Research ArticleAutoimmunity

Biased signaling by thyroid-stimulating hormone receptor–specific antibodies determines thyrocyte survival in autoimmunity

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Sci. Signal.  23 Jan 2018:
Vol. 11, Issue 514, eaah4120
DOI: 10.1126/scisignal.aah4120

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Antibodies determine thyrocyte fate

Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism and the presence of autoantibodies against the thyroid-stimulating hormone receptor (TSHR), which are classified as stimulatory, blocking, or neutral and which bind to different receptor epitopes. Binding of TSH to the TSHR, a member of the GPCR superfamily, leads to the activation of G proteins and, in response to receptor phosphorylation, the activation of β-arrestin–dependent signaling. Through imaging analysis, Morshed et al. showed that exposure of thyrocytes to the stimulatory antibody S-TSHR-Ab led to G protein signaling, receptor internalization, and endosomal formation. In contrast, a neutral antibody (C-TSHR-Ab) induced β-arrestin–dependent signaling, but not G protein–dependent signaling, had defective trafficking, and accumulated intracellularly. This, in turn, triggered thyrocyte death by apoptosis. Together, these data suggest a mechanism by which different autoantibodies differentially affect thyrocyte homeostasis, which may have implications for the treatment of GD.