Abstract
Background
Acute coronary syndrome (ACS) is a complex cardiovascular disease whose development involves the dysregulation of adaptive immune responses. Though it has been proven that T cells associate with inflammation in the development of ACS, the function of B cells in disease remains unclear.
Objective
The aim of this study was to reveal the diversity of the B cell receptor (BCR) repertoire of patients with ACS.
Methods
We conducted a pilot study to sequence the immune repertoire of peripheral blood mononuclear cells (PBMCs) from patients with ACS, including acute myocardial infarction (AMI) and unstable angina (UA), and quantitatively characterized BCR repertoires by bioinformatics analysis.
Results
We found that patients with AMI and UA had lower BCR repertoire diversity compared with controls with normal coronary arteries (NCA). Lower percentages of productive unique BCR nt sequences and higher percentages of top 200 unique BCR sequences were identified in AMI and UA patients than NCA controls. Patients had various preferential usage of V and J genes from B cell clones in accordance with the disease severity of coronary arteries. AMI patients had distinct CDR3 amino acids, and their frequency differed among patients with ACS.
Conclusions
Our results indicate that differential BCR signatures represent an imprint of distinct repertoires among ACS patients. This study thereby opens up the prospect of studying disease-relevant B cells to better understand and treat ACS.
Similar content being viewed by others
Data availability
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
References
Ait-Oufella H, Herbin O, Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L, Taleb S, Van Vré E, Esposito B, Vilar J et al (2010) B cell depletion reduces the development of atherosclerosis in mice. J Exp Med 207:1579–1587
Allan GM, Nouri F, Korownyk C, Kolber MR, Vandermeer B, McCormack J (2013) Agreement among cardiovascular disease risk calculators. Circulation 127:1948–1956
Bashford-Rogers RJM, Smith KGC, Thomas DC (2018) Antibody repertoire analysis in polygenic autoimmune diseases. Immunology 155:3–17
Beltrán E, Obermeier B, Moser M, Coret F, Simó-Castelló M, Boscá I, Pérez-Miralles F, Villar LM, Senel M, Tumani H et al (2014) Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain 137:2703–2714
Bolotin DA, Poslavsky S, Mitrophanov I, Mamedov IZ, Putintseva EV, Chudakov DM, Shugay M (2015) MiXCR: software for comprehensive adaptive immunity profiling. Nat Methods 12:380–381
Caligiuri G, Nicoletti A, Poirier B, Hansson GK (2002) Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 109:745–753
Crea F, Liuzzo G (2013) Pathogenesis of acute coronary syndromes. J Am Coll Cardiol 61:1–11
Damman P, van ‘t Hof AW, Ten Berg JM, Jukema JW, Appelman Y, Liem AH, de Winter RJ (2017) 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: comments from the Dutch ACS working group. Neth Heart J 25:181–185
Fiskesund R, Stegmayr B, Hallmans G, Vikström M, Weinehall L, de Faire U, Frostegård J (2010) Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden. Stroke 41:607–612
Georgiou G, Ippolito GC, Beausang J, Busse CE, Wardemann H, Quake SR (2014) The promise and challenge of high-throughput sequencing of the antibody repertoire. Nat Biotechnol 32:158–168
Giudicelli V, Lefranc MP (2011) IMGT/junctionanalysis: IMGT standardized analysis of the V-J and V-D-J junctions of the rearranged immunoglobulins (IG) and T cell receptors (TR). Cold Spring Harb Protoc 2011:716–725
Grönwall C, Akhter E, Oh C, Burlingame RW, Petri M, Silverman GJ (2012) IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE. Clin Immunol 142:390–398
Jackson KJ, Kidd MJ, Wang Y, Collins AM (2013) The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor. Front Immunol 4:263
Kyaw T, Tay C, Khan A, Dumouchel V, Cao A, To K, Kehry M, Dunn R, Agrotis A, Tipping P et al (2010) Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J Immunol 185:4410–4419
Kyaw T, Tay C, Hosseini H, Kanellakis P, Gadowski T, MacKay F, Tipping P, Bobik A, Toh BH (2012) Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PLoS One 7:e29371
Kyaw T, Cui P, Tay C, Kanellakis P, Hosseini H, Liu E, Rolink AG, Tipping P, Bobik A, Toh BH (2013) BAFF receptor mAb treatment ameliorates development and progression of atherosclerosis in hyperlipidemic ApoE(-/-) mice. PLoS One 8:e60430
Laslett LJ, Alagona P Jr, Clark BA 3rd, Drozda JP Jr, Saldivar F, Wilson SR, Poe C, Hart M (2012) The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 60:S1–S49
Ley K, Miller YI, Hedrick CC (2011) Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 31:1506–1516
