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 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.
Kung
A W
AW
Department of Medicine, University of Hong Kong, Queen Mary, Hong Kong, China. awckung@hkucc.hku.hk
Lau
K S
KS
Kohn
L D
LD
D000328:Adult; D000704:Analysis of Variance; D013956:Antithyroid Agents / Q000627:therapeutic use; D000939:Epitopes / Q000032:analysis; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood*; D049590:Postpartum Period / Q000097:blood / Q000276:immunology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000276:immunology*; D011989:Receptors, Thyrotropin / Q000276:immunology*; D013960:Thyroid Function Tests; D013972:Thyrotropin / Q000097:blood / Q000276:immunology; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood
D013956:Antithyroid Agents; D000939:Epitopes; D007074:Immunoglobulin G; D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin; D014284:Triiodothyronine; D013972:Thyrotropin; D013974:Thyroxine