
<ArticleTitle>Epitope mapping of <prot>tsh receptor</prot>-blocking antibodies in Graves' disease that appear during pregnancy.</ArticleTitle>
<AbstractText>Spontaneous remission of Graves' disease during pregnancy is thought to be due to a reduction of thyroid-stimulating antibody activity. We suspected, however, that a broader change in <prot>TSH receptor</prot> antibody characteristics might play an important role in modulating disease activity during pregnancy. We measured <prot>TSH</prot> binding inhibitory Ig, thyroid-stimulating antibody, and thyroid stimulating-blocking antibody activities in 13 pregnant Graves' disease patients at first, second, and third trimesters and 4 months postpartum. To measure and epitope-map thyroid-stimulating antibody and thyroid stimulating-blocking antibody activities, we used CHO cells transfected with wild-type human <prot>TSH</prot> receptor or with several <prot>TSH receptor</prot>-<prot>LH/hCG receptor</prot> chimeras: Mc1+2, Mc2, and Mc4. These chimeric cells have their respective <prot>TSH</prot> receptor residues 9-165, 90-165, and 261-370 substituted with equivalent residues of the <prot>LH/hCG receptor</prot>. Overall thyroid-stimulating antibody decreased, whereas thyroid stimulating-blocking antibody increased progressively during pregnancy. <prot>TSH</prot> binding inhibitory Ig fluctuated in individual patients, but overall the activities remained statistically unchanged. Thyroid stimulating-blocking antibody appeared in subjects who were either negative for thyroid-stimulating antibody or whose thyroid-stimulating antibody activity increased or decreased during pregnancy. Epitope mapping showed that the thyroid-stimulating antibodies were mainly directed against residues 9-165 of the N-terminus of the <prot>TSH</prot> receptor extracellular domain. All thyroid stimulating-blocking antibodies had blocking activities against residues 261-370 of the C-terminus of the ectodomain. However, the majority of the thyroid stimulating-blocking antibodies had a hybrid conformational epitope directed against N-terminal residues 9-89 or 90-165 as well. Despite a change in the activity level, we did not observe any change in the epitope of either the stimulatory or blocking Abs as pregnancy advanced. In conclusion, a change in the specificity of <prot>TSH</prot> receptor antibody from stimulatory to blocking activity was observed during pregnancy, and the appearance of thyroid stimulating-blocking antibody may contribute to the remission of Graves' disease during pregnancy.</AbstractText>
