ReviewThyrotropin-receptor antibodies in thyroid diseases: advances in detection techniques and clinical applications
Introduction
Thyroid disorders are the most common autoimmune endocrinopathies. Thyroid autoimmunity is complex, involving multiple autoantigens with variable immune responses. Although the topic has been studied extensively, it has been difficult to determine the links between these immune responses and the pathogenesis of thyroid disease. The exception is the Graves’ disease, in which thyrotropin-receptor (TSH-R) antibodies (TRAbs) directly affect TSH-R function and thus play a major role in the pathogenesis of the disease. The TRAbs not only compete with TSH for receptor binding but often mimic TSH and initiate the post-receptor signal transduction process. The heterogeneous nature of TRAbs is well established. Antibodies capable of interacting with multiple epitopes on TSH-R molecule and showing variable TSH activities, both agonistic and antagonistic are generally present in a given patient. This variation in epitope specificity is reflected by the influence of TRAbs on TSH-receptor function.
The clinical role of these antibodies could not be fully understood until the epitopes on TSH-R were identified and their interaction with the TRAbs studied. In recent years, a number of investigators have advanced our understanding of how TSH and TRAbs interact with TSH-R [1], [2], [3], [4] and have led to new molecular technologies to detect TRAbs activities with precision. The purposes of this review are, first, to summarize recent advances in these assay techniques for measuring various TRAb activities, and second, to describe their potential clinical uses.
Before describing the details of the newer assay technologies, it seems appropriate to discuss the molecular structure of TSH-R and its interaction with TSH and TRAbs. The knowledge of these interactions is necessary to understand the mechanisms that lead to signal transduction and the activation of the thyroid cell [5], [6], [7], [8].
Section snippets
TSH-R structure and functional relationships
The TSH-R gene has been cloned and sequenced [9], [10], [11] and has been located on the long arm of chromosome 14q31 [12]. It contains 10 exons spreading over 60 kilobases [13]. Exons 1–9 code for the extracellular domain (ECD) of the receptor, and exon 10 codes for the transmembrane region. Exons 2–8 code for the leucine-rich repeats [9].
By binding to TSH, TSH-R regulates thyroid cell function, differentiation, and proliferation [14]. It belongs to the superfamily of G-protein coupled
Historical perspectives
Beginning in 1956, Adams, Purves and McKezie established that a factor distinct from TSH, which they named the long-acting thyroid stimulator (LATS), was the cause of hyperthyroidism in Graves’ disease [41], [42], [43], [44]. Studies in 1964 found that LATS was an immunoglobulin (IgG) [45], which later become known as thyroid stimulating immunoglobulin or TSAb. The McKenzie bioassay using mice for the detection of LATS activity remained the method of choice until early 1970s. In 1971, Onaya et
Heterogeneity of TRAbs
The heterogeneous nature of TRAbs is well recognized. Many attempts have been made to correlate the two activities of TRAb that are detected by TBI and TSAb assays [107], [108], [109], [110], [111], [112]. Although some reports observed good correlation between TSAb and TBII in Graves’ disease patients [112], most studies have found no such correlation. This disparity between TBII and TSAb results could be related to species specificity, as porcine receptor has been used for most TBII studies
Clinical significance
The clinical utility of TRAbs in routine cost-effective management of patients with thyroid disease has been a subject of controversy for years [119]. The newer simple, precise, and cost-effective methods using CHO-TSHR cells have made it practical to detect TRAbs, and this has enhanced the utility of TRAbs in a number of clinical situations that are summarized in Table 3. These include the differential diagnosis of hyperthyroidism and hypothyroidism, predicting the response to therapy in
Summary
The cloning and sequencing of TSH-R, combined with advances in molecular techniques, have facilitated the development of new refined assays to measure TRAbs. The availability of recombinant human TSH-R for TBI assay and of stable TSH-R-transfected CHO cells for functional assays have encouraged the development of simple, precise, and sensitive tests of the biologic effects of TRAbs on thyroid function. Furthermore, an understanding of the interaction of these antibodies with the TSH-R at the
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