The role of thyroid hormone in graves' orbitopathy

GD is a common autoimmune hyperthyroid disorder caused by the production of TSAbs. One of its extra-thyroidal clinical manifestations is GO, which is an autoimmune disorder in the orbital region of eyes characterized by eye proptosis, diplopia, and inflammation of the OFs. TSHR is present in the OFs and functionally activated by TSAbs. Therefore, it is now widely known that TSAbs link the autoimmune reaction in GD and GO. While GD patients with longer symptoms of hyperthyroidism carry higher risk to develop GO, the role of TH overproduction and accompanying hyperthyroidism in GO pathogenesis remains unknown. A reproducible preclinical mouse model of GD and GO was already established in the laboratory by plasmid electroporation encoding human TSHR A-subunit. The aim of this thesis was to elucidate the role of TH and its receptors in in vitro OF cultures established from patients and from the mouse model. To address the aim, firstly the expression of THR/Thr and TH- responsive genes was examined in the two OF cultures. In addition, TH-responsive genes expression was assessed in OFs derived from KO mice lacking Thra or Thrb to determine if a specific Thr plays a more important role than the other on TH signalling in mOFs. In the in vitro experiments with human and mouse OFs cultures, hyperthyroidism was artificially induced by overnight treatment of T3. Both THR genes, namely THRA and THRB in human and Thra and Thrb in mouse OFs, were expressed. Importantly, THRA/Thra was predominantly expressed in both species of OFs. The examination of TH-responsive genes showed that T3 treatment induces KLF9 gene expression in GO OFs but only weakly induces Klf9 gene in TSHR mOFs. Furthermore, hr gene expression was significantly induced in TSHR mOFs. The analysis on mOFs derived from KO mouse model lacking of Thra or Thrb revealed that Klf9 and hr gene were not responsive to T3. Finally, the expression of a TH transporter gene, Mct8, was significantly upregulated in mOFs derived from GD/GO mouse model compared to control Beta-Gal immunized mice. In summary, the interaction between T3 and its receptors in OFs was important to induce the expression of TH-responsive genes. However, T3 might only indirectly involve in GO development. Furthermore, TSAbs production in BALB/c mice immunized with human TSHR-A subunit plasmid might have impact on TH transport to mOFs.


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