A complex interaction between genetic and environmental factors is the proposed cause which triggers immune system to produce autoantibodies stimulating the TSH receptor, leading to clinical manifestations such as hyperthyroidism, diffuse thyroid enlargement (goiter) and often ophthalmopathy in affected individuals.
No significant correlations were found between smoking status (p = 0.58), goiter size (p = 0.50), the presence of ophthalmopathy (p = 0.42) or thyroid-stimulating hormone receptor antibody titers (p = 0.45) and the mean value of immunoglobulin G4 levels at diagnosis.
When compared with controls, all the test monkeys had significantly higher TSHR antibody levels, half of them had increased total thyroxine (T₄) and free T₄, and 50% developed goiter.
When we measured the p66Shc levels induced by individual Igs from 130 patients with Graves' disease, TSH receptor stimulating activity and goiter size showed a weak correlation.
On the other hand, coinjection of DNA plasmids encoding TSHR and IL-12 did not significantly enhance GD development since two out of seven animals became thyrotoxic, but had no goitre.These results demonstrate that i.d. delivery of human TSHR DNA can break tolerance and elicit GD in inbred mice.
Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits.
Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated.
The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions.
To investigate the molecular cause of these autonomous areas, small autoradiographically hot areas were examined for somatic TSH receptor mutations using archival tissue sections from 14 patients with euthyroid goitres, which had been originally prepared nearly 20 years ago.
A novel heterozygous germline mutation (ATG --> GTG; Met463Val) was identified in the second membrane spanning TSHR region in 6 relatives with thyrotoxicosis and goiter and absence of TSHR antibodies.
Augmented expression of Gs alpha protein was detected in all toxic adenomas, independent of the presence of mutations, and in the nodular tissue of the toxic goiter, but not in the nonnodular hyperplastic tissue of the toxic goiter with the mutated TSH-R. Analogously, the expression of the alpha-subunit of the inhibitory G protein (Gi alpha) was also increased in all adenomas and the nodular tissue of the goiter, but, again, not in the hyperplastic goiter tissue.
Such observations support the hypothesis that goiter formation in patients with Graves' disease is, at least in part, secondary to the growth stimulating activity of TRAb-hIgG.