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Submitted on June 23, 2004
Accepted on July 29, 2004
Department of Medicine, Mount Sinai School of Medicine, New York, New York and The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
* To whom correspondence should be addressed. E-mail: takao.ando{at}mssm.edu.
The TSH receptor (TSHR) is the primary antigen in Graves' disease. In this condition, autoantibodies to the TSHR develop which have intrinsic thyroid stimulating activity. We have studied the epitopes on the native TSHR using polyclonal anti-sera and monoclonal antibodies (mAbs) derived from an Armenian Hamster model of Graves' disease. Of 14 hamster mAbs analyzed, five were shown to bind to conformational epitopes including one mAb with potent thyroid stimulating activity. Overlapping conformational epitopes were determined by cell-binding competition assays using fluorescently labeled mAbs. We identified two distinct conformational epitopes; epitope A for both stimulating and blocking mAbs and epitope B for only blocking mAbs. Examination of an additional 3 mouse-derived stimulating TSHR-mAbs also showed exclusive binding to epitope A. The remaining 9 hamster-derived mAbs were neutral or low-affinity blocking antibodies which recognized linear epitopes within the TSHR cleaved region (residues 316-366) (Epitope C). Serum from the immunized hamsters also recognized conformational epitopes A and B but, in addition, also contained high levels of TSHR-Abs interacting within the linear epitope C region.
In summary, these studies indicated that the natively conformed TSHR had a restricted set of epitopes recognized by TSHR-mAbs and that the binding site for stimulating TSHR-Abs was highly conserved. However, high affinity TSHR blocking antibodies recognized two conformational epitopes, one of which was indistinguishable from the thyroid stimulating epitope. Hence, TSHR stimulating and blocking antibodies cannot be distinguished purely on the basis of their conformational epitope recognition.
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