Graves’ disease is the most common cause of hyperthyroidism in which antibodies directed against the thyroid-stimulating hormone (TSH) receptor cause continuous stimulation of the thyroid gland leading to hyperthyroidism. TSH receptor antibodies (TRAbs) are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating TSHR Abs, blocking TSHR Abs, or neutral (N-TSHR-Abs) depending on their effect on TSH receptor. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when activating TSHR Abs predominate. There is a reason why there is an overactivity of the gland. Antibodies produced in the disease targeting thyroid-stimulating hormone (TSH) receptor (TSHR-Abs) can be “neutral,” “suppressing,” and “stimulating.” In Graves’, all three antibodies are present, thus, stimulating increased thyroid epithelial proliferation. However, the so-called “neutral” TSHR-Abs (N-TSHR-Abs) differ as they neither stimulate nor suppress. Instead, they lead to apoptosis of thyroid cells or programmed cell death. The role of each of the antibodies in Graves’ disease is still poorly understood. Researchers think that understanding the role of N-TSHR-Abs may help find an effective treatment for Graves’s disease.
Previously, Professor Terry Davies and his research group at the Thyroid Research Unit in Icahn School of Medicine at Mount Sinai demonstrated that N-TSHR-Abs were frequently present in sera from patients with Graves’ disease. They were actually more frequent in Graves’ disease than other autoimmune disorders. Now, Dr. Syed Morshed, Dr. Rauf Latif, and Professor Terry Davies conducted new research study to try to understand further the role of N-TSHR-Abs in the disease. They also sought to modify its role to know if it could be a way of managing the condition. The original research article is now published in Journal of Autoimmunity.
The research team used several elegant cell and molecular biology experiments such as apoptosis assay, quantification of proteins using In-Cell Western, live-cell imaging, Western blot, Fluorometry for Cyto-ID and Mito-ID, and more. They authors showed that N-TSHR-Abs cause significant oxidative stress and thus mitochondrial DNA damage and dysfunction. This mitochondrial dysfunction induced by N-TSHR-Abs leads to programmed cell death or apoptosis. Additionally, it appears that N-TSHR-Abs enhance autophagy and mitophagy, too. An exciting finding in the study was that TSH or the antioxidant N-acetyl-L-cysteine (NAC) can help prevent this apoptosis and promote autophagy and thus cell survival. Hence TSH/NAC could play a vital role in maintaining cellular homeostasis. This means that TSH/NAC could be used as a cellular rescue method. Furthermore, the authors reported detailed effect of TSH/NAC on the over-expression of autophagy proteins like LC3A, LC3B, ULK1, and p62. Moreover, they found increased expression of PKA, Akt, mTORC, AMPK, Sirtuins, PGC1α, NRF-2, mitofusin-2, and TFAM in stressed cells.
Thus, researchers demonstrated in the new study that TSH or antioxidants can help rescue thyroid cells from N-TSHR- Abs induced stress and cell death. These findings indicates that high N-TSHR- Abs and low TSH in hyperthyroidism is one of the major factors that precipitate autoinflammation and thus cause worsening of the disease.
There are many practical implications of these findings. Researchers have known for long time that low TSH in hypothyroidism is characteristic of Graves’ disease. However, Syed Morshed and colleagues defined for the first time the underlying mechanism of action. They showed how low TSH plays an important role in increased cell death caused by stress due to N-TSHR- Abs. Though using TSH to treat Graves’ disease is not a new thing, the researchers also demonstrated the important role of antioxidants. Thus, the research team confirm that treating stressed thyroid cells with antioxidants may help prevent disease progression. Indeed, antioxidants could be a new therapeutic tool to improve the clinical manifestation of this illness.
Morshed, S., Latif, R., & Davies, T. F. (2021). Rescue of thyroid cells from antibody-induced cell death via induction of autophagy. Journal of Autoimmunity, 126, 102746.