Download PDF
Horm Metab Res 2009; 41(6): 448-455
DOI: 10.1055/s-0029-1220913
Review

© Georg Thieme Verlag KG Stuttgart · New York

TSH Receptor – Autoantibody Interactions

B. Rees Smith 1 , J. Sanders 1 , M. Evans 1 , T. Tagami 2 , J. Furmaniak 1
  • 1FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff, UK
  • 2National Hospital Organization, Kyoto Medical Center, 1-1, Mukaihata-cho, Fukakusa Fushmi-ku, Kyoto, Japan
Further Information

Publication History

received 03.03.2009

accepted 22.04.2009

Publication Date:
20 May 2009 (online)

Also available at
    Permissions and Reprints

Abstract

TSH receptor (TSHR) autoantibodies (TRAbs) activate the TSHR cyclic AMP cascade (stimulating TRAbs) or act as TSHR antagonist (blocking TRAbs), and both types inhibit TSH binding to the TSHR. Isolation of human monoclonal TSHR autoantibodies (stimulating M22 and blocking 5C9) has been a key milestone in studies of the TSHR and TSHR autoimmunity. Comparison of M22 and TSH interactions with the TSHR at the atomic level reveal that M22 heavy and light chains mimic TSH α and β chains, respectively, in the way they bind to the receptor, but the evolutionary forces which have caused this close molecular mimicry are as yet completely unknown. More recently two more human monoclonal antibodies to the TSHR (K1-18 with stimulating and K1-70 with blocking activities) have been isolated from a single blood sample collected from a patient with hypothyroidism who previously presented with hyperthyroidism. K1-18 and K1-70 were derived from different lymphocytes as shown by V region genes analysis. This provides, for the first time, clear proof that a patient can produce both blocking and stimulating TRAbs at the same time. Although it has been postulated that stimulating and blocking TRAbs bind to different regions on the TSHR, our studies showed that antibodies of both types bind well to the TSHR containing only N-terminal amino acids 22–260. Whether TRAbs make contact with other parts of the TSHR in order to produce their biological effects (stimulation or blocking) remains to be elucidated.

