Major and minor lymphocytes subpopulations in peripheral blood and cerebrospinal fluid of children with meningitis

Cover Page


Cite item

Full Text

Abstract

Introduction. The analysis of current publications indicates at our insufficient understanding of subpopulation composition of lymphocytes in peripheral blood and cerebrospinal fluid (CSF) during pediatric neuroinfectious diseases. It has been found that the main lymphocyte populations are divided into many small (minor) subpopulations.

The purpose of this research was to assess percentage of major and minor blood and CSF lymphocyte subsets in children with aseptic viral meningitis (AM) or bacterial purulent meningitis (BM).

Materials and methods. Phenotyping of blood and CSF lymphocytes of children aged from 4 months to 17 years diagnosed with AM (n = 86) and BM (n = 39) was carried out by using flow cytometry. As a comparison group, we analyzed peripheral blood and CSF samples collected from children with acute respiratory viral infections (ARVIs) associated with syndrome of meningism (n = 27). There was evaluated percentage of the major cell subpopulations (CD3+ T-lymphocytes, T-helpers — CD3+CD4+ Th, cytotoxic T-lymphocytes — CD3+CD8+ CTL, natural killer cells — CD3-CD16+CD56+ NK, B-cells — CD3-CD19+), as well as minor lymphocyte subsets (double positive (DP) (CD3+CD4+CD8+), double negative (DN) (CD3+CD4-CD8-) T-cells, NKT (CD3+CD16+CD56+), CD3-CD8+ NK, CD3+CD8dim and CD3+CD8 8bright).

Results. It was found that the acute period of BM and AM vs. the comparison group (ARVI) was characterized by significant differences in the blood and CSF composition of major and minor lymphocyte subsets. In particular, blood T-cells, Th, CTL, NK, NKT, DN, CD3-CD8+ NK, CD3+CD8bright and CD3+CD8dim dominated in parallel with significantly lowered B-cell frequency in AM vs. BM. In the CSF of children with AM, T-cells and Th prevailed, whereas count of B-cells and CD3-CD8+ NK was lower compared to those in BM. In addition, further differences were revealed in CSF and blood cell subset composition depending on nosological entity, while maintaining differences in some major and minor lymphocyte subpopulations lacked in the comparison group. Calculating the CSF/blood ratio for the major and minor lymphocyte subsets uncovered the prevalence for the majority of cell subpopulations (the coefficients ranged from 1.2 to 16.4) in the CSF of the comparison group (ARVI), except B-cells, NK and CD3-CD8+ NK (coefficients ranged from 0.07 to 0.31). AM and BM were featured with various changes in the CSF/blood ratio found for most of the studied subpopulations in the acute period as well as the recovery phase highlighted with characteristic traits for each nosological form.

Conclusion. The data obtained indicate about finding specific features in the activation of systemic and intrathecal immune response during viral and bacterial meningitis in children, which may be used as an additional differential diagnostic criterion.

About the authors

A. A. Zhirkov

Pediatric Research and Clinical Center for Infectious Diseases of the Russian Federal Medical-Biological Agency

Author for correspondence.
Email: ant-zhirkov@yandex.ru
ORCID iD: 0000-0002-7720-2175

Anton A. Zhirkov - Junior Researcher, Department of Clinical Laboratory Diagnostics, PRCCID.

197002, St. Petersburg, Prof. Popova str., 9, Phone: +7 (911) 932-55-32 (mobile) Russian Federation

L. A. Alekseeva

Pediatric Research and Clinical Center for Infectious Diseases of the Russian Federal Medical-Biological Agency

Email: kldidi@mail.ru

PhD, MD (Biology), Head and Leading Researcher of the Department of Clinical Laboratory Diagnostics, PRCCID

St. Petersburg

Russian Federation

G. F. Zheleznikova

Pediatric Research and Clinical Center for Infectious Diseases of the Russian Federal Medical-Biological Agency

Email: zheleznikova.galina@gmail.com

PhD, MD (Medicine), Professor, Senior Researcher, Department of Clinical Laboratory Diagnostics, PRCCID

St. Petersburg

N. V. Sckripchenko

Pediatric Research and Clinical Center for Infectious Diseases of the Russian Federal Medical-Biological Agency; St. Petersburg State Pediatric Medical University

Email: snv@niidi.ru
ORCID iD: 0000-0001-8927-3176

PhD, MD (Medicine), Professor, Deputy Director of Science, PRCCID; Head of the Department of Infectious Diseases of Postgraduate and Continuing Professional Education SPbSPMU of the Ministry of Health of Russia.

