Thyrotropin receptor antibodies and Graves' orbitopathy

Abstract

Context and purpose: The thyrotropin receptor (TSHR) is the key autoantigen in Graves' disease (GD) and associated orbitopathy (GO). Antibodies targeting the TSHR (TSHR-Ab) impact the pathogenesis and the course of GO. This review discusses the role and clinical relevance of TSHR-Ab in GO.

Methods: Review of the current and pertinent literature.

Results: GO is the most common extrathyroidal manifestation of GD and is caused by persistent, unregulated stimulation of TSHR-expressing orbital target cells (e.g. fibroblasts and pre-adipocytes). Serum TSHR-Ab and more specifically, the stimulatory Ab (TSAb) are observed in the vast majority of patients with GD and GO. TSHR-Ab are a sensitive serological parameter for the differential diagnosis of GO. TSHR-Ab can be detected either with conventional binding immunoassays that measure binding of Ab to the TSHR or with cell-based bioassays that provide information on their functional activity and potency. Knowledge of the biological activity and not simply the presence or absence of TSHR-Ab has relevant clinical implications e.g. predicting de-novo development or exacerbation of pre-existing GO. TSAb are specific biomarkers of GD/GO and responsible for many of its clinical manifestations. TSAb strongly correlate with the clinical activity and clinical severity of GO. Further, the magnitude of TSAb indicates the onset and acuity of sight-threatening GO (optic neuropathy). Baseline serum values of TSAb and especially dilution analysis of TSAb significantly differentiate between thyroidal GD only versus GD + GO.

Conclusion: Measurement of functional TSHR-Ab, especially TSAb, is clinically relevant for the differential diagnosis and management of GO.

Keywords: Graves’ orbitopathy; Pathogenesis; Thyrotropin receptor; Thyrotropin receptor antibodies.

Fig. 1

Schematic of the role of TSHR signal transduction pathways in the pathogenesis of GO. The Gα(alpha)s subunit induces the activation of the adenylate cyclase (AC) which causes an increase of cyclic adenosine monophosphate (cAMP) production and further activates the protein kinase A (PKA) and the transcription factor cAMP response element-binding (CREB). The Gαq subunit activates phospholipase C (PLC) which in turn activates the phosphoinositide 3-kinase (PI3K), the protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). Thyrotropin receptor stimulating antibodies (TSAb) bind to orbital fibroblasts and adipocytes in the orbital connective tissue. Binding of TSAb to the TSHR activates orbital fibroblasts hence causing increased synthesis of glycosaminoglycan (GAG) and in the long-term induction of adipogenesis

Fig. 2

Schematic of functional cell-based bioassays. The Gα(alpha)s subunit induces the activation of the adenylate cyclase (AC) which causes an increase of cyclic adenosine monophosphate (cAMP) production and further activates the protein kinase A (PKA) and the transcription factor cAMP response element-binding (CREB). The Gαq subunit activates phospholipase C (PLC) which in turn activates the phosphoinositide 3-kinase (PI3K), the protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). Serum thyrotropin receptor stimulating antibodies (TSAb) bind to the TSHR which are expressed on the surface of genetically engineered cells. The activation leads to an increase of cyclic adenosine monophosphate (cAMP) production. Subsequently, CREB (cAMP response element-binding) binds to CREs (cAMP response elements) and the luciferase reporter gene (luc) is transcribed and translated. Measurement of luciferase activity produces a luminescent signal which can be measured in a luminometer. Serum thyrotropin receptor blocking antibodies (TBAb) inhibit bovine (b) TSH-induced stimulation of luciferase leading to a reduced luminescent signal