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Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA

The TSH receptor (TSHR) is the critical target for antibody production in Graves' disease (GD). Insulin-like growth factor 1 receptor (IGF1R) has been proposed as a second autoantigen in complications of GD such as orbitopathy. We attempted to induce orbital tissue remodeling in mice undergoing...

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Autores principales: Zhao, Shuang-Xia, Tsui, Shanli, Cheung, Anthony, Douglas, Raymond S, Smith, Terry J, Banga, J Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioScientifica 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152291/
https://www.ncbi.nlm.nih.gov/pubmed/21715431
http://dx.doi.org/10.1530/JOE-11-0162
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author Zhao, Shuang-Xia
Tsui, Shanli
Cheung, Anthony
Douglas, Raymond S
Smith, Terry J
Banga, J Paul
author_facet Zhao, Shuang-Xia
Tsui, Shanli
Cheung, Anthony
Douglas, Raymond S
Smith, Terry J
Banga, J Paul
author_sort Zhao, Shuang-Xia
collection PubMed
description The TSH receptor (TSHR) is the critical target for antibody production in Graves' disease (GD). Insulin-like growth factor 1 receptor (IGF1R) has been proposed as a second autoantigen in complications of GD such as orbitopathy. We attempted to induce orbital tissue remodeling in mice undergoing immunizations with plasmids encoding TSHR and IGF1R delivered by in vivo skeletal muscle electroporation, a procedure known to give a sustained, long-term antibody response. Female BALB/c mice were challenged with TSHR A-subunit or IGF1Rα subunit plasmid by injection and electroporation. Mice challenged with TSHR A-subunit plasmid resulted in high frequency (75%) of hyperthyroidism and thyroid-stimulating antibodies. But strikingly, immunization with TSHR A-subunit plasmid also elicited antibody to IGF1Rα subunit. Mice challenged in the same manner with IGF1Rα subunit plasmid produced strong antibody responses to IGF1R, but did not undergo any changes in phenotype. Simultaneous challenge by double antigen immunization with the two plasmids in distant anatomical sites reduced the incidence of hyperthyroidism, potentially as a consequence of antigenic competition. Thyroid glands from the TSHR A-subunit plasmid-challenged group were enlarged with patchy microscopic infiltrates. Histological analysis of the orbital tissues demonstrated moderate connective tissue fibrosis and deposition of Masson's trichrome staining material. Our findings imply that immunization with TSHR A-subunit plasmid leads to generation of IGF1R antibodies, which together with thyroid-stimulating antibodies may precipitate remodeling of orbital tissue, raising our understanding of its close association with GD.
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spelling pubmed-31522912011-09-01 Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA Zhao, Shuang-Xia Tsui, Shanli Cheung, Anthony Douglas, Raymond S Smith, Terry J Banga, J Paul J Endocrinol Regular Papers The TSH receptor (TSHR) is the critical target for antibody production in Graves' disease (GD). Insulin-like growth factor 1 receptor (IGF1R) has been proposed as a second autoantigen in complications of GD such as orbitopathy. We attempted to induce orbital tissue remodeling in mice undergoing immunizations with plasmids encoding TSHR and IGF1R delivered by in vivo skeletal muscle electroporation, a procedure known to give a sustained, long-term antibody response. Female BALB/c mice were challenged with TSHR A-subunit or IGF1Rα subunit plasmid by injection and electroporation. Mice challenged with TSHR A-subunit plasmid resulted in high frequency (75%) of hyperthyroidism and thyroid-stimulating antibodies. But strikingly, immunization with TSHR A-subunit plasmid also elicited antibody to IGF1Rα subunit. Mice challenged in the same manner with IGF1Rα subunit plasmid produced strong antibody responses to IGF1R, but did not undergo any changes in phenotype. Simultaneous challenge by double antigen immunization with the two plasmids in distant anatomical sites reduced the incidence of hyperthyroidism, potentially as a consequence of antigenic competition. Thyroid glands from the TSHR A-subunit plasmid-challenged group were enlarged with patchy microscopic infiltrates. Histological analysis of the orbital tissues demonstrated moderate connective tissue fibrosis and deposition of Masson's trichrome staining material. Our findings imply that immunization with TSHR A-subunit plasmid leads to generation of IGF1R antibodies, which together with thyroid-stimulating antibodies may precipitate remodeling of orbital tissue, raising our understanding of its close association with GD. BioScientifica 2011-09 /pmc/articles/PMC3152291/ /pubmed/21715431 http://dx.doi.org/10.1530/JOE-11-0162 Text en © 2011 Society for Endocrinology http://www.endocrinology.org/journals/reuselicence/ This is an Open Access article distributed under the terms of the Society for Endocrinology's Re-use Licence (http://www.endocrinology.org/journals/reuselicence/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Regular Papers
Zhao, Shuang-Xia
Tsui, Shanli
Cheung, Anthony
Douglas, Raymond S
Smith, Terry J
Banga, J Paul
Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA
title Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA
title_full Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA
title_fullStr Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA
title_full_unstemmed Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA
title_short Orbital fibrosis in a mouse model of Graves' disease induced by genetic immunization of thyrotropin receptor cDNA
title_sort orbital fibrosis in a mouse model of graves' disease induced by genetic immunization of thyrotropin receptor cdna
topic Regular Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152291/
https://www.ncbi.nlm.nih.gov/pubmed/21715431
http://dx.doi.org/10.1530/JOE-11-0162
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