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The Thyrotropin (TSH)-Releasing Hormone Receptor: Interaction with TSH and Autoantibodies¹

Autoimmune Disease Unit, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, and the University of California, Los Angeles, California 90048

I. Introduction

II. TSHR Ectodomain Structure

A. Primary amino acid structure

B. Subunit structure

C. Disulfide bonds in the TSHR ectodomain

D. Carbohydrate moieties in the TSHR ectodomain

E. TSHR dimerization

III. Recombinant TSHR Expression

A. Approaches to TSHR expression

B. TSHR expression in prokaryotes

C. TSHR expression as cell-free translates or as synthetic peptides

D. TSHR expression in eukaryotic insect cells

E. TSHR expression in mammalian cells

IV. TSH and Autoantibody Binding to the TSHR Ectodomain

A. Holoreceptor vs. ectodomain

B. Conformational nature of binding sites

C. TSHR carbohydrate: part of the binding site?

D. TSHR amino acid residues in TSH-binding site

E. Autoantibody epitopes

V. TSHR Autoantibody Assays

A. Historical background

B. In vivo and in vitro bioassays

C. Indirect TBI assays

D. Direct assays for TSHR autoantibodies

E. Confusion on the terminology and types of TSHR autoantibodies

VI. Monoclonal Autoantibodies to the TSHR Ectodomain

A. Introduction

B. Mouse TSHR mAb

C. Human monoclonal TSHR autoantibodies

D. Interpretation of the data on human TSHR-specific mAbs

E. Why is the subject of TSHR mAbs controversial?

F. Source of B cells used to obtain human TSHR monoclonal antibodies

VII. T Cell Epitopes

A. Background

B. Approaches to studying T cell responses

C. TSHR synthetic peptides

D. Endogenous antigen processing

E. TSHR-specific T cell receptor genes and cytokine production

F. Summary

VIII. Molecular Mimicry

IX. Animal Models of Graves’ Disease

A. Immunization with soluble TSHR antigen and adjuvant

B. Genetic immunization

C. Severe combined immunodeficiency (SCID) mouse model of Graves’ disease

D. Immunization with live syngeneic fibroblasts expressing the TSHR and class II molecules

X. Ectodomain Mutations and Polymorphisms

A. Spontaneous ectodomain mutations leading to enhanced TSHR function

B. Spontaneous ectodomain mutations leading to decreased TSHR function

C. Nonfunctional polymorphisms in the TSHR ectodomain

D. TSHR ectodomain splice variants

XI. Extrathyroidal Manifestations of Graves’ Disease

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				P. Pichurin, X.-M. Yan, L. Farilla, J. Guo, G. D. Chazenbalk, B. Rapoport, and S. M. McLachlan Naked TSH Receptor DNA Vaccination: A TH1 T Cell Response in Which Interferon-{gamma} Production, Rather than Antibody, Dominates the Immune Response in Mice Endocrinology, August 1, 2001; 142(8): 3530 - 3536. [Abstract] [Full Text] [PDF]

				G. D. Chazenbalk, S. M. McLachlan, P. Pichurin, X.-M. Yan, and B. Rapoport A Prion-Like Shift between Two Conformational Forms of a Recombinant Thyrotropin Receptor A-Subunit Module: Purification and Stabilization Using Chemical Chaperones of the Form Reactive with Graves' Autoantibodies J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1287 - 1293. [Abstract] [Full Text]

				D. Russo, C. Betterle, F. Arturi, E. Chiefari, M. E. Girelli, and S. Filetti A Novel Mutation in the Thyrotropin (TSH) Receptor Gene Causing Loss of TSH Binding But Constitutive Receptor Activation in a Family with Resistance to TSH J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4238 - 4242. [Abstract] [Full Text]

				A. P. Weetman Graves' Disease N. Engl. J. Med., October 26, 2000; 343(17): 1236 - 1248. [Full Text] [PDF]

				Y. Nagayama, E. Nishihara, H. Namba, S. Yamashita, and M. Niwa Identification of the Sites of Asparagine-Linked Glycosylation on the Human Thyrotropin Receptor and Studies on Their Role in Receptor Function and Expression J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 404 - 409. [Abstract] [Full Text]

				K. Tanaka, G. D. Chazenbalk, S. M. McLachlan, and B. Rapoport Evidence that Cleavage of the Thyrotropin Receptor Involves a "Molecular Ruler" Mechanism: Deletion of Amino Acid Residues 305-320 Causes a Spatial Shift in Cleavage Site 1 Independent of Amino Acid Motif Endocrinology, October 1, 2000; 141(10): 3573 - 3577. [Abstract] [Full Text] [PDF]

				Y.-X. Tao, A. N. Abell, X. Liu, K. Nakamura, and D. L. Segaloff Constitutive Activation of G Protein-Coupled Receptors as a Result of Selective Substitution of a Conserved Leucine Residue in Transmembrane Helix III Mol. Endocrinol., August 1, 2000; 14(8): 1272 - 1282. [Abstract] [Full Text]

				T. Akamizu, L. D. Kohn, H. Hiratani, M. Saijo, K. Tahara, and K. Nakao Hashimoto's Thyroiditis with Heterogeneous Antithyrotropin Receptor Antibodies: Unique Epitopes May Contribute to the Regulation of Thyroid Function by the Antibodies J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2116 - 2121. [Abstract] [Full Text]

