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DOI: 10.1055/s-0035-1559648
Mechanisms of Action of TSHR Autoantibodies
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Abstract
The availability of human monoclonal antibodies (MAbs) to the TSHR has enabled major advances in our understanding of how TSHR autoantibodies interact with the receptor. These advances include determination of the crystal structures of the TSHR LRD in complex with a stimulating autoantibody (M22) and with a blocking type autoantibody (K1-70). The high affinity of MAbs for the TSHR makes them particularly suitable for use as ligands in assays for patient serum TSHR autoantibodies. Also, M22 and K1–70 are effective at low concentrations in vivo as TSHR agonists and antagonists respectively. K1-70 has important potential in the treatment of the hyperthyroidism of Graves’ disease and Graves’ ophthalmopathy. Small molecule TSHR antagonists described to date do not appear to have the potency and/or specificity shown by K1-70. New models of the TSHR ECD in complex with various ligands have been built. These models suggest that initial binding of TSH to the TSHR causes a conformational change in the hormone. This opens a positively charged pocket in receptor-bound TSH which attracts the negatively charged sulphated tyrosine 385 on the hinge region of the receptor. The ensuing movement of the receptor's hinge region may then cause activation. Similar activation mechanisms seem to take place in the case of FSH and the FSHR and LH and the LHR. However, stimulating TSHR autoantibodies do not appear to activate the TSHR in the same way as TSH.
Publication History
Received: 09 April 2015
Accepted: 24 July 2015
Article published online:
11 September 2015
Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart,
Germany
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References
- 1 Rees Smith B, Sanders J, Furmaniak J. TSH receptor antibodies. Thyroid 2007; 17: 923-938
- 2 Sanders J, Núñez Miguel R, Furmaniak J, Rees Smith B. TSH receptor monoclonal antibodies with agonist antagonist and inverse agonist activities. Meth Enzymol 2010; 485: 393-420
- 3 Furmaniak J, Sanders J, Rees Smith B. Blocking type TSH receptor antibodies. Autoimmun Highlights 2013; 4: 11-26
- 4 McLachlan SM, Rapoport B. Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocrine Rev 2014; 35: 59-105
- 5 Zakarija M, McKenzie JM. Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves’ disease. J Clin Invest 1983; 72: 1352-1356
- 6 Zakarija M, McKenzie JM, Eidson MS. Transient neonatal hypothyroidism: characterization of maternal antibodies to the thyrotropin receptor. J Clin Endocrinol Metab 1990; 70: 1239-1246
- 7 Rees Smith B, Sanders J, Evans M, Tagami T, Furmaniak J. TSH receptor – autoantibody interactions. Horm Metab Res 2009; 41: 448-455
- 8 Evans M, Sanders J, Tagami T, Sanders P, Young S, Roberts E, Wilmot J, Hu X, Kabelis K, Clark J, Holl S, Richards T, Collyer A, Furmaniak J, Rees Smith B. Monoclonal autoantibodies to the TSH receptor one with stimulating activity and one with blocking activity obtained from the same blood sample. Clin Endocrinol 2010; 73: 404-412
- 9 Kamath C, Young S, Kabelis K, Sanders J, Adlan MA, Furmaniak J, Rees Smith B, Premawardhana LD. Thyrotropin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves’ disease and pretibial myxoedema. Clin Endocrinol 2012; 77: 465-470
- 10 Sanders J, Evans M, Premawardhana LDKE, Depraetere H, Jeffreys J, Richards T, Furmaniak J, Rees Smith B. Human monoclonal thyroid stimulating autoantibody. Lancet 2003; 362: 126-128
- 11 Sanders J, Evans M, Betterle C, Sanders P, Bhardwaja A, Young S, Roberts E, Wilmot J, Richards T, Kiddie A, Small K, Platt H, Summerhayes S, Harris R, Reeve M, Coco G, Zanchetta R, Chen S, Furmaniak J, Rees Smith B. A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity. Thyroid 2008; 18: 735-746
