Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self‐tolerance for a murine model of autoimmune thyroid disease and Graves' orbitopathy |
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| Authors: | A. Schlüter M. Horstmann S. Diaz‐Cano S. Plöhn K. Stähr S. Mattheis M. Oeverhaus S. Lang U. Flögel U. Berchner‐Pfannschmidt A. Eckstein J. P. Banga |
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| Affiliation: | 1. Molecular Ophthalmology, Departments of Ophthalmology University Hospital Essen, Germany;2. Oto‐Rhino‐Laryngology, Head and Neck Surgery, University Hospital Essen, Essen, Germany;3. Department of Histopathology, King's College Hospital NHS, London, UK;4. Department of Ophthalmology, University Hospital Essen, Essen, Germany;5. Experimental Cardiovascular Imaging, Department of Molecular Cardiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany |
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| Abstract: | Experimental models of Graves' hyperthyroid disease accompanied by Graves' orbitopathy (GO) can be induced efficiently in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A‐subunit plasmid. In this study, we report on the development of a bona fide murine model of autoimmune Graves' disease induced with homologous mouse TSHR A‐subunit plasmid. Autoimmune thyroid disease in the self‐antigen model was accompanied by GO and characterized by histopathology of hyperplastic glands with large thyroid follicular cells. Examination of orbital tissues showed significant inflammation in extra‐ocular muscle with accumulation of T cells and macrophages together with substantial deposition of adipose tissue. Notably, increased levels of brown adipose tissue were present in the orbital tissue of animals undergoing experimental GO. Further analysis of inflammatory loci by 19F‐magnetic resonance imaging showed inflammation to be confined to orbital muscle and optic nerve, but orbital fat showed no difference in inflammatory signs in comparison to control β‐Gal‐immunized animals. Pathogenic antibodies induced to mouse TSHR were specific for the self‐antigen, with minimal cross‐reactivity to human TSHR. Moreover, compared to other self‐antigen models of murine Graves' disease induced in TSHR knock‐out mice, the repertoire of autoantibodies to mouse TSHR generated following the breakdown of thymic self‐tolerance is different to those that arise when tolerance is not breached immunologically, as in the knock‐out models. Overall, we show that mouse TSHR A‐subunit plasmid immunization by electroporation overcomes tolerance to self‐antigen to provide a faithful model of Graves' disease and GO. |
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| Keywords: | autoimmunity Graves' disease Graves' orbitopathy self‐antigen mouse model thyroid disease |
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