TSBAbs with TBII Activity

The TBII activity present in the sera of patients with GD is most likely due to TSAbs, and they primarily bind to epitopes in the N-terminus of TSHR as demonstrated by using LH/CGR-TSHR chimeras. In contrast, the TBII activity found in the sera of patients with HT or PM most likely represents TSBAb activity, and they predominantly bind to epitopes in the C-terminus of the TSHR ECD. This indicates that the TSBAb activity, however, does not always correlate with the TBII activity and vice versa. Epitopes involved in TSBAb binding are primarily located on the C-terminal portion of the TSHR ECD, probably within residues 261-395. This is in contrast to TSAb epitopes (TSAbl), which are primarily located at the N-terminal portion of the TSHR ECD (Fig. 14.3). Evidence to date suggests that these N-terminal and C-terminal areas come together due to protein folding and that the function of the receptor is critically maintained by proper three-dimensional structure. Another study, in which insect cell-derived fragments of TSHR were used, showed binding of TSBAbs to the C-termi-nus region of the TSHR [47]. The clinical relevance of these antibodies in PM is evident in that they can block TSH-mediated activation of the thyroid and result in hypothyroidism. However, more recently their importance in modulating GD has become clearer. It had been previously suspected that during pregnancy the amelioration of Graves' disease was due to a decrease in TSAbs; however, Kung et al. showed that disease remission during pregnancy [78] was associated with the appearance of TSBAbs whose epitopes were located in the C-terminus of the TSHR ECD [79].

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