Hashimoto's thyroiditis with heterogeneous antithyrotropin receptor antibodies: Unique epitopes may contribute to the regulation of thyroid function by the antibodies

Blocking-type TSH-binding inhibitor Igs (TBIIs) are known to cause hypothyr oidism and an atrophic thyroid gland in patients with primary myxedema. The y can block the activity of thyroid-stimulating antibodies (TSAbs) in Grave s' patients as well as the activity of TSH. The majority of the epitopes fo r these blocking-type TBIIs have been, and are shown herein, to be present on the C-terminal region of the extracellular domain of the human TSH recep tor (TSHR), whereas those for Graves' TSAbs are on the N-terminus. We repor t on a patient with Hashimoto's thyroiditis who suffered from mild hypothyr oidism and a moderately sized goiter. Her serum had a potent blocking-type TBII and a weak TSAb in human and porcine TSHR systems. Using human TSHR/lu tropin-CG receptor chimeras, we determined that the functional epitope of h er blocking-type TBII was uniquely present on the N-terminal, rather than t he C-terminal, region of the extracellular domain of the TSHR, unlike the c ase for blocking-type TBIIs in primary myxedema patients. The epitope of he r TSAb was also unusual. Although the functional epitopes of most TSAbs are known to involve the N-terminal region of the receptor, her TSAb epitope d id not seem to be present solely on the N- or C-terminus of the extracellul ar domain of the receptor. Blocking-type TBIIs from patients with primary m yxedema blocked her TSAb activity as well as stimulation by TSH; her blocki ng-type TBII was able to only partially block her TSAb. In contrast, her bl ocking-type TBII almost completely blocked TSAbs from Graves' patients. Thu s, we suggest that the unique epitopes of this patient's heterogeneous popu lation of TSH receptor antibodies, at least in part, contribute to regulati on of her thyroid function.