Mechanism of GPCR-Directed Autoantibodies in Diseases

  • Hamiyet Unal
  • Rajaganapathi Jagannathan
  • Sadashiva S. Karnik
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (volume 749)

Abstract

Receptor-activating autoantibodies targeting different G-protein-coupled receptors (GPCRs) have been discovered that exhibit agonist-like activity in several human pathologies. For example, autoimmune pathogenesis of Graves’ disease is attributed to autoantibody-mediated activation of the thyrotropin receptor, a GPCR. Likewise, diseases such as preeclampsia and vascular allograft rejection are caused by autoantibodies against angiotensin II type 1 receptor (AT1R). The serum of patients with Chagas disease causing congestive heart failure contains an autoantibody for the β1-adrenergic receptor. Autoantibodies against α1- and β1- and β2-adrenergic receptors found in serum from patients are linked to malignant hypertension and idiopathic dilated cardiomyopathy, respectively. Additional examples of GPCR-activating antibodies include those against the mGluR, GABA, 5HT4, calcium-sensing receptor, muscarinic M1 and M2 receptors, which have been identified in various chronic neurological diseases patients. The GPCR-directed autoantibodies may actually initiate the cellular signaling responsible for the disease since each disorder is associated with a specific GPCR-directed autoantibody. Empirical evidence suggests that the autoantibody induces GPCR activation without the endogenous ligand; however, the mechanism of antibody mediated receptor activation is not known. We show that the conformational dynamics of the extracellular domain of the AT1R generates the epitope for an autoantibody on the plasma membrane surface. This allows the antibody to bind and stabilize the activated state of AT1R, thus providing a molecular basis for the autoantibody action.