- 12 Yoshida T, Ichikawa Y, Ito K, Homma M. Monoclonal antibodies to the thyrotropin receptor bind to a 56-kDa subunit of the thyrotropin receptor and show heterogeneous bioactivities. J Biol Chem 1988; 263: 16341-16347
- 13 Akamizu T, Moriyama K, Miura M, Saijo M, Matsuda F, Nakao K. Characterization of recombinant monoclonal antithyrotropin receptor antibodies (TSHRAbs) derived from lymphocytes of patients with Graves’ disease: epitope and binding study of two stimulatory TSHRAbs. Endocrinol 1999; 140: 1594-1601
- 14 Valente WA, Vitti P, Yavin Z, Yavin E, Rotella CM, Grollman EF, Toccafondi RS, Kohn LD. Monoclonal antibodies to the thyrotropin receptor: stimulating and blocking antibodies derived from the lymphocytes of patients with Graves’ disease. Proc Natl Acad Sci USA 1982; 79: 6680-6684
- 15 Kohn LD, Suzuki K, Hoffman WH, Tombaccini D, Marocci C, Shimojo N, Watanabe Y, Amino N, Cho BY, Kohno Y, Hirai A, Tahara K. Characterization of monoclonal thyroid-stimulating and thyrotropin binding-inhibiting autoantibodies from a Hashimoto’s patient whose children had intrauterine and neonatal thyroid disease. J Clin Endocrinol Metab 1997; 82: 3998-4009
- 16 Nakatake N, Sanders J, Richards T, Burne P, Barrett C, Dal Pra C, Presotto F, Betterle C, Furmaniak J, Rees Smith B. Estimation of TSH receptor autoantibody serum concentration and affinity. Thyroid 2006; 16: 1077-1084
- 17 Sanders J, Oda Y, Roberts SA, Maruyama M, Furmaniak J, Rees Smith B. Understanding the thyrotropin receptor function-structure relationship. In: Davies TF (ed.). Baillière’s Clinical Endocrinology & Metabolism. London: Baillière Tindall; 1997: 11: 451–479
- 18 Farid NR, Szkudlinski MW. Structural and functional evolution of the thyrotropin receptor. Endocrinol 2004; 145: 4048-4057
- 19 Vassart G, Pardo L, Costagliola S. A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci 2004; 29: 119-126
- 20 Grossman M, Weintraub BD, Szkudlinski MW. Novel insights into the molecular mechanisms of human thyrotropin action: structural, physiological, and therapeutic implications for the glycoprotein hormone family. Endocr Rev 1997; 18: 476-501
- 21 Tonacchera M, Ferrarini E, Dimida A, Agretti P, De Marco G, Pinchera A, Sanders J, Evans M, Richards T, Furmaniak J, Rees Smith B. Effects of a thyroid-stimulating human monoclonal autoantibody (M22) on functional activity of LH and FSH receptors. Thyroid 2006; 16: 1085-1089
- 22 Sanders J, Jeffreys J, Depraetere H, Evans M, Richards T, Kiddie A, Brereton K, Premawardhana LDKE, Chirgadze DY, Núñez Miguel R, Blundell TL, Furmaniak J, Rees Smith B. Characteristics of a human monoclonal autoantibody to the thyrotropin receptor: sequence structure and function. Thyroid 2004; 14: 560-570
- 23 Núñez Miguel R, Sanders J, Sanders P, Young S, Clark J, Kabelis K, Wilmot J, Evans M, Roberts E, Hu X, Furmaniak J, Rees Smith B. Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor. J Mol Endocrinol 2012; 49: 137-151
- 24 Sanders J, Chirgadze DY, Sanders P, Baker S, Sullivan A, Bhardwaja A, Bolton J, Reeve M, Nakatake N, Evans M, Richards T, Powell M, Núñez Miguel R, Blundell TL, Furmaniak J, Rees Smith B. Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody. Thyroid 2007; 17: 395-410
- 25 Sanders J, Bolton J, Sanders P, Jeffreys J, Nakatake N, Richards T, Evans M, Kiddie A, Summerhayes S, Roberts E, Núñez Miguel R, Furmaniak J, Rees Smith B. Effects of TSH receptor mutations on binding and biological activity of monoclonal antibodies and TSH. Thyroid 2006; 16: 1195-1206
- 26 Sanders J, Núñez Miguel R, Bolton J, Bhardwaja A, Sanders P, Nakatake N, Evans M, Furmaniak J, Rees Smith B. Molecular interactions between the TSH receptor and a thyroid-stimulating monoclonal autoantibody. Thyroid 2007; 17: 699-706
