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BioNanoScience

, Volume 8, Issue 2, pp 647–653 | Cite as

Changes in HLA-DR Expression on Monocytes and Lymphocytes in Neonatal Sepsis

  • Khalit S. Khaertynov
  • Vladimir A. Anokhin
  • Ilshat G. Mustafin
  • Albert A. Rizvanov
  • Sergey A. Lubin
  • Asiya Kh. Khaertynova
  • Svetlana A. Sofronova
Article

Abstract

HLA-DR is a key marker of leukocyte activation, which suppression determines the effectiveness of immune response and prognosis in neonatal sepsis (NS). The aim of this study was to evaluate the HLA-DR expression on lymphocytes and monocytes in the peripheral blood of neonates with sepsis. The study involved 21 neonates with sepsis and 10 healthy neonates born during the study period. Bacteremia was detected in five cases (24%). The most frequent pathogens found were Klebsiella pneumoniae (n = 2) and Staphylococcus aureus (n = 2) followed by Streptococcus agalactae (n = 1). NS was associated with pneumonia (n = 17), meningitis (n = 3), and necrotizing enterocolitis (n = 1). The onset of NS was accompanied with high blood monocyte activity which ranged from 96 to 100%. Blood CD3+ lymphocyte population and CD4+ and CD8+ lymphocyte subset levels were decreased, with their median values being 1.7, 2.2, and 2.4 times lower than those in the control group, respectively (р = 0.005, р = 0.0002, р = 0.003). The HLA-DR expression on CD3+ lymphocytes, as well as on CD4+ and CD8+ lymphocyte subsets, was extremely low ranging from 0.1 to 7% both in the onset of the disease and in a week after admission to a hospital. Absolute counts of activated CD4+ and CD8+ lymphocyte subsets were significantly lower on the disease first days as compared to the control group (р = 0.02 and р = 0.003, respectively). These results demonstrate adaptive immunity to be non-effective in neonates with sepsis. Low expression of HLA-DR on CD3 lymphocytes as well as on CD4 and CD8 lymphocyte subsets is a reason for immunostimulating therapy.

Keywords

Neonatal sepsis Monocytes Lymphocytes HLA-DR 

Notes

Funding Information

This study was supported by the Russian Government Program of Competitive Growth of the Kazan Federal University. Albert A. Rizvanov was supported by the state assignment 20.5175.2017/6.7 of the Ministry of Education and Science of the Russian Federation.

Compliance with Ethical Standards

The Ethics Committee of the City Children’s Hospital approved this study, and a written informed consent was obtained from the parents in accordance with the principles authorized under this protocol (the Federal Law N323-FL dated on 21.11. 2011 “On Protection of Health of the Citizens in the Russian Federation”).

