective, randomized clinical trials conducted in patients with moderate GO treated with intravenous glucocorticoids. Although there seemed to be no difference in the long term, compared with near total thyroidectomy alone TTA was associated with a shorter time required for GO to improve, or anyway to reach its best possible outcome, and with a lesser requirement for additional treatments for GO to improve. Whether this is sufficient to offer ablation to patients remains a matter of discussion. At present, this procedure could be offered only to patients scheduled to thyroidectomy and glucocorticoid treatment.

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Section: Thyroid Autoantigens Possibly Involved In the Pathogenesis Omentioning

confidence: 99%

Total thyroid ablation in Graves’ orbitopathy

Menconi

Leo

Vitti

et al. 2015

J Endocrinol Invest

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“…We describe a detailed analysis of the pathology of the thyroid gland in a mouse model of experimental GD [8, 9]. The disease was characterized by all features of GD such as increased serum levels of total T 4 and the production of antibodies to TSHR.…”

Section: Discussionmentioning

confidence: 99%

“…Investigations involving animals have been approved by the institutional ethics animal committee of North Rhine Westphalia State Agency for Nature, Environment and Consumer Protection, Germany. At the age of 6–8 weeks, the mice were immunized with intramuscular injection and electroporation of 50 µg (1 mg/mL) plasmid into each biceps femoris muscle 4 times every 3 weeks [8, 9, 17]; 14 animals were immunized with pTRiEx1.1 human TSHR A-subunit plasmid and 17 animals with control ß-Gal plasmid (Ctrl). Six weeks after the end of immunization, the mice were sacrificed, and serum was collected and stored at –80°C.…”

Section: Methodsmentioning

confidence: 99%

“…Because of human diversity as well as distinct ethical limitations, syngeneic animal models of hyperplastic and autoimmune diseases are invaluable investigative tools for complex pathological conditions such as GD and autoimmune thyroiditis [5-7]. We have recently reported the development of a robust and reproducible model of experimental GD that also develops the complication of Graves orbitopathy (GO) in female BALB/c mice due to immunization by electroporation with plasmid encoding heterologous human TSHR ectodomain (human TSHR A-subunit) [8, 9], but did not describe the thyroid pathology in detail.…”

Section: Introductionmentioning

confidence: 99%

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Noninflammatory Diffuse Follicular Hypertrophy/Hyperplasia of Graves Disease: Morphometric Evaluation in an Experimental Mouse Model

Schlüter¹,

Eckstein²,

Brenzel³

et al. 2018

Eur Thyroid J

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Objectives: Experimental models of Graves hyperthyroid disease accompanied by Graves orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. The interrelated pathological findings in the thyroid glands of Graves disease (GD) that explain the core changes classically include diffuse follicular hyperplasia and multifocal mild lymphocytic infiltrate. However, the relative contributions of different thyroid tissue components (colloid, follicular cells, and stroma) have not been previously evaluated. In this study, we characterize the thyroid gland of an experimental mouse model of autoimmune GD. Our objective was to define the relative contribution of the different thyroid tissue components to the pathology of glands in the experimental model. Methods: Mice were immunized with human TSHR A-subunit plasmid. Antibodies induced to human TSHR were pathogenic in vivo due to their cross-reactivity to mouse TSHR. Results: Autoimmune thyroid disease in the model was characterized by histopathology of hyperplastic glands with large follicular cells. Further examination of thyroid glands of immunized animals revealed a significantly increased follicular area and follicle/stroma ratio, morphometrically correlated with a noninflammatory follicular hyperplasia/hypertrophy. The increased follicle/stroma ratio was the most relevant morphometrically variable summarizing the pathological changes for screening purposes. Conclusion: GD thyroid glands are enlarged and characterized by a noninflammatory diffuse follicular cell hyperplasia/hypertrophy and a significant increase in the follicles with an increased follicle/stroma ratio. Overall, this mouse model is a faithful model of an early hyperthyroid status of GD (diffuse glandular involvement and follicular expansion).

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“…Our patient undertook thyroidectomy on the understanding that this was experimental therapy. Rationale for surgery was that there is a likely role for TSH receptor antigen in TED, as supported by animal models [23].…”

Section: Discussionmentioning

confidence: 99%

Sight Threatening Thyroid Eye Disease Complicating Hashimoto’s Thyroiditis

Young¹,

Depczynski²,

Wall³

et al. 2017

Endocrinol Metab Syndr

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A case of sight threatening thyroid eye disease (TED), arising in a 55 year old woman with primary hypothyroidism due to Hashimoto's thyroiditis (HT), is described. TSH receptor antibody (TSHRab) was positive as were orbital antibodies. Initial management consisted of methylprednisone intravenously followed by prednisone orally in a tapering dose, orbital irradiation and decompressive surgery. Visual acuity improved but 9 months later, there was evidence of relapse with features of compressive optic neuropathy, and exophthalmos had worsened. Prednisone dose was increased. At that time, TSHRab was negative. She underwent total thyroidectomy on the understanding that this was experimental therapy, surgery confirmed that thyroid pathology was solely TH without any evidence of Graves' disease. Prednisone was successively tapered without further relapse. Rehabilitative ocular muscle surgery is planned. Whether the improvement seen in TED can be attributed to effect of removal of thyroid antigens following thyroidectomy is purely speculative. Our case illustrates that relapsing sight threatening TED is part of spectrum of TED in HT and demonstrates that clinical features can be severe.

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Cutting Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a Preclinical Female Mouse Model of Graves' Orbitopathy Induced by Thyrotropin Receptor Plasmid-in Vivo Electroporation

Cited by 104 publications

References 28 publications

Total thyroid ablation in Graves’ orbitopathy

Total thyroid ablation in Graves’ orbitopathy

Noninflammatory Diffuse Follicular Hypertrophy/Hyperplasia of Graves Disease: Morphometric Evaluation in an Experimental Mouse Model

Sight Threatening Thyroid Eye Disease Complicating Hashimoto’s Thyroiditis

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