- 27 Fan QR, Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 2005; 433: 269-277
- 28 Núñez Miguel R, Sanders J, Chirgadze DY, Furmaniak J, Rees Smith B. Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein-protein interactions. J Mol Endocrinol 2009; 42: 381-395
- 29 Okuda J, Akimizu T, Sugawa H, Matsuda F, Hua L, Mori T. Preparation and characterization of monoclonal antithyrotropin receptor antibodies obtained from peripheral lymphocytes of hypothyroid patients with primary myxedema. J Clin Endocrinol Metab 1994; 79: 1600-1604
- 30 Moriyama K, Okuda J, Saijo M, Hattori Y, Kanamoto N, Hataya Y, Matsuda F, Mori T, Nakao K, Akimizu T. Recombinant monoclonal thyrotropin-stimulation blocking antibody (TSBAb) established from peripheral lymphocytes of a hypothyroid patient with primary myxedema. J Endocrinol Invest 2003; 26: 1076-1080
- 31 Morgenthaler NG, Rim Kim M, Tremble J, Cai Huang G, Richter W, Gupta M, Scherbaum WA, McGregor AM, Banga JP. Human immunoglobulin G autoantibodies to the thyrotropin receptor from Epstein-Barr virus-transformed B lymphocytes: characterization by immunoprecipitation with recombinant antigen and biological activity. J Clin Endocrinol Metab 1996; 81: 3155-3161
- 32 Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Núñez Miguel R, Furmaniak J, Rees Smith B. Crystal structure of the TSH receptor TSHR bound to a blocking-type TSHR autoantibody. J Mol Endocrinol 2011; 46: 81-99
- 33 Takasu N, Matsushita M. Changes of TSH-stimulation blocking antibody (TSBAb) and thyroid stimulating antibody (TSAb) over 10 years in 34 TSBAb-positive patients with hypothyroidism and in 98 TSAb-positive Graves’ patients with hyperthyroidism: reevaluation of TSBAb and TSAb in TSH-receptor-antibody (TRAb)-positive patients. J Thyroid Res 2012; 2012: 182176
- 34 Sanders J, Jeffreys J, Depraetere H, Richards T, Evans M, Kiddie A, Brereton K, Groenen M, Oda Y, Furmaniak J, Rees Smith B. Thyroid-stimulating monoclonal antibodies. Thyroid 2002; 12: 1043-1050
- 35 Ando T, Latif R, Pritsker A, Moran T, Nagayama Y, Davies TF. A monoclonal thyroid-stimulating antibody. J Clin Invest 2002; 110: 1667-1674
- 36 Costagliola S, Bonomi M, Morganthaler NG, Van Durme J, Panneels V, Refetoff S, Vassart G. Delineation of the discontinuous-conformational epitope of a monoclonal antibody displaying full in vitro and in vivo thyrotropin activity. Mol Endocrinol 2004; 18: 3020-3034
- 37 Sanders J, Allen F, Jeffreys J, Bolton J, Richards T, Depraetere H, Nakatake N, Evans M, Kiddie A, Premawardhana LDKE, Chirgadze DY, Núñez Miguel R, Blundell TL, Furmaniak J, Rees Smith B. Characteristics of a monoclonal antibody to the thyrotropin receptor that acts as a powerful thyroid-stimulating autoantibody antagonist. Thyroid 2005; 15: 672-682
- 38 Gilbert J, Gianoukakis A, Salehi S, Moorhead J, Rao P, Kahn MZ, McGregor A, Smith T, Banga JP. Monoclonal pathogenic antibodies to the thyroid stimulating hormone receptor in Graves’ disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signalling pathways. J Immunol 2006; 176: 5084-5092
- 39 Chen CR, McLachlan SM, Rapoport B. Suppression of thyrotropin receptor constitutive activity by a monoclonal antibody with inverse agonist activity. Endocrinology 2007; 148: 2375-2382
- 40 Chen CR, McLachlan SM, Rapoport B. Identification of key amino acid residues in a thyrotropin receptor monoclonal antibody epitope provides insight into its inverse agonist and antagonist properties. Endocrinology 2008; 149: 3427-3434
- 41 Southgate K, Creagh F, Teece M, Kingswood C, Rees Smith B. A receptor assay for the measurement of TSH receptor antibodies in unextracted serum. Clin Endocrinol (Oxf) 1984; 20: 539-548
