Epitope mapping of tsh receptor-blocking antibodies in Graves' disease that appear during pregnancy

J Clin Endocrinol Metab. 2001 Aug;86(8):3647-53. doi: 10.1210/jcem.86.8.7704.


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 TSH receptor antibody characteristics might play an important role in modulating disease activity during pregnancy. We measured TSH 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 TSH receptor or with several TSH receptor-LH/hCG receptor chimeras: Mc1+2, Mc2, and Mc4. These chimeric cells have their respective TSH receptor residues 9-165, 90-165, and 261-370 substituted with equivalent residues of the LH/hCG receptor. Overall thyroid-stimulating antibody decreased, whereas thyroid stimulating-blocking antibody increased progressively during pregnancy. TSH 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 TSH 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 TSH 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Antithyroid Agents / therapeutic use
  • Epitopes / analysis
  • Female
  • Graves Disease / blood
  • Graves Disease / drug therapy
  • Graves Disease / immunology*
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulins, Thyroid-Stimulating / blood*
  • Postpartum Period / blood
  • Postpartum Period / immunology
  • Pregnancy
  • Pregnancy Complications / blood
  • Pregnancy Complications / immunology*
  • Receptors, Thyrotropin / immunology*
  • Thyroid Function Tests
  • Thyrotropin / blood
  • Thyrotropin / immunology
  • Thyroxine / blood
  • Time Factors
  • Triiodothyronine / blood


  • Antithyroid Agents
  • Epitopes
  • Immunoglobulin G
  • Immunoglobulins, Thyroid-Stimulating
  • Receptors, Thyrotropin
  • Triiodothyronine
  • Thyrotropin
  • Thyroxine