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

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 pregna...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2001-08, Vol.86 (8), p.3647-3653
Main Authors: KUNG, A. W. C, LAU, K. S, KOHN, L. D
Format: Article
Language:English
Subjects:
Adult
Analysis of Variance
Antithyroid Agents - therapeutic use
Biological and medical sciences
Diseases of mother, fetus and pregnancy
Endocrinopathies
Epitopes - analysis
Female
Graves Disease - blood
Graves Disease - drug therapy
Graves Disease - immunology
Gynecology. Andrology. Obstetrics
Humans
Immunoglobulin G - blood
Immunoglobulins, Thyroid-Stimulating - blood
Medical sciences
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Postpartum Period - blood
Postpartum Period - immunology
Pregnancy
Pregnancy Complications - blood
Pregnancy Complications - immunology
Pregnancy. Fetus. Placenta
Receptors, Thyrotropin - immunology
Thyroid Function Tests
Thyroid. Thyroid axis (diseases)
Thyrotropin - blood
Thyrotropin - immunology
Thyroxine - blood
Time Factors
Triiodothyronine - blood
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Summary: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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.86.8.3647