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Characterization of Monoclonal Thyroid-Stimulating and Thyrotropin Binding-Inhibiting Autoantibodies from a Hashimoto’s Patient Whose Children Had Intrauterine and Neonatal Thyroid Disease

Cell Regulation Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (L.D.K., W.H.H., D.T., C.M., K.S.), Bethesda, Maryland 20892; the Department of Pediatrics, Section of Pediatric Endocrinology, Medical College of Georgia (W.H.H.), Augusta, Georgia 30912; the Department of Pediatrics, Chiba University School of Medicine (N.S., Y.K.), Chiba 260, Japan; SRL, Inc. (Y.W.), Hachioji 192, Japan; the Department of Laboratory Medicine, Osaka University Medical School (N.A.), Suita 565, Japan; the Department of Internal Medicine, Seoul National University College of Medicine (B.Y.C.), Seoul 110–744, Korea; and the Division of Endocrinology and Metabolism, Second Department of Internal Medicine (A.H., K.T.), Chiba University School of Medicine, Chiba 280, Japan

Address all correspondence and requests for reprints to: Dr. Leonard D. Kohn, Cell Regulation Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9C101B, National Institutes of Health, 10 Center DR MSC 1800, Bethesda, Maryland 20892-1800. E-mail: lenk{at}bdg10.NIDDK.nih.gov

A multiplicity of TSH receptor autoantibodies (TSHRAbs) have been characterized after subcloning heterohybridomas produced from the lymphocytes of a patient who has Hashimoto’s thyroiditis and had three children with intrauterine or neonatal hyperthyroidism. Twelve clones produced stimulating TSHRAbs that increased cAMP levels and iodide uptake in rat FRTL-5 thyroid cells and increased cAMP levels in Chinese hamster ovary (CHO) cells transfected with the human TSHR; like 95% of Graves’ stimulating TSHRAbs, all 12 have their functional epitope on the N-terminus of the TSHR extracellular domain, requiring residues 90–165 for activity. All 12 bind to human thyroid membranes in the absence, but not the presence, of TSH, but are only weak inhibitors of TSH binding in assays measuring TSH binding-inhibiting Igs (TBIIs). In contrast, 8 different clones produced TSHRAbs that did not increase cAMP levels, but, instead, exhibited significant TBII activity. Four inhibited the ability of TSH or a stimulating TSHRAb to increase cAMP levels and had their functional epitope on the C-terminal portion of the TSHR external domain, residues 261–370, mimicking the properties of blocking TSHRAbs that cause hypothyroidism in patients with idiopathic myxedema. The 4 other TBIIs inhibited the ability of TSH, but not that of a stimulating TSHRAb, to increase cAMP levels, like TBIIs in Graves’ patients. The functional epitope for 3 of these Graves’-like TBIIs was residues 90–165; the functional epitope for the fourth was residues 24–89. The fourth also increased arachidonic acid release and inositol phosphate levels in FRTL-5 thyroid cells and exhibited conversion activity, i.e. the ability to increase cAMP levels in the presence of an anti-human IgG. Thus, this TBII exhibited signal transduction activity, unlike the other 3 Graves’-like TBIIs. The patient, therefore, has stimulating TSHRAbs and 3 different types of TBIIs, each with different functional properties and different epitopes on the TSHR.

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