Autoimmune mediated G-protein receptor activation in cardiovascular and renal pathologies

Duska Dragun; Aurélie Philippe; Rusan Catar; Björn Hegner

doi:10.1160/TH08-10-0710

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(04): 643-648
DOI: 10.1160/TH08-10-0710

Theme Issue Article

Schattauer GmbH

Autoimmune mediated G-protein receptor activation in cardiovascular and renal pathologies

Authors

Duska Dragun

¹Department of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum and Center for Cardiovascular Research Medical Faculty of the Charité Berlin, Berlin, Germany
Aurélie Philippe

¹Department of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum and Center for Cardiovascular Research Medical Faculty of the Charité Berlin, Berlin, Germany
Rusan Catar

¹Department of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum and Center for Cardiovascular Research Medical Faculty of the Charité Berlin, Berlin, Germany
Björn Hegner

¹Department of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum and Center for Cardiovascular Research Medical Faculty of the Charité Berlin, Berlin, Germany

Abstract

Summary

Antibodies directed against G-protein coupled receptors (GPCR) can act as allosteric receptor agonists or antagonists. Prototypic disease for agonistic antibody action is a Graves disease of the thyroid gland where antibodies that stimulate G-protein coupled thyroid-stimulating hormone receptor (TSHR) were first described 50 years ago. Myasthenia gravis is the prototype for antagonistic autoimmune actions, where antibodies directed against the nicotinic acetylcholine receptor (AChR) cause blockade of neuromuscular junctions. Antibodies and B-cells are increasingly recognised as major modulators of various cardiovascular and renal pathologies. We aim to critically review the notion that antibodies targeting other GPCRs may amplify or cause various cardiovascular and renal pathologies and summarise the current state of research, as well as perspectives in diagnostic and therapeutic strategies. In terms of targets we will focus on the α-adrenergic receptor (α₁AR), the β-adrenergic receptor (β1AR), and the angiotensin II type 1 receptor (AT₁R).

Keywords

α1-adrenergic receptor (α1AR) - β1-adrenergic receptor (β1AR) - angiotensin II type 1 receptor - autoantibodies

