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

Abstract

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.

• Authors: A W Kung, K S Lau, L D Kohn
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 86 Issue 8 Pg. 3647-53 (Aug 2001) ISSN: 0021-972X [Print] United States
• PMID: 11502791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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