Liaskou E, Klemsdal Henriksen EK, Holm K, Kaveh F, Hamm D, Fear J, Viken MK, Hov JR, Melum E, Robins H et al (2016) High-throughput T-cell receptor sequencing across chronic liver diseases reveals distinct disease-associated repertoires. Hepatology 63:1608–1619
Libby P (2013) Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 368:2004–2013
Libby P, Nahrendorf M, Swirski FK (2013) Monocyte heterogeneity in cardiovascular disease. Semin Immunopathol 35:553–562
Libby P, Tabas I, Fredman G, Fisher EA (2014) Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867–1879
Liu S, Zhong Z, Zhong W, Weng R, Liu J, Gu X, Chen Y (2020) Comprehensive analysis of T-cell receptor repertoire in patients with acute coronary syndrome by high-throughput sequencing. BMC Cardiovasc Disord 20:253
Liuzzo G, Montone RA, Gabriele M, Pedicino D, Giglio AF, Trotta F, Galiffa VA, Previtero M, Severino A, Biasucci LM et al (2013) Identification of unique adaptive immune system signature in acute coronary syndromes. Int J Cardiol 168:564–567
Magoč T, Salzberg SL (2011) FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics 27:2957–2963
Müller C (2012) New ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Swiss Med Wkly 142:w13514
Saeed A, Kampangkaew J, Nambi V (2017) Prevention of Cardiovascular Disease in Women. Methodist Debakey Cardiovasc J 13:185–192
Sage AP, Tsiantoulas D, Binder CJ, Mallat Z (2019) The role of B cells in atherosclerosis. Nat Rev Cardiol 16:180–196
Słomka A, Korbal P, Piekuś A, Pawliszak W, Anisimowicz L, Żekanowska E (2017) Plasma levels of the A subunit of factor XIII in patients undergoing off-pump coronary artery bypass surgery. Pol Arch Intern Med 127:550–553
Słomka A, Piekuś A, Kowalewski M, Pawliszak W, Anisimowicz L, Żekanowska E (2018) Assessment of the Procoagulant Activity of Microparticles and the Protein Z System in Patients Undergoing Off-Pump Coronary Artery Bypass Surgery. Angiology 69:347–357
Smith SC Jr, Collins A, Ferrari R, Holmes DR Jr, Logstrup S, McGhie DV, Ralston J, Sacco RL, Stam H, Taubert K et al (2012) Our time: a call to save preventable death from cardiovascular disease (heart disease and stroke). Circulation 126:2769–2775
Tipton CM, Fucile CF, Darce J, Chida A, Ichikawa T, Gregoretti I, Schieferl S, Hom J, Jenks S, Feldman RJ et al (2015) Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. Nat Immunol 16:755–765
Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ (2014) B cells and humoral immunity in atherosclerosis. Circ Res 114:1743–1756
Tsimikas S, Willeit P, Willeit J, Santer P, Mayr M, Xu Q, Mayr A, Witztum JL, Kiechl S (2012) Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 60:2218–2229
Zhang W, Du Y, Su Z, Wang C, Zeng X, Zhang R, Hong X, Nie C, Wu J, Cao H et al. (2015) IMonitor: A Robust Pipeline for TCR and BCR Repertoire Analysis. Genetics 201:459-472
Zhang S, Zhang S, Lin Z, Zhang X, Dou X, Zhou X, Wang X, Wang Z, Zhang Q (2021) Deep sequencing reveals 10 the skewed B-cell receptor repertoire in plaques and the association between pathogens and atherosclerosis. Cell Immunol 360:104256
Acknowledgements
The author would like to thank other colleagues whom were not listed in the authorship of Center for Cardiovascular Diseases and Center for Precision Medicine, Meizhou People’s Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University for their helpful comments on the manuscript.
Funding
This study was supported by Key Scientific and Technological Project of Meizhou People’s Hospital, (Grant No.: MPHKSTP-20170101 and MPHKSTP-20180101 to MD Zhixiong Zhong), Science and Technology Program of Meizhou (Grant No.:2018B027 to Dr Sudong Liu), the Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population (Grant No.:2018B030322003).
Author information
Authors and Affiliations
Contributions
RQW and ZXZ conceived and designed the experiments; recruited subjects and collected clinical data were performed by SDL and XDG. Data analysis and manuscript writing were performed by RQW and SDL. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of the Meizhou People’s Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou 514031, P. R. China (No.: MPH-HEC 2016-A-43). Written informed consent was obtained from each patient..
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Weng, R., Liu, S., Gu, X. et al. Characterization of the B cell receptor repertoire of patients with acute coronary syndrome. Genes Genom 44, 19–28 (2022). https://doi.org/10.1007/s13258-021-01110-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13258-021-01110-2