Full Text

References

References
1 Fu ML, Wallukat G, Hjalmarson A. et al. Characterization of anti-peptide antibodies directed against an extracellular immunogenic epitope on the human alpha 1-adrenergic receptor. Clin Exp Immunol 1994; 97: 146-151.
2 Fu ML, Herlitz H, Wallukat G. et al. Functional autoimmune epitope on alpha 1-adrenergic receptors in patients with malignant hypertension. Lancet 1994; 344: 1660-1663.
3 Luther HP, Homuth V, Wallukat G. Alpha 1-adrenergic receptor antibodies in patients with primary hypertension. Hypertension 1997; 29: 678-682.
4 Wenzel K, Haase H, Wallukat G. et al. Potential relevance of α1-adrenergic receptor autoantibodies in refractory hypertension. PLoS ONE 2008; 3: e3742.
5 Guillet JG, Hoebeke J, Lengagne R. et al. Haplo-type specific homology scanning algorithm to predict T-cell epitopes from protein sequences. J Mol Recognit 1991; 4: 17-25.
6 Hoebeke J. Structural basis of autoimmunity against G protein coupled membrane receptors. Int J Cardiol 1996; 54: 103-111.
7 Jahns R, Boivin V, Siegmund C. et al. Autoanti-bodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation 1999; 99: 649-654.
8 Magnusson Y, Wallukat G, Waagstein F. et al. Auto-immunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect. Circulation 1994; 89: 2760-2767.
9 Wallukat G, Morwinski M, Kowal K. et al. Auto-antibodies against the beta-adrenergic receptor in human myocarditis and dilated cardiomyopathy: beta-adrenergic agonism without desensitization. Eur Heart J 1991; 12 (Suppl D) 178-181.
10 Jahns R, Boivin V, Siegmund C. et al. Activating beta-1-adrenoceptor antibodies are not associated with cardiomyopathies secondary to valvular or hypertensive heart disease. J Am Coll Cardiol 1999; 34: 1545-1551.
11 Jahns R, Boivin V, Krapf T. et al. Modulation of beta1-adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies. J Am Coll Cardiol 2000; 36: 1280-1287.
12 Wallukat G, Homuth V, Fischer T. et al. Patients with preeclampsia develop agonistic antibodies against the angiotensin AT1 receptor. J Clin Invest 1999; 1103: 945-952.
13 Dragun D, Müller DN, Bräsen JH. et al. Angiotensin II type 1-receptor activating antibodies in renal allo-graft rejection. N Engl J Med 2005; 352: 558-569.
14 Fu ML, Herlitz H, Schulze W. et al. Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension. J Hypertens 2000; 18: 945-953.
15 Xia Y, Wen H, Bobst S. et al. Maternal autoanti-bodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig 2003; 10: 82-93.
16 Mellor AL, Munn DH. Immunology at the maternal-fetal interface: Lessons for T cell tolerance and suppression. Annu Rev Immunol 2000; 18: 367-391.
17 Liao YH, Wei YM, Wang M. et al. Autoantibodies against AT1-receptor and alpha1-adrenergic receptor in patients with hypertension. Hypertens Res 2002; 25: 641-646.
18 Zhou Z, Liao YH, Wei Y. et al. Cardiac remodeling after long-term stimulation by antibodies against the alpha1-adrenergic receptor in rats. Clin Immunol 2005; 114: 164-173.
19 Magnusson Y, Marullo S, Hoyer S. et al. Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J Clin Invest 1990; 86: 1658-1663.
20 Wallukat G, Wollenberger A, Morwinski R. et al. Anti-beta 1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J Mol Cell Cardiol 1995; 27: 397-406.
21 Fraser CM, Venter JC, Kaliner M. Autonomic abnormalities and autoantibodies to beta-adrenergic receptors. N Engl J Med 1981; 305: 1165-1170.
22 Wallukat G, Wollenberger A. Effects of the serum gamma globulin fraction of patients with allergic asthma and dilated cardiomyopathy on chronotropic beta adrenoceptor function in cultured neonatal rat heart myocytes. Biomed Biochim Acta 1987; 46: S634-639.
23 Leiros CP, Sterin-Borda L, Borda E. Beta-adrenergic cardiac antibody in autoimmune myocarditis. Auto-immunity 1989; 2: 223-234.
24 Eng H, Magnusson Y, Matell G. et al. Beta 2-adrenergic receptor antibodies in myasthenia gravis. J Auto-immun 1992; 5: 213-227.
25 Sterin-Borda LJ, Borda ES. Participation of autonomic nervous system in the pathogenesis of Chagas disease. Acta Physiol Pharmacol Ther Latinoam 1994; 44: 109-123.
26 Matsui S, Fu ML, Katsuda S. et al. Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits. J Mol Cell Cardiol 1997; 29: 641-655.
27 Jahns R, Boivin V, Hein L. et al. Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 2004; 113: 1419-1429.
28 Dechend R, Gratze P, Wallukat G. et al. Agonistic autoantibodies to the AT1 receptor in a transgenic rat model of preeclampsia. Hypertension 2005; 45: 742-746.