- 42 Rees Smith B, Bolton J, Young S, Collyer A, Weeden A, Bradbury J, Weightman D, Perros P, Sanders J, Furmaniak W. A new assay for thyrotropin receptor autoantibodies. Thyroid 2004; 14: 830-835
- 43 Hermsen D, Broekcer-Preuss M, Casati M, Camara Mas J, Eckstein A, Gassner D, van Helden J, Inomata K, Jaraush J, Kratzsch J, Mann K, Miyazaki N, Navarro Morena MA, Murakami T, Roth H-J, Yoshimura Noh J, Scherbaum WA, Schott M. Technical evaluation of the first fully automated assay for the detection of TSH receptor autoantibodies. Clin Chim Acta 2009; 401: 84-89
- 44 Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJT. The safety and side effects of monoclonal antibodies. Nature Rev Drug Disc 2010; 9: 325-338
- 45 Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nature Rev Immunol 2010; 10: 345-352
- 46 Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nature Rev Drug Disc 2010; 9: 767-774
- 48 Furmaniak J, Sanders J, Young S, Kabelis K, Sanders P, Evans M, Clark J, Wilmot J, Rees Smith B. In vivo effects of a human thyroid stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70). Autoimmun Highlights 2012; 3: 19-25
- 47 Luster M. Present status of the use of recombinant human TSH in thyroid cancer management. Acta Oncol 2006; 45: 1018-1030
- 49 Fast S, Hegedüs L, Grupe P, Nielsen VE, Bluhme C, Bastholt L, Bonnema SJ. Recombinant human thyrotropin-stimulated radioiodine therapy of nodular goiter allows major reduction of the radiation burden with retained efficacy. J Clin Endocrinol Metab 2010; 95: 3719-3725
- 50 Fast S, Nielsen VE, Bonnema SJ, Hegedüs L. Dose-dependent acute effects of recombinant human TSH (rhTSH) on thyroid size and function: comparison of 0.1, 0.3 and 0.9 mg of rhTSH. Clin Endocrinol 2010; 72: 411-416
- 51 Bonnema SJ, Hegedüs L. Radioiodine therapy in benign thyroid diseases: effects, side effects and factors affecting therapeutic outcome. Endocrine Rev 2012; 33: 920-980
- 52 Pearce EN. Diagnosis and management of thyrotoxicosis. Br Med J 2006; 332: 1369-1373
- 53 Laurberg P. Remission of Graves’ disease during anti-thyroid drug therapy: time to reconsider the mechanism?. Eur J Endocrinol 2006; 155: 783-786
- 54 Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011; 21: 593-646
- 55 Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical practice patterns in the management of Graves’ disease. J Endocrinol Metab 2012; 97: 4549-4558
- 56 Arey BJ. Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential. Endocr 2008; 34: 1-10
- 57 Davies TF, Ali MJ, Latif R. Allosteric modulators hit the TSH receptor. Endocrinol 2014; 155: 1-5
- 58 Gerrits M, Mannaerts B, Kramer H, Addo S, Hanssen R. First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age. J Clin Endocrinol Metab 2013; 98: 1558-1566
- 59 van Koppen CJ, de Gooyer ME, Karstens W-J, Plate R, Conti PGM, van Achterberg TAE, van Amstel MGA, Brands JHGM, Wat J, Bert RJW, Lane JRD, Miltenburg AMM, Timmers CM. Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor. Brit J Pharmacol 2012; 165: 2314-2324
- 60 Neumann S, Huang W, Titus S, Krause G, Kleinau G, Alberobello AT, Zheng W, Southall NT, Inglese J, Austin CP, Celi FS, Gavrilova O, Thomas CJ, Raaka BM, Gershengorn MC. Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc Natl Acad Sci USA 2009; 106: 12471-12476
- 61 Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinol 2014; 155: 310-314
- 62 Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin N Am 2012; 96: 385-403
- 63 Kumar S, Schiefer R, Coenen MJ, Bahn RS. A stimulatory thyrotropin receptor antibody (M22) and thyrotropin increase interleukin-6 expression and secretion in Graves’ orbital preadipocyte fibroblasts. Thyroid 2010; 20: 59-65