References

  1. Abd Alla S, Quitterer U, Grigoriev S, Maidhof A, Haasemann M, Jarnagin K, Müller-Esterl W (1996) Extracellular domains of the bradykinin B2 receptor involved in ligand binding and agonist sensing defined by anti-peptide antibodies. J Biol Chem 271:1748–55. doi:10.1074/jbc.271.3.1748 CrossRefGoogle Scholar
  2. Ahuja S, Hornak V, Yan EC, Syrett N, Goncalves JA, Hirshfeld A, Ziliox M, Sakmar TP, Sheves M, Reeves PJ, Smith SO, Eilers M (2009) Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation. Nat Struct Mol Biol 16:168–175. doi:10.1038/nsmb.1549 PubMedCrossRefGoogle Scholar
  3. Biondi B, Kahaly GJ (2010) Cardiovascular involvement in patients with different causes of hyperthyroidism. Nat Rev Endocrinol 6:431–43. doi:10.1038/nrendo.2010.105 PubMedCrossRefGoogle Scholar
  4. Borda T, Gomez R, Berría MI, Sterin-Borda L (2004) Antibodies against astrocyte M1 and M2 muscarinic cholinoceptor from schizophrenic patients’ sera. Glia 45:144–154. doi:10.1002/glia.10312 PubMedCrossRefGoogle Scholar
  5. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human β2-adrenergic G-protein-coupled receptor. Science 318:1258–1265. doi:10.1126/science.1150577 PubMedCrossRefGoogle Scholar
  6. Coesmans M, Smitt PA, Linden DJ, Shigemoto R, Hirano T, Yamakawa Y, van Alphen AM, Luo C, van der Geest JN, Kros JM, Gaillard CA, Frens MA, de Zeeuw CI (2003) Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Ann Neurol 53:325–336. doi:10.1002/ana.10451 PubMedCrossRefGoogle Scholar
  7. Colvin RB, Smith RN (2005) Antibody-mediated organ-allograft rejection. Nat Rev Immunol 5:807–817. doi:10.1038/nri1702 PubMedCrossRefGoogle Scholar
  8. Dechend R, Homuth V, Wallukat G, Kreuzer J, Park JK, Theuer J, Juepner A, Gulba DC, Mackman N, Haller H, Luft FC (2000) AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. Circulation 101:2382–2387PubMedCrossRefGoogle Scholar
  9. Dechend R, Viedt C, Müller DN, Ugele B, Brandes RP, Wallukat G, Park JK, Janke J, Barta P, Theuer J, Fiebeler A, Homuth V, Dietz R, Haller H, Kreuzer J, Luft FC (2003) AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation 107:1632–9. doi:10.1161/01.CIR.0000058200.90059.B1 PubMedCrossRefGoogle Scholar
  10. Dragun D (2007) The role of angiotensin II type 1 receptor-activating antibodies in renal allograft vascular rejection. Pediatr Nephrol 22:911–914. doi:10.1007/s00467-007-0452-z PubMedCrossRefGoogle Scholar
  11. Dragun D, Müller DN, Bräsen JH, Fritsche L, Nieminen-Kelhä M, Dechend R, Kintscher U, Rudolph B, Hoebeke J, Eckert D, Mazak I, Plehm R, Schönemann C, Unger T, Budde K, Neumayer HH, Luft FC, Wallukat GN (2005) Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 352:558–569. doi:10.1038/nri1702 PubMedCrossRefGoogle Scholar
  12. Eftekhari P, Sallé L, Lezoualc’h F, Mialet J, Gastineau M, Briand JP, Isenberg DA, Fournié GJ, Argibay J, Fischmeister R, Muller S, Hoebeke J (2000) Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block. Eur J Immunol 30:2782–2790. doi:10.1002/1521-4141(200010)30:10<2782::AID-IMMU2782>3.0.CO;2-9PubMedCrossRefGoogle Scholar
  13. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272. doi:10.1124/mol.63.6.1256 PubMedCrossRefGoogle Scholar
  14. Gavalas NG, Kemp EH, Krohn KJI, Brown EM, Watson PF, Weetman AP (2007) The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 92:2107–2114. doi:10.1210/jc.2006-2466 PubMedCrossRefGoogle Scholar
  15. Iwata M, Yoshikawa T, Baba A, Anzai T, Mitamura H, Ogawa S (2001) Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 37:418–424. doi:10.1016/S0735-1097(00)01109-8 PubMedCrossRefGoogle Scholar
  16. Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, IJzerman AP, Stevens RC (2008) The 2.6 Angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322:1211–1217. doi: 10.1126/science.1164772 Google Scholar
  17. Jahns R, Boivin V, Hein L, Triebel S, Angermann CE, Ertl G, Lohse MJ (2004) Direct evidence for a β1-adrenergic receptor–directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 113:1419–1429. doi:10.1172/JCI20149 PubMedGoogle Scholar
  18. Karnik SS, Gogonea C, Saad Y, Patil S, Takezako T (2003) Activation of G-protein-coupled receptors: a common molecular mechanism. Trends Endocrinol Metab 14:431–437. doi:10.1016/j.tem.2003.09.007 PubMedCrossRefGoogle Scholar
  19. Kimura A, Sakurai T, Suzuki Y, Hayashi Y, Hozumi I, Watanabe O, Arimura K, Takahashi Y, Inuzuka T (2007) Autoantibodies against glutamate receptor epsilon2-subunit detected in a subgroup of patients with reversible autoimmune limbic encephalitis. Eur Neurol 58:152–158. doi:10.1159/000104716 PubMedCrossRefGoogle Scholar
