Immunological and cellular basis of orbital inflammation and tissue remodeling in a mouse model of Graves’ orbitopathy
Final Report Abstract
Graves' orbitopathy (GO), also known as thyroid eye disease, is a consequence of autoimmunity to the TSH receptor (TSHR) in Graves' disease. Inflammation of the orbital muscles in conjunction with adipogenesis and deposition of hyaluronic acid leads to remodeling of the orbital soft tissue, resulting in muscle dysfunction and/or protrusion of the eye (proptosis), which significantly impairs quality of life. This orbital disease shows great variability in the clinical appearance of individual patients, such as inflammation, myopathy and adipogenesis, the causes of which are still unclear. Increasing evidence suggests that TSHR- specific autoantibodies and T cells interacting with orbital fibroblasts appear to be primarily responsible for the development of GO. We have described the reproducibility of a preclinical mouse model of GO based on immunization of female BALB/c mice with a plasmid encoding the human TSHR A subunit. One advantage of the model is that it allows us to identify the first events in the development and progression of the disease, which is not possible in GO patients. In our studies, perfluorocarbon 19F MRI-based in vivo visualization of orbital inflammatory infiltrates such as macrophages showed the highest significance level to discriminate between GO and control mice and the best correlation with the established disease score. Our longitudinal studies suggest that initial and early events in orbital pathology depend on macrophages and T cells, and a cytokine milieu characterized primarily by INF-γ and TNF-α. Furthermore, our study on orbital tissue samples from patients suggest that an interaction of TNF-α-positive M1 macrophages with orbital fibroblasts promotes inflammation and adipogenesis during the course of the disease. We investigated the stage-dependent signatures of the disease in mouse orbital fibroblasts by genome-wide microarray profiling. The changes in the different signalling pathways in mouse orbital fibroblasts correspond to the progression of the disease, with an initial inflammatory activation of orbital fibroblasts followed by increased proliferation and adipogenesis. We will further study the initial and early inflammatory events in the development of orbital pathology using cytokine-deficient mice to determine whether the different clinical manifestations of GO depend on specific cytokine patterns in the orbit. The long-term objectives of this work are the understanding of the initial steps in autoimmunity to TSHR in Graves’ disease and the resulting orbital pathogenesis. This will help to identify novel biomarkers for early clinical diagnosis and therapy.
Publications
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Multimodal assessment of orbital immune cell infiltration and tissue remodeling during development of graves disease by 1H19F MRI. Magnetic Resonance in Medicine, 80(2), 711-718.
Flögel, Ulrich; Schlüter, Anke; Jacoby, Christoph; Temme, Sebastian; Banga, J. Paul; Eckstein, Anja; Schrader, Jürgen & Berchner‐Pfannschmidt, Utta
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42nd Annual Meeting of the European Thyroid Association. Budapest, Hungary. September 7–10, 2019. European Thyroid Journal, 8(1), 1-127.
Berchner-Pfannschmidt U., Plöhn S., Hose M., Curdt C., Horstmann M., Schlüter A., Michel L., Banga P.J., Hansen W. & Eckstein A.
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42nd Annual Meeting of the European Thyroid Association. Budapest, Hungary. September 7–10, 2019. European Thyroid Journal, 8(1), 1-127.
Görtz G.E., Schlüter A., Jesenek C., Horstmann M., Banga J.P., Brandau S., Eckstein A. & Berchner-Pfannschmidt U.
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Lessons from mouse models of Graves’ disease. Endocrine, 68(2), 265-270.
Eckstein, A.; Philipp, S.; Goertz, G.; Banga, J. P. & Berchner-Pfannschmidt, U.
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43rd Annual Meeting of the European Thyroid Association. Virtual Conference, September 4–7, 2021. European Thyroid Journal, 10(Suppl. 1), 1-56.
Philipp S., Horstmann M., Hose M., Daser A., Görtz G.E., Jesenek C., Banga J.P., Eckstein A., Berchner-Pfannschmidt U.
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Role of macrophage – fibroblast interaction for immunopathology of Graves` orbitopathy. Eur Thyroid J 2021;10 (suppl 1):1–5
Görtz G.E., Jesenek C., Horstmann M., Bruderek K., Philipp S., Eckstein A., Brandau S. & Berchner-Pfannschmidt U.
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TNF-α, CCL-2 and CCL-20 play an important role in an autoimmune hyperthyroid mouse model. Laryngo-Rhino-Otologie. Georg Thieme Verlag KG.
Daser, A.; Horstmann, M.; Philipp, S.; Görtz, G.-E.; Lang, S.; Mattheis, S.; Bechrakis, NE.; Banga, J.P.; Eckstein, A. & Berchner-Pfannschmidt, U.
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An Early Wave of Macrophage Infiltration Intertwined with Antigen-Specific Proinflammatory T Cells and Browning of Adipose Tissue Characterizes the Onset of Orbital Inflammation in a Mouse Model of Graves' Orbitopathy. Thyroid®, 32(3), 283-293.
Philipp, Svenja; Horstmann, Mareike; Hose, Matthias; Daser, Anke; Görtz, Gina-Eva; Jesenek, Christoph; Flögel, Ulrich; Hansen, Wiebke; Bechrakis, Nikolaos; Banga, Jasvinder Paul S.; Eckstein, Anja & Berchner-Pfannschmidt, Utta
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Macrophage-Orbital Fibroblast Interaction and Hypoxia Promote Inflammation and Adipogenesis in Graves’ Orbitopathy. Endocrinology, 164(2).
Görtz, Gina-Eva; Philipp, Svenja; Bruderek, Kirsten; Jesenek, Christoph; Horstmann, Mareike; Henning, Yoshiyuki; Oeverhaus, Michael; Daser, Anke; Bechrakis, Nikolaos E.; Eckstein, Anja; Brandau, Sven & Berchner-Pfannschmidt, Utta
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Macrophage-orbital fibroblasts interaction in context of hypoxic signaling for inflammatory processes during graves' orbitopathy. Endocrine Abstracts.
Gortz, Gina-Eva; Eckstein, Anja; Jesenek, Christoph; Horstmann, Mareike; Philipp, Svenja; Bruderek, Kirsten; Oeverhaus, Michael; Daser, Anke; Bechrakis, Nikolaos; Brandau, Sven & Berchner-Pfannschmidt, Utta