- 64 Iyer S, Bahn R. Immunopathogenesis of Graves’ ophthalmopathy: the role of the TSH receptor. Best Pract Res Clin Endocrinol Metab 2012; 26: 281-289
- 65 Krieger CC, Gershengorn MC. A modified ELISA accurately measures secretion of high molecular weight hyaluronan (HA) by Graves’ disease orbital cells. Endocrinol 2014; 155: 627-634
- 66 Kumar S, Nadeem S, Stan MS, Coenen M, Bahn RS. A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves’ ophthalmopathy. J Mol Endocrinol 2011; 46: 155-163
- 67 Tanda ML, Piantanida E, Bartalena L. Treating Graves’ orbitopathy: where are we?. Endocr 2012; 41: 167-168
- 68 Smith HB, Porteous C, Bunce C, Bonstein K, Hickey J, Dayan CM, Adams G, Rose GE, Ezra DG. Description and evaluation of the first national patient and public involvement day for thyroid eye disease in the United Kingdom. Thyroid 2014; 24: 1400-1406
- 69 El Fassi D, Nielsen CH, Hasselbalch HC, Hegedüs L. The rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option. Eur J Endocrinol 2006; 154: 623-632
- 70 El Fassi D, Banga JP, Gilbert JA, Padoa C, Hegedüs L, Nielsen CH. Treatment of Graves’ disease with rituximab specifically reduces the production of thyroid stimulating antibodies. Clin Immunol 2009; 130: 252-258
- 71 Núñez Miguel R, Sanders J, Sanders P, Young S, Furmaniak J, Rees Smith B. Glycosylation pattern analysis of glycoprotein hormones and their receptors. Eur Thyroid J 2014; 3 (Suppl. 01) 84
- 72 Chen CR, Tanaka K, Chazenbalk GD, McLachlan SM, Rapoport B. 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 2001; 276: 14767-14772
- 73 Jiang X, Liu H, Chen X, Chen PH, Fischer D, Sriraman V, Yu HN, Arkinstall S, He X. Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc Natl Acad Sci USA 2012; 109: 12491-12496
- 74 Sanders J, Núñez Miguel R, Sanders P, Young S, Furmaniak J, Rees Smith B. Mechanism of TSHR activation by TSH and thyroid stimulating antibodies. Eur Thyroid J 2014; 3 (Suppl. 01) 82
- 75 Krause G, Kreuchwig A, Kleinau G. Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor. PLoS ONE 2012; 7: e52920
- 76 Duprez L, Parma J, Costagliola S, Hermans J, Van Sande J, Dumont JE, Vassart G. Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett 1997; 409: 469-474
- 77 Grzesik P, Teichmann A, Furkert J, Rutz C, Wiesner B, Kleinau G, Schülein R, Gromoll J, Krause G. Differences between lutropin-mediated and choriogonadotropin-mediated receptor activation. FEBS J 2014; 281: 1479-1492
- 78 Jaeschke H, Schaarschmidt J, Günther R, Mueller S. The hinge region of the TSH receptor stabilizes ligand binding and determines different signalling profiles of human and bovine TSH. Endocrinology 2011; 152: 3986-3996
- 79 Schaarschmidt J, Huth S, Meier R, Paschke R, Jaeschke H. Influence of the hinge region and its adjacent domains on binding and signalling patterns of the thyrotropin and follitropin receptor. PLoS One 2014; 9: e111570
- 80 Horimoto M, Petersen VB, Pegg CAS, Fukuma N, Wabayashi N, Kiso Y, Furmaniak J, Rees Smith B. Production and characterization of a human monoclonal thyroid peroxidase autoantibody. Autoimmunity 1992; 14: 1-7
- 81 De Lano WL. The Pymol molecular graphics system. DeLano Scientific; San Carlos, CA: 2002. http://pymol.sourceforge.net/
- 82 Jäschke H, Neumann S, Moore S, Thomas CJ, Colson A-O, Costanzi S, Kleinau G, Jiang J-K, Paschke R, Raaka BM, Krause G, Gershengorn MC. A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem 2006; 281: 9841-9844
- 83 Latif R, Ali MR, Ma R, David M, Morshed SA, Ohlmeyer M, Felsenfeld DP, Lau Z, Mezei M, Davies TF. New small molecule agonists to the thyrotropin receptor. Thyroid 2015; 25: 51-62
- 84 Neumann S, Kleinau G, Costanzi S, Moor S, Jiang J-K, Raaka BM, Thomas CJ, Krause G, Gershengorn MC. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology 2008; 149: 5945-5950