Skip to main content
SpringerLink
Log in

Loss of Regulatory Immune Function in Coronary Artery Disease Patients from the Indian Population

  • Original Article
  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

The pathogenic roles of inflammatory T cells and monocytes subsets have not been explored in different manifestations of coronary artery disease. We studied the frequency of these cells, their response to autoantigens, regulatory cell functional assay, foam cell formation and macrophage differentiation in 181 patients (stable angina, ST-elevated myocardial infarction (STEMI), NSTEMI, and unstable angina), and 34 controls and in samples collected during recurrent cardiac events and from patients showing clinical improvement. The proportion of Th17 cells and monocytes gradually increased in patients with stable angina at one end of the spectrum followed by NSTEMI, STEMI, and unstable angina at other end. Inflammatory cells were positively and inversely associated with recurrent events and clinical improvement, respectively. Patients showed expansion of Th17 cells in response to autoantigen (HSP60) and compromised Treg function. Our results suggest that stress-induced activation of inflammatory cells expands in the absence of regulatory control in CAD patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Writing Group, M, Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., et al. (2016). Heart disease and stroke Statistics-2016 update: A report from the American Heart Association. Circulation, 133(4), e38–e360. https://doi.org/10.1161/CIR.0000000000000350.

    Article  Google Scholar 

  2. Ambrose, J. A., & Singh, M. (2015). Pathophysiology of coronary artery disease leading to acute coronary syndromes. F1000Prime Rep, 7, 08. https://doi.org/10.12703/P7-08.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thygesen, K., Alpert, J. S., Jaffe, A. S., Simoons, M. L., Chaitman, B. R., White, H. D., et al. (2012). Third universal definition of myocardial infarction. Journal of the American College of Cardiology, 60(16), 1581–1598. https://doi.org/10.1016/j.jacc.2012.08.001.

    Article  PubMed  Google Scholar 

  4. Weber, C., Zernecke, A., & Libby, P. (2008). The multifaceted contributions of leukocyte subsets to atherosclerosis: Lessons from mouse models. Nature Reviews. Immunology, 8(10), 802–815. https://doi.org/10.1038/nri2415.

    Article  CAS  PubMed  Google Scholar 

  5. Hansson, G. K., & Libby, P. (2006). The immune response in atherosclerosis: A double-edged sword. Nature Reviews. Immunology, 6(7), 508–519. https://doi.org/10.1038/nri1882.

    Article  CAS  PubMed  Google Scholar 

  6. Ait-Oufella, H., Salomon, B. L., Potteaux, S., Robertson, A. K., Gourdy, P., Zoll, J., et al. (2006). Natural regulatory T cells control the development of atherosclerosis in mice. Nature Medicine, 12(2), 178–180. https://doi.org/10.1038/nm1343.

    Article  CAS  PubMed  Google Scholar 

  7. Pastrana, J. L., Sha, X., Virtue, A., Mai, J., Cueto, R., Lee, I. A., et al. (2012). Regulatory T cells and Atherosclerosis. Journal of Clinical and Experiment Cardiology, 2012(Suppl 12), 2. https://doi.org/10.4172/2155-9880.S12-002.

    Article  CAS  Google Scholar 

  8. Mallat, Z., Taleb, S., Ait-Oufella, H., & Tedgui, A. (2009). The role of adaptive T cell immunity in atherosclerosis. Journal of Lipid Research, 50(Suppl), S364–S369. https://doi.org/10.1194/jlr.R800092-JLR200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Daugherty, A., & Rateri, D. L. (2002). T lymphocytes in atherosclerosis: The yin-yang of Th1 and Th2 influence on lesion formation. Circulation Research, 90(10), 1039–1040.

    Article  CAS  PubMed  Google Scholar 

  10. Rogacev, K. S., Ulrich, C., Blomer, L., Hornof, F., Oster, K., Ziegelin, M., et al. (2010). Monocyte heterogeneity in obesity and subclinical atherosclerosis. European Heart Journal, 31(3), 369–376. https://doi.org/10.1093/eurheartj/ehp308.

    Article  CAS  PubMed  Google Scholar 

  11. Shantsila, E., Wrigley, B., Tapp, L., Apostolakis, S., Montoro-Garcia, S., Drayson, M. T., et al. (2011). Immunophenotypic characterization of human monocyte subsets: Possible implications for cardiovascular disease pathophysiology. Journal of Thrombosis and Haemostasis, 9(5), 1056–1066. https://doi.org/10.1111/j.1538-7836.2011.04244.x.

    Article  CAS  PubMed  Google Scholar 

  12. Maganto-Garcia, E., Tarrio, M. L., Grabie, N., Bu, D. X., & Lichtman, A. H. (2011). Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation, 124(2), 185–195. https://doi.org/10.1161/CIRCULATIONAHA.110.006411.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Erbel, C., Dengler, T. J., Wangler, S., Lasitschka, F., Bea, F., Wambsganss, N., et al. (2011). Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability. Basic Research in Cardiology, 106(1), 125–134. https://doi.org/10.1007/s00395-010-0135-y.

    Article  CAS  PubMed  Google Scholar 

  14. Hashmi, S., & Zeng, Q. T. (2006). Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coronary Artery Disease, 17(8), 699–706. https://doi.org/10.1097/01.mca.0000236288.94553.b4.

    Article  PubMed  Google Scholar 

  15. Cheng, X., Yu, X., Ding, Y. J., Fu, Q. Q., Xie, J. J., Tang, T. T., et al. (2008). The Th17/Treg imbalance in patients with acute coronary syndrome. Clinical Immunology, 127(1), 89–97. https://doi.org/10.1016/j.clim.2008.01.009.

    Article  CAS  PubMed  Google Scholar 

  16. Eid, R. E., Rao, D. A., Zhou, J., Lo, S. F., Ranjbaran, H., Gallo, A., et al. (2009). Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation, 119(10), 1424–1432. https://doi.org/10.1161/CIRCULATIONAHA.108.827618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Burkett, P. R., Meyer zu Horste, G., & Kuchroo, V. K. (2015). Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. The Journal of Clinical Investigation, 125(6), 2211–2219. https://doi.org/10.1172/JCI78085.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ponnusamy, T., Srikanth, K. V., Manjunatha, R., Kakkar, V. V., & Mundkur, L. (2015). Circulating Th17 and Tc17 cells and their imbalance with regulatory T cells is associated with myocardial infarction in young Indian patients. World Journal of Cardiovascular Diseases, 05(12), 15. https://doi.org/10.4236/wjcd.2015.512043.

    Article  CAS  Google Scholar 

  19. Friedewald, W. T., Levy, R. I., & Fredrickson, D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry, 18(6), 499–502.

    CAS  PubMed  Google Scholar 

  20. Steinbrecher, U. P., Witztum, J. L., Parthasarathy, S., & Steinberg, D. (1987). Decrease in reactive amino groups during oxidation or endothelial cell modification of LDL. Correlation with changes in receptor-mediated catabolism. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.]. Arteriosclerosis, 7(2), 135–143.

    Article  CAS  PubMed  Google Scholar 

  21. Larigauderie, G., Furman, C., Jaye, M., Lasselin, C., Copin, C., Fruchart, J. C., et al. (2004). Adipophilin enhances lipid accumulation and prevents lipid efflux from THP-1 macrophages: Potential role in atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(3), 504–510. https://doi.org/10.1161/01.ATV.0000115638.27381.97.

    Article  CAS  PubMed  Google Scholar 

  22. Lin, J., Li, M., Wang, Z., He, S., Ma, X., & Li, D. (2010). The role of CD4+CD25+ regulatory T cells in macrophage-derived foam-cell formation. Journal of Lipid Research, 51(5), 1208–1217. https://doi.org/10.1194/jlr.D000497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tousoulis, D., Antoniades, C., Bosinakou, E., Kotsopoulou, M., Tsoufis, C., Marinou, K., et al. (2007). Differences in inflammatory and thrombotic markers between unstable angina and acute myocardial infarction. International Journal of Cardiology, 115(2), 203–207. https://doi.org/10.1016/j.ijcard.2006.03.011.

    Article  PubMed  Google Scholar 

  24. Caligiuri, G., Paulsson, G., Nicoletti, A., Maseri, A., & Hansson, G. K. (2000). Evidence for antigen-driven T-cell response in unstable angina. Circulation, 102(10), 1114–1119.

    Article  CAS  PubMed  Google Scholar 

  25. Nakajima, T., Schulte, S., Warrington, K. J., Kopecky, S. L., Frye, R. L., Goronzy, J. J., et al. (2002). T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation, 105(5), 570–575.

    Article  CAS  PubMed  Google Scholar 

  26. Liston, A., & Rudensky, A. Y. (2007). Thymic development and peripheral homeostasis of regulatory T cells. Current Opinion in Immunology, 19(2), 176–185. https://doi.org/10.1016/j.coi.2007.02.005.

    Article  CAS  PubMed  Google Scholar 

  27. Shen, H., Goodall, J. C., & Hill Gaston, J. S. (2009). Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis and Rheumatism, 60(6), 1647–1656. https://doi.org/10.1002/art.24568.

    Article  CAS  PubMed  Google Scholar 

  28. Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., et al. (2006). The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell, 126(6), 1121–1133. https://doi.org/10.1016/j.cell.2006.07.035.

    Article  CAS  PubMed  Google Scholar 

  29. Toussirot, E. (2012). The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflammation & Allergy Drug Targets, 11(2), 159–168.

    Article  CAS  PubMed  Google Scholar 

  30. Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., et al. (2005). IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of Experimental Medicine, 201(2), 233–240. https://doi.org/10.1084/jem.20041257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Furuzawa-Carballeda, J., Vargas-Rojas, M. I., & Cabral, A. R. (2007). Autoimmune inflammation from the Th17 perspective. Autoimmunity Reviews, 6(3), 169–175. https://doi.org/10.1016/j.autrev.2006.10.002.

    Article  CAS  PubMed  Google Scholar 

  32. Chung, Y., Chang, S. H., Martinez, G. J., Yang, X. O., Nurieva, R., Kang, H. S., et al. (2009). Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity, 30(4), 576–587. https://doi.org/10.1016/j.immuni.2009.02.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sherlock, J. P., Joyce-Shaikh, B., Turner, S. P., Chao, C. C., Sathe, M., Grein, J., et al. (2012). IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nature Medicine, 18(7), 1069–1076. https://doi.org/10.1038/nm.2817.

    Article  CAS  PubMed  Google Scholar 

  34. Lim, H., Kim, Y. U., Sun, H., Lee, J. H., Reynolds, J. M., Hanabuchi, S., et al. (2014). Proatherogenic conditions promote autoimmune T helper 17 cell responses in vivo. Immunity, 40(1), 153–165. https://doi.org/10.1016/j.immuni.2013.11.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dart, M. L., Jankowska-Gan, E., Huang, G., Roenneburg, D. A., Keller, M. R., Torrealba, J. R., et al. (2010). Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis. Circulation Research, 107(9), 1106–1116. https://doi.org/10.1161/CIRCRESAHA.110.221069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sakaguchi, S., Yamaguchi, T., Nomura, T., & Ono, M. (2008). Regulatory T cells and immune tolerance. Cell, 133(5), 775–787. https://doi.org/10.1016/j.cell.2008.05.009.

    Article  CAS  PubMed  Google Scholar 

  37. Wigren, M., Bjorkbacka, H., Andersson, L., Ljungcrantz, I., Fredrikson, G. N., Persson, M., et al. (2012). Low levels of circulating CD4+FoxP3+ T cells are associated with an increased risk for development of myocardial infarction but not for stroke. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(8), 2000–2004. https://doi.org/10.1161/ATVBAHA.112.251579.

    Article  CAS  PubMed  Google Scholar 

  38. Hansson, G. K., & Hermansson, A. (2011). The immune system in atherosclerosis. Nature Immunology, 12(3), 204–212. https://doi.org/10.1038/ni.2001.

    Article  CAS  PubMed  Google Scholar 

  39. Weber, C., & Noels, H. (2011). Atherosclerosis: Current pathogenesis and therapeutic options. Nature Medicine, 17(11), 1410–1422. https://doi.org/10.1038/nm.2538.

    Article  CAS  PubMed  Google Scholar 

  40. Butcher, M., & Galkina, E. (2011). Current views on the functions of interleukin-17A-producing cells in atherosclerosis. Thrombosis and Haemostasis, 106(5), 787–795. https://doi.org/10.1160/TH11-05-0342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhu, F., Wang, Q., Guo, C., Wang, X., Cao, X., Shi, Y., et al. (2011). IL-17 induces apoptosis of vascular endothelial cells: A potential mechanism for human acute coronary syndrome. Clinical Immunology, 141(2), 152–160. https://doi.org/10.1016/j.clim.2011.07.003.

    Article  CAS  PubMed  Google Scholar 

  42. Ma, T., Gao, Q., Zhu, F., Guo, C., Wang, Q., Gao, F., et al. (2013). Th17 cells and IL-17 are involved in the disruption of vulnerable plaques triggered by short-term combination stimulation in apolipoprotein E-knockout mice. Cellular & Molecular Immunology, 10(4), 338–348. https://doi.org/10.1038/cmi.2013.4.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We are extremely grateful to Late Professor Vijay V Kakkar, Scientific Chairman, Thrombosis Research Institute, Bangalore, for his constant encouragement and support.. The support from Bharathi foundation for Ph.D. students is gratefully acknowledged.

Funding

Research grants were from Tata Social Welfare Trust, India, (TSWT/IG/SNB/JP/Sdm) and Indian Council of Medical Research (ICMR) Government of India (5/4/1-4/11-NCD-II).

Author information

Authors and Affiliations

  1. Research Scholar at Manipal University, Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India

    Thiruvelselvan Ponnusamy

  2. Narayana Institute of cardiac sciences, Bangalore, India

    Srikanth Komarulu Venkatachala

  3. Clinical research unit Thrombosis Research Institute, Bangalore, India

    Manjunatha Ramanujappa

  4. Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India

    Lakshmi Mundkur

  5. Thrombosis Research Institute, Narayana Hrudayalaya, 258/A, Bommasandra Industrial Area, Anekal Taluk, Bangalore, 560099, India

    Lakshmi Mundkur

Authors
  1. Thiruvelselvan Ponnusamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Srikanth Komarulu Venkatachala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manjunatha Ramanujappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lakshmi Mundkur
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study was planned by LM and executed by TP. SKV was the cardiologist who identified and classified the patients, while RM was the clinical coordinator to collect the sample demographic data and follow-up. The draft of the MS was written by TP with inputs from other authors and finally corrected by LM.

Corresponding author

Correspondence to Lakshmi Mundkur.

Ethics declarations

The investigation was approved by the Institutional ethics committees of Thrombosis research Institute and Narayana Hrudayalaya hospital and conformed to the Declaration of Helsinki and the Indian Council of medical research (ICMR, India) guidelines.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

Informed Consent

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

Animal Studies

No animal studies were carried out by the authors for this article.

Additional information

Associate Editor Angela Taylor oversaw the review of this article

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(PDF 606 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ponnusamy, T., Komarulu Venkatachala, S., Ramanujappa, M. et al. Loss of Regulatory Immune Function in Coronary Artery Disease Patients from the Indian Population. J. of Cardiovasc. Trans. Res. 12, 378–388 (2019). https://doi.org/10.1007/s12265-019-09872-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-019-09872-7

Keywords

Search

Navigation