St. Petersburg

Russian Federation

N. E. Monakhova

Pediatric Research and Clinical Center for Infectious Diseases of the Russian Federal Medical-Biological Agency

Email: immidi@yandex.ru

Researcher, Department of Clinical Laboratory Diagnostics, PRCCID

St. Petersburg

Russian Federation

T. V. Bessonova

Pediatric Research and Clinical Center for Infectious Diseases of the Russian Federal Medical-Biological Agency

Email: kldidi@mail.ru

Researcher, Department of Clinical Laboratory Diagnostics, PRCCID

St. Petersburg

Russian Federation

References

  1. Акинфиева О.В., Бубнова Л.Н., Бессмельцев С.С. NKT-клетки: характерные свойства и функциональная значимость для регуляции иммунного ответа // Онкогематология. 2010. Т. 5, № 4. C. 39—47.
  2. Алексеева Л.А., Железникова Г.Ф., Жирков А.А., Скрипченко Н.В., Вильниц А.А., Монахова Н.Е., Бессонова Т.В. Субпопуляции лимфоцитов и цитокины в крови и цереброспинальной жидкости при вирусных и бактериальных менингитах у детей // Инфекция и иммунитет. 2016. Т. 6, № 1. С. 33—44. doi: 0.15789/2220-7619-2016-1-33-44
  3. Балмасова И.П., Венгеров Ю.Я., Раздобарина С.Е., Нагибина М.В. Иммунопатогенетические особенности бактериальных гнойных менингитов // Эпидемиология и инфекционные болезни. 2014. Т. 19, № 5. С. 17—22.
  4. Жирков А.А., Алексеева Л.А., Железникова Г.Ф., Монахова Н.Е., Бессонова Т.В. Субпопуляционный состав лимфоцитов цереброспинальной жидкости детей с острой респираторной вирусной инфекцией, протекающей с синдромом менингизма // Медицинская иммунология. 2019. Т. 21, № 6. С. 1033—1042. doi: 10.15789/1563-0625-2019-6-1033-1042
  5. Хайдуков С.В. Малые субпопуляции Т-хелперов (Th наивные тимические, Th наивные центральные, Th9, Th22 и CD4+CD8+ дважды положительные Т-клетки // Медицинская иммунология. 2013. Т. 15, № 6. С. 503—512. doi: 10.15789/1563-0625-2013-6-503-512
  6. Хайдуков С.В., Байдун Л.В. Современные подходы к оценке клеточной составляющей иммунного статуса // Медицинский алфавит. 2015. Т. 2, № 8. С. 44—51.
  7. Ярилин А.А. Иммунология. Москва: ГЭОТАР-Медиа, 2010. 752 c.
  8. Ahmed R.K., Poiret T., Ambati A., Rane L., Remberger M., Omazic B., Vudattu N.K., Winiarski J., Ernberg I., Axelsson-Robertson R., Magalhaes I., Castelli C., Ringden O., Maeurer M. TCR+CD4-CD8- T cells in antigen-specific MHC class I-restricted T-cell responses after allogeneic hematopoietic stem cell transplantation. J. Immunother., 2014, vol. 37, no. 8, pp. 416425. doi: 10.1097/CJI.0000000000000047
  9. Bristeau-Leprince A., Mateo V., Lim A., Magerus-Chatinet A., Solary E., Fischer A., Rieux-Laucat F., Gougeon M.-L. Human TCRa/e+ CD4-CD8- double-negative t cells in patients with autoimmune lymphoproliferative syndrome express restricted Ve TCR diversity and are clonally related to CD8+ t cells. J. Immunol., 2014, vol. 181, no. 1, pp. 440-448. doi: 10.4049/jimmunol.181.1.440
  10. Campbell J.P., Guy K., Cosgrove C., Florida-James G.D., Simpson R.J. Total lymphocyte CD8 expression is not a reliable marker of cytotoxic T-cell populations in human peripheral blood following an acute bout of high-intensity exercise. Brain. Behav. Immun., 2008, vol. 22, no. 3, pp. 375-380. doi: 10.1016/j.bbi.2007.09.001
