Abstract
Graves’ orbitopathy (GO) is the most common extra thyroidal complication of Graves’ disease (GD) and occurs predominantly in women but more severe in men. The reason for this effect of gender on GO is unknown. Herein we studied the manifestation of GO in both sexes of an induced mouse model in absence of additional risk factors present in patients like advanced age, genetic variabilities or smoking. Male and female mice were immunized with human TSHR A-subunit encoding plasmid. Both sexes comparably developed autoimmune hyperthyroidism characterized by TSHR stimulating autoantibodies, elevated T4 values, hyperplastic thyroids and hearts. Autoimmune mice developed inflammatory eye symptoms and proptosis, although males earlier than females. Serial in vivo1H/19F-magnetic resonance imaging revealed elevated inflammatory infiltration, increased fat volume and glycosaminoglycan deposition in orbits of both sexes but most significantly in female mice. Histologically, infiltration of T-cells, extension of brown fat and overall collagen deposition were characteristics of GO in male mice. In contrast, female mice developed predominately macrophage infiltration in muscle and connective tissue, and muscle hypertrophy. Apart from sex-dependent variabilities in pathogenesis, disease classification revealed minor sex-differences in incidence and total outcome. In conclusion, sex does not predispose for autoimmune hyperthyroidism and associated GO.
Highlights
Graves’ orbitopathy (GO) is the most common extra thyroidal complication of Graves’ disease (GD) and occurs predominantly in women but more severe in men
We reported on the development of a robust and reproducible model of experimental autoimmune hyperthyroidism with associated GO in female BALB/c mice immunized by electroporation with a plasmid encoding hTSHR A-subunit and more recently, further shown that by this method we can disturb the normal mechanism of immune tolerance by inducing disease with self-anitgen, mouse TSHR in the model[22,23,24]
To investigate whether immunization with hTSHR A-subunit encoding plasmid has led to an immune reaction we evaluated total TSHR antibodies (TRAbs) in the mice sera by measuring TSH binding inhibitory immunoglobulin values in competition with labeled bTSH to human TSHR. 100% of GO mice of both sexes developed TRAbs with an inhibition activity range of 80% inhibition of TSH binding (Fig. 1A)
Summary
Graves’ orbitopathy (GO) is the most common extra thyroidal complication of Graves’ disease (GD) and occurs predominantly in women but more severe in men. We studied the manifestation of GO in both sexes of an induced mouse model in absence of additional risk factors present in patients like advanced age, genetic variabilities or smoking. We reported on the development of a robust and reproducible model of experimental autoimmune hyperthyroidism with associated GO in female BALB/c mice immunized by electroporation with a plasmid encoding hTSHR A-subunit and more recently, further shown that by this method we can disturb the normal mechanism of immune tolerance by inducing disease with self-anitgen, mouse TSHR in the model[22,23,24]. Additional risk factors linked to gender in patients most likely genetic variabilities, advanced age and/or smoking may be major determinants for development of substantial female-bias in GO
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
