title: Comparative Assessment of Female Mouse Model of Graves' Orbitopathy Under Different Environments, Accompanied by Proinflammatory Cytokine and T-Cell Responses to Thyrotropin Hormone Receptor Antigen.
abstract: We recently described a preclinical model of Graves' orbitopathy (GO), induced by genetic immunization of eukaryotic expression plasmid encoding human TSH receptor (TSHR) A-subunit by muscle electroporation in female BALB/c mice. The onset of orbital pathology is characterized by muscle inflammation, adipogenesis, and fibrosis. Animal models of autoimmunity are influenced by their environmental exposures. This follow-up study was undertaken to investigate the development of experimental GO in 2 different locations, run in parallel under comparable housing conditions. Functional antibodies to TSHR were induced in TSHR A-subunit plasmid-immunized animals, and antibodies to IGF-1 receptor α-subunit were also present, whereas control animals were negative in both locations. Splenic T cells from TSHR A-subunit primed animals undergoing GO in both locations showed proliferative responses to purified TSHR antigen and secreted interferon-γ, IL-10, IL-6, and TNF-α cytokines. Histopathological evaluation showed orbital tissue damage in mice undergoing GO, manifest by adipogenesis, fibrosis, and muscle damage with classic signs of myopathy. Although no inflammatory infiltrate was observed in orbital tissue in either location, the appearances were consistent with a "hit-and-run" immune-mediated inflammatory event. A statistically significant increase of cumulative incidence of orbital pathology when compared with control animals was shown for both locations, confirming onset of orbital dysimmune myopathy. Our findings confirm expansion of the model in different environments, accompanied with increased prevalence of T cell-derived proinflammatory cytokines, with relevance for pathogenesis. Wider availability of the model makes it suitable for mechanistic studies into pathogenesis and undertaking of novel therapeutic approaches.
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Utta
authors.initials: U
authors.lastname: Berchner-Pfannschmidt
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Sajad
authors.initials: S
authors.lastname: Moshkelgosha
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Salvador
authors.initials: S
authors.lastname: Diaz-Cano
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Edelmann
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Gina-Eva
authors.initials: GE
authors.lastname: Görtz
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Mareike
authors.initials: M
authors.lastname: Horstmann
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Alistair
authors.initials: A
authors.lastname: Noble
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: Anja
authors.initials: A
authors.lastname: Eckstein
authors.affiliation: Molecular Ophthalmology (U.B.-P., S.M., G.-E.G., M.H., A.E., J.P.B.), Department of Ophthalmology; Department of Molecular Biology (B.E.); and Institute of Medical Microbiology (W.H.), University Hospital Essen/University of Duisburg-Essen, 45147 Essen, Germany; Faculty of Life Sciences and Medicine (S.M., A.N., J.P.B.), King's College London, London, SE5 9NU United Kingdom; and King's College Hospital NHS Foundation Trust (S.D.-C.), London, SE5 9RS United Kingdom.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Banga
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D049970:Graves Ophthalmopathy / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011989:Receptors, Thyrotropin / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000941:Antigens; D017252:CD3 Complex; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D011989:Receptors, Thyrotropin; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma