Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling

  • Yunhui Du
  • Xiao Li
  • Haicun Yu
  • Li Yan
  • Wayne Bond Lau
  • Shihan Zhang
  • Yanwen Qin
  • Wen Wang
  • Xinliang Ma
  • Huirong LiuEmail author
  • Michael Fu



Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of β1-adrenoceptor (β1-AA), a catecholamine-like substance with β1-adrenergic activity, in patients with heart failure. Although evidence demonstrates that this autoantibody may alter T cell proliferation and secretion, the role of T lymphocytes in heart failure induced by β1-AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by β1-AA.

Methods and Results

β1-AA monoclonal antibodies (β1-AAmAb) produced using the hybridoma technique were administered in wild-type mice or T lymphocyte deficiency nudes for 12 weeks. T lymphocytes from heart failure patients and neonatal cardiomyocytes were utilized in vitro. Mouse protein antibody array analysis was employed to detect the cytokines responsible for β1-AAmAb-induced heart failure. Compared to wild-type mice, T lymphocyte deficiency mice prevented cardiac function from getting worse, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. As shown by protein array, the serum level of interleukin (IL)-6 was significantly lower in the nude group as compared to wild-type after β1-AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by β1-AAmAb caused direct damage in the cardiomyocytes, and β1-AAmAb promoted proliferation of T lymphocytes isolated from patients with heart failure and increased IL-6 release. IL-6-specific siRNA virtually abolished cardiomyocyte apoptosis, suggesting that IL-6 may be a key cytokine released by T lymphocytes and responsible for β1-AAmAb-induced cardiac remodeling.


Collectively, we demonstrate that β1-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.


T lymphocytes Autoantibody Receptors adrenergic Beta-1 Remodeling 



Autoantibodies against the second extracellular loop of β1-adrenergic receptor


β1-AA monoclonal antibody


β1-adrenergic receptor


The second extracellular loop of β1-adrenergic receptor


Chronic heart failure


Dilated cardiomyopathy

LVID (d)

Left ventricular diastolic diameter


Left ventricular mass


Left ventricular ejection fraction


Percent fractional shortening


Enzyme-linked immunosorbent assay


Immunoglobulin fractions G


Phosphate-buffered saline



We thank Dr. Yongxiang Wei who helped us in conducting the BLI assay.


This study was funded by the following grants: Natural Science Foundation of China 81470540 (L. Yan) and Natural Science Foundation of Beijing 7151001 (W. Wang).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All animal experiments were performed in accordance with the guidelines for the care and use of laboratory animals, published by the Ministry of the People’s Republic of China (issued June 3, 2004), and were approved by the Institutional Committee of Animal Care at Capital Medical University.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Institutional Committee for the Protection of Human Subjects of Capital Medical University approved this research protocol.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10557_2019_6856_MOESM1_ESM.docx (459 kb)
ESM 1 (DOCX 458 kb)


  1. 1.
    Guo A, Zhang C, Wei S, Chen B, Song LS. Emerging mechanisms of T-tubule remodeling in heart failure. Cardiovasc Res. 2013;98:204–15.CrossRefGoogle Scholar
  2. 2.
    Papageorgiou AP, Swinnen M, Vanhoutte D, Vandendriessche T, Chuah M, Lindner D, et al. Thrombospondin-2 prevents cardiac injury and dysfunction in viral myocarditis through the activation of regulatory T-cells. Cardiovasc Res. 2012;94:115–24.CrossRefGoogle Scholar
  3. 3.
    Nevers T, Salvador AM, Grodecki-Pena A, Knapp A, Velázquez F, Aronovitz M, et al. Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure. Circ Heart Fail. 2015;8(4):776–87.CrossRefGoogle Scholar
  4. 4.
    Liu HR, Zhao RR, Jiao XY, Wang YY, Fu M. Relationship of myocardial remodeling to the genesis of serum autoantibodies to cardiac beta(1)-adrenoceptors and muscarinic type 2 acetylcholine receptors in rats. J Am Coll Cardiol. 2002;39:1866–73.CrossRefGoogle Scholar
  5. 5.
    Wallukat G, Wollenberger A, Morwinski R, Pitschner HF. 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(1):397–406.CrossRefGoogle Scholar
  6. 6.
    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:S634–9.Google Scholar
  7. 7.
    Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, Hoebeke J. Autoimmunity in idiopathic dilated cardiomyopathy: characterization of antibodies against the beta1-adrenoceptor with positive chronotropic effect. Circulation. 1994;89(6):2760–7.CrossRefGoogle Scholar
  8. 8.
    Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse MJ, Boege F. Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation. 1999;99(5):649–54.CrossRefGoogle Scholar
  9. 9.
    Störk S, Boivin V, Horf R, Hein L, Lohse MJ, Angermann CE, et al. Stimulating autoantibodies directed against the cardiac beta1-adrenergic receptor predict increased mortality in idiopathic cardiomyopathy. Am Heart J. 2006;152(4):697–704.CrossRefGoogle Scholar
  10. 10.
    Magnusson Y, Marullo S, Hoyer S, Waagstein F, Andersson B, Vahlne A, et al. Mapping of a functional autoimmune epitope on the beta1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J Clin Invest. 1990;86:1658–63.CrossRefGoogle Scholar
  11. 11.
    Baba A, Akaishi M, Shimada M, Monkawa T, Wakabayashi Y, Takahashi M, et al. Complete elimination of cardiodepressant IgG3 autoantibodies by immunoadsorption in patients with severe heart failure. Circ J. 2010;74:1372–8.CrossRefGoogle Scholar
  12. 12.
    Felix SB, Staudt A, Landsberger M, Grosse Y, Stangl V, Spielhagen T, et al. Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption. J Am Coll Cardiol. 2002;39(4):646–52.CrossRefGoogle Scholar
  13. 13.
    Jahns R, Boivin V, Hein L, Triebel S, Angermann CE, Ertl G, 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(10):1419–29.CrossRefGoogle Scholar
  14. 14.
    Jiménez MAV, Nascimento JHM, Monnerat G, Maciel L, Paiva CN, Pedrosa RC, et al. Autoantibodies with beta-adrenergic activity from chronic chagasic patients induce cardiacarrhythmias and early afterdepolarization in a drug-induced LQT2 rabbit hearts. Int J Cardiol. 2017;240:354–9.CrossRefGoogle Scholar
  15. 15.
    Warraich RS, Griffiths E, Falconar A, Pabbathi V, Bell C, Angelini G, et al. Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship. FASEB J. 2006;20(6):651–60.CrossRefGoogle Scholar
  16. 16.
    Jane-wit D, Altuntas CZ, Johnson JM, Yong S, Wickley PJ, Clark P, et al. Beta 1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis. Circulation. 2007;116(4):399–410.CrossRefGoogle Scholar
  17. 17.
    Lv T, Du Y, Cao N, Zhang S, Gong Y, Bai Y, et al. Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms. Sci Rep. 2016;6:32430.CrossRefGoogle Scholar
  18. 18.
    Du Y, Yan L, Wang J, Zhan W, Song K, Han X, et al. Liu H. β1-adrenergic receptor autoantibodies from heart failure patients enhance the proliferation and secretion of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways. PLoS One. 2012;7:e52911.CrossRefGoogle Scholar
  19. 19.
    Tutor AS, Penela P, Mayor F. Anti-β1-adrenergic receptor autoantibodies are potent stimulators of the ERK1/2 pathway in cardiac cells. Cardiovasc Res. 2007;76:51–60.CrossRefGoogle Scholar
  20. 20.
    Ma LP, Premaratne G, Bollano E, Lindholm C, Fu M. Interleukin-6-deficient mice resist development of experimental autoimmune cardiomyopathy induced by immunization of β1-adrenergic receptor. Int J Cardiol. 2012;155:20–5.CrossRefGoogle Scholar
  21. 21.
    Buvall L, Bollano E, Chen J, Shultze W, Fu M. Phenotype of early cardiomyopathic changes induced by active immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the human beta-adrenergic receptor. Clin ExpImmunol. 2006;143:209–15.Google Scholar
  22. 22.
    Zuo L, Bao H, Tian J, Wang X, Zhang S, He Z, et al. Long-term active immunization with a synthetic peptide corresponding to the second extracellular loop of beta(1)-adrenoceptor induces both morphological and functional cardiomyopathic changes in rats. Int J Cardiol. 2011;149:89–94.CrossRefGoogle Scholar
  23. 23.
    Stavrakis S, Kem DC, Patterson E, Lozano P, Huang S, Szabo B, et al. Opposing cardiac effects of autoantibody activation of β-adrenergic and M2 muscarinic receptors in cardiac-related diseases. Int J Cardiol. 2011;148:331–6.CrossRefGoogle Scholar
  24. 24.
    Patel PA, Hernandez AF. Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy. Eur J Heart Fail. 2013;15(7):724–9.CrossRefGoogle Scholar
  25. 25.
    Alvarez P, Briasoulis A. Immune modulation in heart failure: the promise of novel biologics. Curr Treat Options Cardiovasc Med. 2018;20(3):26.CrossRefGoogle Scholar
  26. 26.
    Boivin-Jahns V, Jahns R. GPCR-autoantibodies in chronic heart failure. Front Biosci (Landmark Ed). 2018;23:2065–81.CrossRefGoogle Scholar
  27. 27.
    Nezlin R. Aptamers in immunological research. Immunol Lett. 2014;162(2 Pt B):252–5.CrossRefGoogle Scholar
  28. 28.
    Haberland A, Holtzhauer M, Schlichtiger A, Bartel S, Schimke I, Müller J, et al. Aptamer BC 007-a broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors. Eur J Pharmacol. 2016;789:37–45.CrossRefGoogle Scholar
  29. 29.
    Haberland A, Wallukat G, Schimke I. Aptamer binding and neutralization of β1-adrenoceptor autoantibodies: basics and a vision of its future in cardiomyopathy treatment. Trends Cardiovasc Med. 2011;21(6):177–82.CrossRefGoogle Scholar
  30. 30.
    Loza MJ, Peters SP, Foster S, Khan IU, Penn RB. β-agonist enhances type 2 T-cell survival and accumulation. J Allergy Clin Immunol. 2007;119:235–44.CrossRefGoogle Scholar
  31. 31.
    Aihara M, Dobashi K, Iizuka K, Nakazawa T, Mori M. Comparison of effects of Y-27632 and Isoproterenol on release of cytokines from human peripheral T cells. Int Immunopharmacol. 2003;3:1619–25.CrossRefGoogle Scholar
  32. 32.
    Ghandadi M, Sahebkar A. Interleukin-6: a critical cytokine in cancer multidrug resistance. Curr Pharm Des. 2016;22(5):518–26.CrossRefGoogle Scholar
  33. 33.
    McMaster WG, Kirabo A, Madhur MS, Harrison DG. Inflammation, immunity, and hypertensive end-organ damage. Circ Res. 2015;116(6):1022–33.CrossRefGoogle Scholar
  34. 34.
    Aulin J, Siegbahn A, Hijazi Z, Ezekowitz MD, Andersson U, Connolly SJ, et al. Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation. Am Heart J. 2015;170(6):1151–60.CrossRefGoogle Scholar
  35. 35.
    Fontes JA, Rose NR, Čiháková D. The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine. 2015;74(1):62–8.CrossRefGoogle Scholar
  36. 36.
    Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, Bauersachs J, Ertl G, et al. Activation of CD4+ T-lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation. 2012;125(13):1652–63.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yunhui Du
    • 1
    • 2
  • Xiao Li
    • 3
  • Haicun Yu
    • 2
    • 4
  • Li Yan
    • 5
  • Wayne Bond Lau
    • 6
  • Shihan Zhang
    • 2
    • 4
  • Yanwen Qin
    • 1
  • Wen Wang
    • 2
    • 4
  • Xinliang Ma
    • 4
    • 6
  • Huirong Liu
    • 2
    • 4
    Email author
  • Michael Fu
    • 7
  1. 1.Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel DiseasesCapital Medical UniversityBeijingChina
  2. 2.Department of Physiology and Pathophysiology, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  3. 3.Department of Pathology, School of Basic Medical SciencesShandong University of Traditional Chinese MedicineJinanChina
  4. 4.Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Ministry of EducationCapital Medical UniversityBeijingChina
  5. 5.Department of pathophysiology, Institute of Basic Medical ScienceChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
  6. 6.Department of Emergency MedicineThomas Jefferson UniversityPhiladelphiaUSA
  7. 7.Department of Molecular and Clinical Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden

Personalised recommendations