TSH Receptor Antibodies

Abstract

The discovery of thyroid-stimulating autoantibodies by Adams and Purves 50 years ago was one of the most important observations in the history of thyroidology. Since that time, the thyroid-stimulating hormone receptor (TSHR) has been shown to be the antigen recognized by these autoantibodies (1974) and the receptor cloned (1989). More recently, different mouse monoclonal antibodies (MAbs) to the TSHR have been produced, culminating in 2002 in the preparation of mouse and hamster MAbs with strong thyroid-stimulating activity. Further, in 2003 a human MAb to the TSHR (M22) with the characteristics of patient thyroid-stimulating autoantibodies was described. M22 has been particularly useful in advancing our knowledge of the TSHR and TSHR autoimmunity, including the development of new assays for TSHR autoantibodies (2004) and determination of a high-resolution (2.55 A) crystal structure of the TSHR leucine-rich domain in combination with M22 (2007). The structure shows that M22 positions itself on the TSHR in an almost identical way to the native hormone TSH but the evolutionary forces that have resulted in production of a common autoantibody that mimics the actions of TSH so well are far from clear at this time. Very recently, a human MAb (5C9) with the characteristics of blocking-type patient serum TSHR autoantibodies has been isolated (2007). Studies on how 5C9 interacts with the TSHR at the molecular level are planned and should provide key insights as to the differences between TSHR autoantibodies with blocking and with stimulating activities. Also, 5C9 and similar MAbs have considerable potential as drugs to inhibit TSHR stimulation by autoantibodies. Further, now the M22-TSHR structure is known at the atomic level, rational design of specific low-molecular-weight inhibitors of the TSHR-TSHR autoantibody interaction is feasible.

Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions

“…the gap volume index of the TSHR-TSH complex is 26% higher than that of the TSHR-M22 complex. This observation together with stronger interactions in the M22-TSHR complex is in agreement with the higher binding affinity of M22 for the TSHR compared with TSH found in experimental studies , Rees Smith et al 2007.…”

“…The binding characteristics of M22 to the TSHR are representative of TSHR autoantibodies in sera from patients with Graves' disease , Rees Smith et al 2007. Furthermore, M22 and patient TSHR autoantibodies interact with the same region of the TSHR although there are some discrete differences in the actual amino acids on the concave surface of the TSHR LRD which contact different autoantibodies .…”

“…This area is exposed in the TSH-TSHR complex and is a good candidate for the development of small molecules which would bind to this patch in a way that would prevent autoantibody binding yet allow TSH to bind. Such small molecule inhibitors have the potential, at least hypothetically, to stop the biological activity of stimulating antibodies , 2007a, Rees Smith et al 2007). M22 interactions with the TSHR LRD observed in the M22-TSHR crystal structure are in good agreement with extensive experimental studies carried out with full-length TSHRs and therefore it would be expected that small molecules acting on the LRD would also inhibit antibody binding to intact TSHRs , 2007a,b, Rees Smith et al 2007.…”

“…Of particular significance are antibodies that are able to mimic hormone-receptor interactions in such a way as to give rise to full activation of receptor mediated signal transduction. Here, we report a detailed analysis of interactions involving an autoantibody that activates the TSH receptor (TSHR) in Graves' disease , 2007a, Rees Smith et al 2007) and a comparison of these interactions with those of TSH with the TSHR.…”

Association between thyroid stimulating hormone receptor gene intron polymorphisms and autoimmune thyroid disease in a Chinese Han population

“…TSHR is expressed on the thyroid follicular cell surface membrane, regulates thyroid growth, hormone synthesis and secretion physiologically by binding to TSH, However, in AITD patients, the body produces auto-antibodies including TSAb (thyroid-stimulating antibody) and TSBAb (TSH-stimulation blocking antibody) against TSHR, affecting the thyroid cell growth and differentiation and ultimately leading to thyroid dysfunction [23].…”