The measurement technologies of thyrotropin receptor antibodies from the past to the present

Thyroid Stimulating Hormone Receptor (TSH-R) autoantibodies are the main cause of Graveschr('39') disease and its external thyroid manifestations such as ophtalmopathy and dermatopathy. These antibodies are functionally different and are commonly called TSH receptor antibodies (TRAbs). In fact, TRAbs are a set of autoantibodies including TSHR-stimulating antibodies (TSAbs), TSHR- blocking antibodies (TBAbs), and neutral antibodies. The measurement of TRAbs is clinically important and various commercial tests with high sensitivity and specificity are available for diagnostic purposes. If the diagnostic purpose of the TRAbs assay is the non-functional evaluation of autoantibodies, competitive binding immunoassays are used.  These methods are based on the ability of TRAbs in patient’s sample to compete and prevent ligand binding (TSH or anti-TSHR monoclonal antibodies) to the receptor. TSAbs and TBAbs appear to have common overlapping epitopes of the TSH-binding site which hinders them to be differentiated by competitive TRAbs assays. On the other hand, if the diagnostic purpose is to evaluate antibody function and differentiate between TSAbs and TBAbs, cell-based bioassays are used. The basis of these methods are the use of living cells to evaluate the function of autoantibodies and distinguish TSAbs and TBAbs based on the increase and decrease of the intracellular Cyclic adenosine monophosphate (cAMP). Since TSAbs and TBAbs have different pathogenic roles with different clinical symptoms and require different treatment protocols, differential diagnosis of TSAbs and TBAbs is of great clinical importance. In this review, different generations of competitive binding immunoassays and cell-based bioassays in the order of evolution, have been discussed.