Key words

Graves’ disease - TSH - TSH receptor antibodies - autoimmunity

References

  • 1 Adams DD. Pathogenesis of the hyperthyroidism of Graves’ disease.  Br Med J. 1965;  1 1015-1019
    Google Scholar
  • 2 Rees Smith B, McLachlan SM, Furmaniak J. Autoantibodies to the thyrotropin receptor.  Endocr Rev. 1988;  9 106-121
    Google Scholar
  • 3 Rees Smith B, Sanders J, Furmaniak J. TSH receptor antibodies.  Thyroid. 2007;  17 923-938
    Google Scholar
  • 4 Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies.  Endocr Rev. 1998;  19 673-716
    Google Scholar
  • 5 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
    Google Scholar
  • 6 Ando T, Latif R, Daniel S, Eguchi K, Davies TF. Dissecting linear and conformational epitopes on the native thyrotropin receptor.  Endocrinology. 2004;  145 5185-5193
    Google Scholar
  • 7 Costagliola S, Bonomi M, Morgenthaler 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
    Google Scholar
  • 8 Flynn JC, Gilbert JA, Meroueh C, Snower DP, David CS, Kong YM, Banga JP. Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity-prone HLA-DRB1*0301 transgenic mice.  Immunology. 2007;  122 261-267
    Google Scholar
  • 9 Fox KM, Dias JA, van Roey P. Three-dimensional structure of human follicle-stimulating hormone.  Mol Endocrinol. 2001;  15 378-389
    Google Scholar
  • 10 Fan QR, Hendrickson WA. Structure of human follicle-stimulating hormone in complex with its receptor.  Nature. 2005;  433 269-277
    Google Scholar
  • 11 Núñez Miguel R, Sanders J, Chirgadze DY, Blundell TL, Furmaniak J, Rees Smith B. FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity.  J Mol Endocrinol. 2008;  41 145-164
    Google Scholar
  • 12 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
    Google Scholar
  • 13 Nakatake N, Sanders J, Richards T, Burne P, Barrett C, Pra CD, Presotto F, Betterle C, Furmaniak J, Rees Smith B. Estimation of serum TSH receptor autoantibody concentration and affinity.  Thyroid. 2006;  16 1077-1084
    Google Scholar
  • 14 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
    Google Scholar
  • 15 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
    Google Scholar
  • 16 Sanders J, Jeffreys J, Depraetere H, Evans M, Richards T, Kiddie A, Brereton K, Premawardhana LD, 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
    Google Scholar
  • 17 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
    Google Scholar
  • 18 Jeffreys J, Depraetere H, Sanders J, Oda Y, Evans M, Kiddie A, Richards T, Furmaniak J, Rees Smith B. Characterization of the thyrotropin binding pocket.  Thyroid. 2002;  12 1051-1061
    Google Scholar
  • 19 Flanagan JG, Cheng H-J. Alkaline phosphatase fusion proteins for molecular characterization and cloning of receptors and their ligands.  Meth Enzymol. 2000;  327 198-210
    Google Scholar
  • 20 Brooking H, Ananieva-Jordanova R, Arnold C, Amoroso M, Powell M, Betterle C, Zanchetta R, Furmaniak J, Rees Smith B. A sensitive non-isotopic assay for GAD65 autoantibodies.  Clin Chim Acta. 2003;  331 55-59
    Google Scholar
  • 21 Chen S, Willis J, Maclean C, Ananieva-Jordanova R, Amoroso MA, Brooking H, Powell M, Collins A, Bennett S, Mitchell S, Burne P, Furmaniak J, Rees Smith B. Sensitive non-isotopic assays for autoantibodies to IA-2 and to a combination of both IA-2 and GAD65.  Clin Chim Acta. 2005;  357 74-83
    Google Scholar
  • 22 Loos U, Franz C, Minich WB, Büsselmann I. Direct assay of TSH receptor autoantibodies causing Graves’ disease correlates with the clinical diagnosis closer than assays based on TSH displacement.  Horm Res. 2007;  68 ((Suppl 3)) 21-91
    Google Scholar
  • 23 Aalberse RC, Schuurman J. IgG4 breaking the rules.  Immunology. 2002;  105 9-19
    Google Scholar
  • 24 van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, den Bleker TH, Wiegman L, Vink T, Aarden LA, De Baets MH, van de Winkel JGJ, Aalberse RC, Parren PWHI. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange.  Science. 2007;  317 1554-1557
    Google Scholar
  • 25 Weetman AP, Byfield PGH, Black C, Reimer B. IgG heavy chain subclass restriction of thyrotropin binding inhibitory immunoglobulins in Graves’ disease.  Eur J Clin Invest. 1990;  20 406-410
    Google Scholar
  • 26 Kraiem Z, Cho BY, Sadeh O, Shong MH, Pickerill P, Weetman AP. The IgG subclass distribution of TSH receptor blocking antibodies in primary hypothyroidism.  Clin Endocrinol. 1992;  37 135-140
    Google Scholar
  • 27 Minich WB, Loos U. Detection of functionally different types of pathological autoantibodies against thyrotropin receptor in Graves’ patients sera by luminescent immunoprecipitation analysis.  Exp Clin Endocrinol Diabetes. 2000;  108 110-119
    Google Scholar
  • 28 Minich WB, Lenzner C, Bergmann A, Morgenthaler NG. A coated tube assay for the detection of blocking thyrotropin receptor autoantibodies.  J Clin Endocrinol Metab. 2004;  89 352-356
    Google Scholar
  • 29 Chazenbalk GD, Jaume JC, McLachlan SM, Rapoport B. Engineering the human thyrotropin receptor ectodomain from a non-secreted form to a secreted, highly immunoreactive glycoprotein that neutralizes autoantibodies in Graves’ patients’ sera.  J Biol Chem. 1997;  272 18959-18965
    Google Scholar
  • 30 Chazenbalk GD, Wang Y, Guo J, Hutchison JS, Segal D, Jaume JC, McLachlan SM, Rapoport B. 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. 1999;  84 702-710
    Google Scholar
  • 31 Chazenbalk GD, McLachlan SM, Pichurin P, Yan XM, Rapoport B. 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. 2001;  86 1287-1293
    Google Scholar
  • 32 Chazenbalk GD, Pichurin P, Chen CR, Latrofa F, Johnstone AP, McLachlan SM, Rapoport B. Thyroid-stimulating autoantibodies in Graves’ disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor.  J Clin Invest. 2002;  110 209-217
    Google Scholar
  • 33 Schwarz-Lauer L, Chazenbalk GD, McLachlan SM, Ochi Y, Nagayama Y, Rapoport B. Evidence for a simplified view of autoantibody interactions with the thyrotropin receptor.  Thyroid. 2002;  12 115-120
    Google Scholar
  • 34 Da Costa CR, Johnstone AP. Production of the thyrotropin receptor extracellular domain as a glycosylphosphatidylinositol anchored membrane protein and its interaction with thyrotropin and autoantibodies.  J Biol Chem. 1998;  273 11874-11880
    Google Scholar
  • 35 Cornelis S, Uttenweiler-Joseph S, Panneels V, Vassart G, Costagliola S. Purification and characterization of a soluble bioactive amino-terminal extracellular domain of the human thyrotropin receptor.  Biochemistry. 1998;  40 9860-9869
    Google Scholar
  • 36 Osuga Y, Liang SG, Dallas JS, Wang C, Hsueh AJ. Soluble ecto-domain mutant of thyrotropin (TSH) receptor incapable of binding TSH neutralizes the action of thyroid-stimulating antibodies from Graves’ patients.  Endocrinology. 1998;  139 671-676
    Google Scholar
  • 37 Szkudlinski WM, Teh NG, Grossmann M, Tropea JE, Weintraub BD. Engineering human glycoprotein hormone superactive analogues.  Nature Biotechnol. 1996;  14 1257-1263
    Google Scholar
  • 38 Mueller S, Kleinau G, Jaeschke H, Paschke R, Krause G. Extended hormone binding site of the human TSHR: distinctive acidic residues in the hinge region are involved in bovine TSH binding and receptor activation.  J Biol Chem. 2008;  283 18048-18055
    Google Scholar
  • 39 Mizutori U, Chen C-R, McLachlan SM, Rapoport B. The thyrotropin receptor hinge region is not simply a scaffold for the leucine-rich domain but contributes to ligand binding and signal transduction.  Mol Endocrinol. 2008;  22 1171-1182
    Google Scholar
  • 40 Costagliola S, Panneels V, Bonomi M, Koch J, Many MC, Smits G, Vassart G. Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors.  EMBO J. 2002;  21 504-513
    Google Scholar
  • 41 Gallivan JP, Dougherty DA. Cation-π interactions in structural biology.  Proc Natl Acad Sci USA. 1999;  96 9459-9464
    Google Scholar

Correspondence

Dr. B. Rees Smith

FIRS Laboratories

RSR Ltd

Parc Ty Glas

Llanishen

Cardiff CF14 5DU

UK

Phone: +44/29/2076 55 50

Fax: +44/29/2076 45 75

Email: firs@rsrltd.eclipse.co.uk

      >