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Liu, L., Oza, S., Hogan, D., et al. (2016). Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet, 388(10063), 3027–3035.CrossRefGoogle Scholar
  2. 2.
    Camacho-Gonzales, A., Spearman, P. W., & Stoll, B. J. (2013). Neonatal infectious diseases: evaluation of neonatal sepsis. Pediatric Clinics of North America, 60, 367–389.CrossRefGoogle Scholar
  3. 3.
    Wynn, J. L. (2016). Defining neonatal sepsis. Current Opinion in Pediatrics, 28, 135–140.CrossRefGoogle Scholar
  4. 4.
    Hotchkiss, R. S., Coopersmith, G. M., McDunn, J. E., & Ferguson, T. A. (2009). Nature Medicine, 15(5), 496–497.CrossRefGoogle Scholar
  5. 5.
    Boomer, J. S., Green, J. M., & Hotchkiss, R. S. (2014). The changing immune system in sepsis: is individualized immune-modulatory therapy the answer? Virulence, 5(1), 45–56.CrossRefGoogle Scholar
  6. 6.
    Reinhart, K., Bauer, M., Riedemann, N. C., et al. (2012). New approaches to sepsis: molecular diagnostics and biomarkers. Clinical Microbiology Reviews, 25(4), 609–634.CrossRefGoogle Scholar
  7. 7.
    Bhandari, V. (2014). Effective biomarkers for diagnosis of neonatal Sepsis. Journal of the Pediatric Infectious Diseases Society, 3(3), 234–245.CrossRefGoogle Scholar
  8. 8.
    Shah, B. A., & Padbury, J. F. (2014). Neonatal sepsis: an old problem with new insights. Virulence, 54, 449–457.Google Scholar
  9. 9.
    Venet, F., Lepape, A., & Monneret, G. (2011). Clinical review: flow cytometry perspectives in the ICU—from diagnosis of infection to monitoring of injury-induced immune dysfunctions. Critical Care, 15, 231.CrossRefGoogle Scholar
  10. 10.
    Gille, C., & Orlikowsky, T. W. (2007). Flow cytometric methods in the detection of neonatal infection. Transfusion Medicine and Hemotherapy, 34, 157–163.CrossRefGoogle Scholar
  11. 11.
    Monneret, G., & Venet, F. (2014). Monocyte HLA-DR in sepsis: shall we stop following the flow? Critical Care, 18, 102.  https://doi.org/10.1186/cc13179.CrossRefGoogle Scholar
  12. 12.
    Zhuang, Y., Peng, H., Chen, Y., et al. (2017). Dynamic monitoring of monocyte HLA-DR expression for the diagnosis, prognosis, and prediction of sepsis. Frontiers in Bioscience Landmark, 22, 1344–1354.CrossRefGoogle Scholar
  13. 13.
    Monneret, G. (2005). How to identify systemic sepsis-induced immunoparalysis. Advances in Sepsis, 4(2), 42–49.Google Scholar
  14. 14.
    Wu, J.-F., Ma, J., Chen, J., et al. (2011). Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Critical Care, 15, R220.CrossRefGoogle Scholar
  15. 15.
    Rimmele, T., Payen, D., Cantaluppi, V., et al. (2016). Immune cell phenotype and function in sepsis. Shock, 45(3), 282–291.CrossRefGoogle Scholar
  16. 16.
    Litvinova, L. S., Gutsol, A. A., Sokhonevich, N. A., et al. (2014). Basic surface markers of functional activity T-lymphocytes. Medical Immunology (Russia), 16(1), 7–26.CrossRefGoogle Scholar
  17. 17.
    Rossi, P., Botgros, R., Tibby S. et al. (2010). Report on the Expert Meeting on Neonatal and Paediatric Sepsis. London: European Medicines Agency, http://www.ema.europa.eu/docs/enGB/documentlibrary/Report/2010/12/WC500100199.pdf.
  18. 18.
    Rundolph, A. G., & Mc Culloh, R. J. (2014). Pediatric sepsis. Virulence, 5(1), 179–189.CrossRefGoogle Scholar
  19. 19.
    Hotchkiss, R. S., & Karl, I. E. (2003). The pathophysiology and treatment of sepsis. The New England Journal of Medicine, 348(2), 138–150.CrossRefGoogle Scholar
  20. 20.
    Perez, A., Bellon, J. M., Gurbindo, M. D., et al. (2010). Impairment of stimulation ability of very-preterm neonatal monocytes in response to lipopolysaccharide. Human Immunology, 71, 151–157.CrossRefGoogle Scholar
  21. 21.
    Frazier, W. J., & Hall, M. W. (2008). Immunoparalysis and adverse outcomes from critical illness. Pediatric Clinics of North America, 55, 647–668.CrossRefGoogle Scholar
  22. 22.
    Monneret, G., Elmenkouri, N., Bohe, J., et al. (2002). Analytical requirements for measuring monocytic HLA-DR by flow cytometry. Clinical Chemistry, 48, 1589–1592.Google Scholar
  23. 23.
    Wolk, K., Kunz, S., Crompton, N. E., et al. (2003). Multiple mechanisms of reduced major histocompatibility complex class II expression in endotoxin tolerance. The Journal of Biological Chemistry, 278(20), 18030–18036.CrossRefGoogle Scholar
  24. 24.
