TSH Receptor Antibodies

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 Å) 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.