				J. Chung, E. S. Park, D. Kim, J. M. Suh, H. K. Chung, J. Kim, H. Kim, S. J. Park, O-Y. Kwon, H. K. Ro, et al. Thyrotropin Modulates Interferon-{gamma}-Mediated Intercellular Adhesion Molecule-1 Gene Expression by Inhibiting Janus Kinase-1 and Signal Transducer and Activator of Transcription-1 Activation in Thyroid Cells Endocrinology, June 1, 2000; 141(6): 2090 - 2097. [Abstract] [Full Text] [PDF]

				E. S. Park, H. Kim, J. M. Suh, S. J. Park, S. H. You, H. K. Chung, K. W. Lee, O-Y. Kwon, B. Y. Cho, Y. K. Kim, et al. Involvement of JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) in the Thyrotropin Signaling Pathway Mol. Endocrinol., May 1, 2000; 14(5): 662 - 670. [Abstract] [Full Text]

				J. Bolton, J. Sanders, Y. Oda, C. Chapman, R. Konno, J. Furmaniak, and B. Rees Smith Measurement of Thyroid-stimulating Hormone Receptor Autoantibodies by ELISA Clin. Chem., December 1, 1999; 45(12): 2285 - 2287. [Full Text] [PDF]

				K. Tanaka, G. D. Chazenbalk, S. M. McLachlan, and B. Rapoport Subunit Structure of Thyrotropin Receptors Expressed on the Cell Surface J. Biol. Chem., November 26, 1999; 274(48): 33979 - 33984. [Abstract] [Full Text] [PDF]

				J. Sanders, Y. Oda, S. Roberts, A. Kiddie, T. Richards, J. Bolton, V. McGrath, S. Walters, D. Jaskolski, J. Furmaniak, et al. The Interaction of TSH Receptor Autoantibodies with 125I-Labelled TSH Receptor J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3797 - 3802. [Abstract] [Full Text] [PDF]

				H. Devos, C. Rodd, N. Gagné, R. Laframboise, and G. Van Vliet A Search for the Possible Molecular Mechanisms of Thyroid Dysgenesis: Sex Ratios and Associated Malformations J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2502 - 2506. [Abstract] [Full Text]

				J. C. Jaume, J. Guo, Y. Wang, B. Rapoport, and S. M. McLachlan Cellular Thyroid Peroxidase (TPO), Unlike Purified TPO and Adjuvant, Induces Antibodies in Mice That Resemble Autoantibodies in Human Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1651 - 1657. [Abstract] [Full Text]

				J. C. Jaume, J. Guo, D. L. Pauls, M. Zakarija, J. M. McKenzie, J. A. Egeland, C. L. Burek, N. R. Rose, W. H. Hoffman, B. Rapoport, et al. Evidence for Genetic Transmission of Thyroid Peroxidase Autoantibody Epitopic "Fingerprints" J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1424 - 1431. [Abstract] [Full Text]

				G. D. Chazenbalk, Y. Wang, J. Guo, J. S. Hutchison, D. Segal, J. C. Jaume, S. M. McLachlan, and B. Rapoport A Mouse Monoclonal Antibody to a Thyrotropin Receptor Ectodomain Variant Provides Insight into the Exquisite Antigenic Conformational Requirement, Epitopes and in Vivo Concentration of Human Autoantibodies J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 702 - 710. [Abstract] [Full Text]

				K. Tanaka, G. D. Chazenbalk, S. M. McLachlan, and B. Rapoport Thyrotropin Receptor Cleavage at Site 1 Involves Two Discontinuous Segments at Each End of the Unique 50-Amino Acid Insertion J. Biol. Chem., January 22, 1999; 274(4): 2093 - 2096. [Abstract] [Full Text] [PDF]

				H. Kishi and M. Ascoli Multiple Distant Amino Acid Residues Present in the Serpentine Region of the Follitropin Receptor Modulate the Rate of Agonist-induced Internalization J. Biol. Chem., September 29, 2000; 275(40): 31030 - 31037. [Abstract] [Full Text] [PDF]

				K. Nakabayashi, M. Kudo, B. Kobilka, and A. J. W. Hsueh Activation of the Luteinizing Hormone Receptor Following Substitution of Ser-277 with Selective Hydrophobic Residues in the Ectodomain Hinge Region J. Biol. Chem., September 22, 2000; 275(39): 30264 - 30271. [Abstract] [Full Text] [PDF]

				C.-R. Chen, K. Tanaka, G. D. Chazenbalk, S. M. McLachlan, and B. Rapoport A Full Biological Response to Autoantibodies in Graves' Disease Requires a Disulfide-bonded Loop in the Thyrotropin Receptor N Terminus Homologous to a Laminin Epidermal Growth Factor-like Domain J. Biol. Chem., April 27, 2001; 276(18): 14767 - 14772. [Abstract] [Full Text] [PDF]

				S. Li, X. Liu, L. Min, and M. Ascoli Mutations of the Second Extracellular Loop of the Human Lutropin Receptor Emphasize the Importance of Receptor Activation and De-emphasize the Importance of Receptor Phosphorylation in Agonist-induced Internalization J. Biol. Chem., March 9, 2001; 276(11): 7968 - 7973. [Abstract] [Full Text] [PDF]

				R. Latif, P. Graves, and T. F. Davies Oligomerization of the Human Thyrotropin Receptor. FLUORESCENT PROTEIN-TAGGED hTSHR REVEALS POST-TRANSLATIONAL COMPLEXES J. Biol. Chem., November 21, 2001; 276(48): 45217 - 45224. [Abstract] [Full Text] [PDF]