Abstract
Since the discovery 60 years ago of the “long-acting thyroid stimulator” by Adams and Purves, great progress has been made in the detection of thyroid-stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAbs) in Graves’ disease. Today, commercial assays are available that can detect TRAbs with high accuracy and provide diagnostic and prognostic evaluation of patients with Graves’ disease. The present review focuses on the development of TRAbs bioassays, and particularly on the role that Leonard D. Kohn had in this. Indeed, 30 years ago, the Kohn group developed a bioassay based on the use of FRTL-5 cells that was characterized by high reproducibility, feasibility, and diagnostic accuracy. Using this FRTL-5 bioassay, Kohn and his colleagues were the first to develop monoclonal antibodies (moAbs) against the TSHR. Furthermore, they demonstrated the multifaceted functional nature of TRAbs in patients with Graves’ disease, with the identification of stimulating and blocking TRAbs, and even antibodies that activated pathways other than cAMP. After the cloning of the TSHR, the Kohn laboratory constructed human TSHR–rat luteinizing hormone/chorionic gonadotropin receptor chimeras. This paved the way to a new bioassay based on the use of non-thyroid cells transfected with the Mc4 chimera. The new Mc4 bioassay is characterized by high diagnostic and prognostic accuracy, greater than for other assays. The availability of a commercial kit based on the Mc4 chimera is spreading the use of this assay worldwide, indicating its benefits for these patients with Graves’ disease. This review also describes the main contributions made by other researchers in TSHR molecular biology and TRAbs assay, especially with the development of highly potent moAbs. A comparison of the diagnostic accuracies of the main TRAbs assays, as both immunoassays and bioassays, is also provided.
Highlights
Thyroid-stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAbs) are the pathogenic hallmark of Graves’ disease
This study demonstrated the separate and distinct effects of TRAbs on cAMP production and cell growth, which suggested that other transduction mechanisms as well as cAMP might be involved in their interactions with TSHR
This assumption was later confirmed by several studies, most of which were performed in the Kohn laboratory, which showed that the growth and function of thyroid cells were dependent on the ability of TSH to activate cAMP signaling and other signaling pathways, such as those of phospholipase C and phospholipase A2/arachidonic acid [30, 31]
Summary
Thyroid-stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAbs) are the pathogenic hallmark of Graves’ disease. They are detected in most untreated patients with Graves’ disease and are responsible for the pathological features of this disease (i.e., stimulation of thyroid growth and function, onset of orbitopathy, and/or dermopathy) [1]. Several varieties of TRAbs have been described: stimulating (TSAbs), blocking (TBAbs), and neutral (N-TRAbs). Their relative concentrations define the clinical picture and the progression of Graves’ disease.
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