29 Zhou CC, Zhang Y, Irani RA. et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med 2008; 14: 855-862.
30 Wucherpfennig KW. Mechanisms for induction of autoimmunity by infectious agents. J Clin Invest 2001; 108: 1097-1104.
31 Ferrari I, Levin MJ, Wallukat G. et al. Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor. J Exp Med 1995; 182: 59-65.
32 Herse F, Verlohren S, Wenzel K. et al. Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study. Hypertension 2009; 53: 393-398.
33 Stepan H, Wallukat G, Schultheiss HP. et al. Is parvovirus B19 the cause for autoimmunity against the angiotensin II type receptor?. J Reprod Immunol 2007; 73: 130-134.
34 Bkaily G, El-Bizri N, Bui M. et al. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors. Can J Physiol Pharmacol 2003; 81: 234-246.
35 Vilardaga JP, Steinmeyer R, Harms GS. et al. Molecular basis of inverse agonism in a G protein-coupled receptor. Nat Chem Biol 2005; 1: 25-28.
36 Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of beta-adrenergic signaling in heart failure?. Circ Res 2003; 93: 896-906.
37 Mercier JF, Salahpour A, Angers S. et al. Quantitative assessment of beta 1– and beta 2-adrenergic receptor homo- and heterodimerization by bioluminescence resonance energy transfer. J Biol Chem 2002; 277: 44925-44931.
38 Dechend R, Homuth V, Wallukat G. et al. AT1 receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. Circulation 2000; 101: 2382-2387.
39 Saadi S, Takahashi T, Holzknecht RA. et al. Pathways to acute humoral rejection. Am J Pathol 2004; 164: 1073-1080.
40 Dobado Berrios P, Lopez-Pedrera C, Velasco F. et al. The role of tissue factor in the antiphospholipid syndrome. Arthritis Rheum 2001; 44: 2467-2476.
41 Thway TM, Shlykov SG, Day MC. et al. Antibodies from preeclamptic patients stimulate increased intra-cellular Ca2+ mobilization through angiotensin receptor activation. Circulation 2004; 110: 1612-1619.
42 Zhou CC, Ahmad S, Mi T. et al. Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ Res 2007; 100: 88-95.
43 Omerovic E, Bollano E, Andersson B. et al. Induction of cardiomyopathy in severe combined immuno-deficiency mice by transfer of lymphocytes from patients with idiopathic dilated cardiomyopathy. Auto-immunity 2000; 32: 271-280.
44 Yamani MH, Cook DJ, Tuzcu EM. et al. Systemic up-regulation of angiotensin II type 1 receptor in cardiac donors with spontaneous intracerebral hemorrhage. Am J Transplant 2004; 4: 1097-1102.
45 Lamarca B, Wallukat G, Llinas M. et al. Autoanti-bodies to the angiotensin type I receptor in response to placental ischemia and tumor necrosis factor alpha in pregnant rats. Hypertension 2008; 52: 1168-1172.
46 Miller JA, Scholey JW. The impact of renin-angiotensin polymorphisms on physiological and patho-physiological processes in humans. Curr Opin Nephrol Hypert 2004; 13: 101-106.
47 Ando T, Latif R, Davies TF. Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody. J Clin Invest 2004; 113: 1589-1595.
48 Nikolaev VO, Boivin V, Störk S. et al. A novel fluorescence method for the rapid detection of functional beta1-adrenergic receptor autoantibodies in heart failure. J Am Coll Cardiol 2007; 50: 423-431.
49 Nikolaev VO, Bünemann M, Hein L. et al. Novel single chain cAMP sensors for receptor-induced signal propagation. J Biol Chem 2004; 279: 37215-37218.
50 Nikolaev VO, Gambaryan S, Engelhardt S. et al. Real-time monitoring of the PDE2 activity of live cells: hormone-stimulated cAMP hydrolysis is faster than hormone-stimulated cAMP synthesis. J Biol Chem 2005; 280: 1716-1719.
51 Slowinski T, Suker D, Schönemann C. et al. Screening of patients on waiting-list for a renal transplant for agonistic non-HLA antibodies targeting angiotensin II type 1 receptor (Abstract). J Am Soc Nephrol 2006; 17: 393A (abstract).
52 Müller J, Wallukat G, Dandel M. et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 2000; 101: 385-391.
53 Staudt A, Hummel A, Ruppert J. et al. Immunoadsorption in dilated cardiomyopathy: 6-month results from a randomized study. Am Heart J 2006; 152: 712.e1-6.
54 Heinze G, Mitterbauer C, Regele H. et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol 2006; 17: 889-899.
55 Weidanz JA, Jacobson LM, Muehrer RJ. et al. AT1R blockade reduces IFN-? production in lymphocytes in vivo and in vitro. Kidney Int 2005; 67: 2134-2142.
56 Scornik JC, Guerra G, Schold JD. et al. Value of posttransplant antibody tests in the evaluation of patients with renal graft dysfunction. Am J Transplant 2007; 7: 1808-1814.