    Monneret, G., Lepape, A., Voirin, N., et al. (2006). Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Medicine, 32(8), 1175–1183.CrossRefGoogle Scholar
  25. 25.
    Drewry, A. M., Ablordeppey, E. A., Murray, E. T., et al. (2016). Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Critical Care, 20, 334.CrossRefGoogle Scholar
  26. 26.
    Monserrat, J., de Pablo, R., Diaz-Martín, D., et al. (2013). Early alterations of B cells in patients with septic shock. Critical Care, 17(3), R105.CrossRefGoogle Scholar
  27. 27.
    Capasso, L., Borrelli, A. C., Cerullo, J., et al. (2015). Role of immunoglobulins in neonatal sepsis. Translational Medicine, 11(5), 28–33.Google Scholar
  28. 28.
    Hotchkiss, R. S., Osmon, S. B., Chang, K. C., et al. (2005). Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. The Journal of Immunology, 174, 5110–5118.CrossRefGoogle Scholar
  29. 29.
    Khaertynov Kh., S., Boichuk, S. V., Anohin, V. A., et al. (2014). Activity rates of apoptosis of lymphocytes in children with neonatal sepsis. Geny i kletki, 9(3), 267–271.Google Scholar
  30. 30.
    Khaertynov Kh., S., Anohin, V. A., Mustafin, I. G., et al. (2015). Specific features of immunity in neonatal infants with localized and generalized bacterial infections. Russian Bulletin of Perinatology and Pediatrics, 5, 168–173.Google Scholar
  31. 31.
    Boomer, J. S., To, K., Chang, K. C., et al. (2011). Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA, 306, 2594–2605.CrossRefGoogle Scholar
  32. 32.
    Toti, P., De Felice, C., Occhini, R., et al. (2004). Spleen depletion in neonatal sepsis and chorioamnionitis. American Journal of Clinical Pathology, 122, 765–771.CrossRefGoogle Scholar
  33. 33.
    Felmet, K. A., Hall, M. W., Clark, R. S., et al. (2005). Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. Journal of Immunology, 174, 3765–3772.CrossRefGoogle Scholar
  34. 34.
    Cabrera-Perez, J., Condotta, S. A., Badovinac, V. P., et al. (2014). Impact of sepsis on CD4 T cell immunity. Journal of Leukocyte Biology, 96(5), 767–777.CrossRefGoogle Scholar
  35. 35.
    Wilson, C. B., Rowell, E., & Sekimata, M. (2009). Epigenetic control of T-helper cell differentiation. Nature Reviews Immunology, 9, 91–105.CrossRefGoogle Scholar
  36. 36.
    Boomer, J. C., Shuherk-Shaffer, J., Hotchkiss, R. S., et al. (2012). A prospective analysis of lymphocytes phenotype and function over the course of acute sepsis. Critical Care, 16, R112.CrossRefGoogle Scholar
  37. 37.
    Wesche, D. E., Lomas-Neira, J. L., Perl, M., et al. (2005). Leukocyte apoptosis and its significance in sepsis and shock. Journal of Leukocyte Biology, 78, 325–337.CrossRefGoogle Scholar
  38. 38.
    Venet, F., Foray, A.-P., Villars-Mechin, A., et al. (2012). IL-7 restores lymphocytes function in septic patients. Journal of Immunology, 189(10), 5073–5081.CrossRefGoogle Scholar
  39. 39.
    Holub, M., Kluckova, Z., Beneda, B., et al. (2000). Changes in lymphocyte subpopulations and CD3+/DR+ expression in sepsis. Clinical Microbiology and Infection, 6, 657–660.CrossRefGoogle Scholar
  40. 40.
    Delano, M. J., & Ward, P. A. (2016). Sepsis-induced immune dysfunction: can immune therapies reduce mortality? The Journal of Clinical Investigation, 126(1), 23–31.CrossRefGoogle Scholar
  41. 41.
    Walker, J. C., Smolders, M. A., Gemen, E. F., et al. (2011). Development of lymphocyte subpopulations in preterm infants. Scandinavian Journal of Immunology, 73, 53–58.CrossRefGoogle Scholar
  42. 42.
    Correa-Rocha, R., Perez, A., Lorente, R., et al. (2012). Preterm neonates show marked leukopenia and lymphopenia that are associated with increased regulatory T-cell values and diminished IL-7. Pediatric Research, 71(5), 590–597.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Khalit S. Khaertynov
    • 1
  • Vladimir A. Anokhin
    • 1
  • Ilshat G. Mustafin
    • 2
  • Albert A. Rizvanov
    • 3
  • Sergey A. Lubin
    • 4
  • Asiya Kh. Khaertynova
    • 5
  • Svetlana A. Sofronova
    • 3
  1. 1.Department of Children Infectious DiseasesKazan State Medical UniversityKazanRussia
  2. 2.Department of BiochemistryKazan State Medical UniversityKazanRussia
  3. 3.Institute of Fundamental Medicine and BiologyKazan (Volga Region) Federal UniversityKazanRussia
  4. 4.Neonatal Intensive Care UnitCity Children’s Hospital No.1KazanRussia
  5. 5.Kazan State Medical UniversityKazanRussia

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