  20. Klco JM, Wiegand CB, Narzinski K, Baranski TJ (2005) Essential role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol 12:320–326. doi:10.1038/nsmb913 PubMedCrossRefGoogle Scholar
  21. Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7:339–357. doi:10.1038/nrd2518 PubMedCrossRefGoogle Scholar
  22. Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, Friedman D, Skeen MB, Grisold W, Kimura A, Ohta K, Iizuka T, Guzman M, Graus F, Moss SJ, Balice-Gordon R, Dalmau J (2010) Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9:67–76. doi:10.1016/S1474-4422(09)70324-2 PubMedCrossRefGoogle Scholar
  23. Liao YH, Wei YM, Wang M, Wang ZH, Yuan HT, Cheng LX (2002) Autoantibodies against AT1-receptor and a1-adrenergic receptor in patients with hypertension. Hypertens Res 25:641–646PubMedCrossRefGoogle Scholar
  24. Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, Hoebeke J (1994) Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect. Circulation 89:2760–2767PubMedCrossRefGoogle Scholar
  25. Massotte D, Kieffer BL (2005) The second extracellular loop: a damper for G protein-coupled receptors? Nat Struct Mol Biol 12:287–288. doi:10.1038/nsmb0405-287 PubMedCrossRefGoogle Scholar
  26. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: a G-protein-coupled receptor. Science 289:739–745. doi:10.1126/science.289.5480.739 PubMedCrossRefGoogle Scholar
  27. Park JH, Scheerer P, Hofmann KP, Choe HW, Ernst OP (2008) Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454:183–187. doi:10.1038/nature07063 PubMedCrossRefGoogle Scholar
  28. Perez DM (2003) The evolutionarily triumphant G-protein-coupled receptor. Mol Pharmacol 63:1202–1205. doi:10.1124/mol.63.6.1202 PubMedCrossRefGoogle Scholar
  29. Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM (1999) The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev 19:673–716. doi:10.1210/er.19.6.673 CrossRefGoogle Scholar
  30. Riemekasten G, Philippe A, Näther M, Slowinski T, Müller DN, Heidecke H, Matucci-Cerinic M, Czirják L, Lukitsch I, Becker M, Kill A, van Laar JM, Catar R, Luft FC, Burmester GR, Hegner B, Dragun D (2010) Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis 70:530–536. doi:10.1136/ard.2010.135772 PubMedCrossRefGoogle Scholar
  31. Roberts JM (2000) Angiotensin-1 receptor autoantibodies: a role in the pathogenesis of preeclampsia? Circulation 101:2335–2337PubMedCrossRefGoogle Scholar
  32. Rosenbaum DM, Rasmussen SG, Kobilka BK (2009) The structure and function of G-protein-coupled receptors. Nature 459:356–363. doi:10.1038/nature08144 PubMedCrossRefGoogle Scholar
  33. Rossi MA, Tanowitz HB, Malvestio LM, Celes MR, Campos EC, Blefari V, Prado CM (2010) Coronary microvascular disease in chronic Chagas cardiomyopathy including an overview on history, pathology, and other proposed pathogenic mechanisms. PLoS Negl Trop Dis 4:e674. doi:10.1371/journal.pntd.0000674 PubMedCrossRefGoogle Scholar
  34. Shi L, Javitch JA (2004) The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. Proc Natl Acad Sci USA 101:440–5. doi:10.1073/pnas.2237265100 PubMedCrossRefGoogle Scholar
  35. Stavrakis S, Yu X, Patterson E, Huang S, Hamlett SR, Chalmers L, Pappy R, Cunningham MW, Morshed SA, Davies TF, Lazzara R, Kem DC (2009) Activating autoantibodies to the beta-1 adrenergic and M2 muscarinic receptors facilitate atrial fibrillation in patients with graves’ hyperthyroidism. J Am Coll Cardiol 54:1309–1316. doi:10.1016/j.jacc.2009.07.015 PubMedCrossRefGoogle Scholar
  36. Unal H, Jagannathan R, Bhat MB, Karnik SS (2010) Ligand-specific conformation of extracellular loop-2 in the angiotensin II type 1 receptor. J Biol Chem 21:16341–50. doi:10.1074/jbc.M109.094870 CrossRefGoogle Scholar
  37. Witebsky E, Rose NR, Terplan K, Paine JR, Egan RW (1957) Chronic thyroiditis and autoimmunization. J Am Med Assoc 164:1439–1447. doi:10.1001/jama.1957.02980130015004 PubMedCrossRefGoogle Scholar
  38. Xia Y, Ramin SM, Kellems RE (2007) Potential roles of angiotensin receptor-activating autoantibody in the pathophysiology of preeclampsia. Hypertension 50:269–275. doi:10.1161/HYPERTENSIONAHA.107.091322 PubMedCrossRefGoogle Scholar
  39. Zhou CC, Zhang Y, Irani RA, Zhang H, Mi T, Popek EJ, Hicks MJ, Ramin SM, Kellems RE, Xia Y (2008) Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med 14:855–62. doi:10.1038/nm.1856 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hamiyet Unal
    • 1
  • Rajaganapathi Jagannathan
    • 1
  • Sadashiva S. Karnik
    • 1
  1. 1.Department of Molecular CardiologyLerner Research Institute, Cleveland Clinic FoundationClevelandUSA

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