  11. D’Acquisto F., Crompton T. CD3+CD4-CD8- (double negative) T cells: saviours or villains of the immune response? Biochem. Pharmacol., 2011, vol. 82, no. 4, pp. 333-340. doi: 10.1016/j.bcp.2011.05.019
  12. Das G., Augustine M.M., Das J., Bottomly K., Ray P., Ray A. An important regulatory role for CD4+CD8aa T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. PNAS, 2003, vol. 100, no. 9, pp. 5324-5329. doi: 10.1073/pnas.0831037100
  13. Eller M.A., Goonetilleke N., Tassaneetrithep B., Eller L.A., Costanzo C., Johnson S., Betts M.R., Krebs S.J., Slike B.M., Nitayaphan S., Rono K., Tovanabutra S., Maganga L., Kibuuka H., Jagodzinski L., Peel S., Rolland M., Marovich M.A., Kim J.H., Michael N.L., Robb M.L., Streeck H. Expansion of inefficient HIV-specific CD8+ T cells during acute infection. J. Virol., 2016, vol. 90, no. 8, pp. 4005-4016. doi: 10.1128/JVI.02785-15
  14. Fernandez C.S., Kelleher A.D., Finlayson R., Godfrey D.I., Kent S.J. NKT cell depletion in humans during early HIV infection. Immunol. Cell Biol., 2014, vol. 92, no. 7, pp. 578-590. doi: 10.1038/icb.2014.25
  15. Frahm M.A., Picking R.A., Kuruc J.D., McGee K.S., Gay C.L., Eron J.J., Hicks C.B., Tomaras G.D., Ferrari G. CD4+CD8+ T-cells represent a significant portion of the anti-HIV T-cell response to acute HIV infection. J. Immunol., 2014, vol. 71, no. 11, pp. 3831-3840. doi: 10.4049/jimmunol.1103701
  16. Gianchecchi E., Vittorio D., Fierabracci A. NK cells in autoimmune diseases: linking innate and adaptive immune responses. Autoimmun. Rev., 2018, vol. 17, no. 2, pp. 142-154. doi: 10.1016/j.autrev.2017.11.018
  17. Graaf De M.T., Smitt P.A., Luitwieler R.L., Van Velzen C., Van Den Broek P.D., Kraan J., Gratama J.W. Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry Part B (Clinical Cytometry), 2011, vol. 80, no. 1, pp. 43-50. doi: 10.1002/cyto.b.20542
  18. Hegde S., Chen X., Keaton J.M., Reddington F., Besra G.S., Gumperz J.E. NKT cells direct monocytes into a DC differentiation pathway. J. Leukoc. Biol., 2007, vol. 81, no. 5, pp. 1224-1235. doi: 10.1189/jlb.1206718
  19. Kaiser P., Joos B., Niederost B., Weber R., Gunthard H.F., Fischer M. Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes. J. Virol., 2007, vol. 81, no. 18, pp. 9693-9706. doi: 10.1128/JVI.00492-07
  20. Keir M.E., Rosenberg M.G., Sandberg J.K., Jordan K.A., Wiznia A., Nixon D.F., Stoddart C.A., McCune J.M. Generation of CD3+CD8low thymocytes in the HIV type 1-infected thymus. J. Immunol., 2014, vol. 169, no. 5, pp. 2788-2796. doi: 10.4049/jimmunol.169.5.2788
  21. Kitchen S.G., Jones N.R., LaForge S., Whitmire J.K., Vu B.A., Galic Z., Brooks D.G., Brown S.J., Kitchen C.M., Zack J.A. CD4 on CD8+ T cells directly enhances effector function and is a target for HIV infection. PNAS, 2004, vol. 101, no. 23, pp. 8727-8732. doi: 10.1073/pnas.0401500101
  22. Kowarik M.C., Grummel V., Wemlinger S., Buck D., Weber M.S., Berthele A., Hemmer B. Immune cell subtyping in the cerebrospinal fluid of patients with neurological diseases. J Neurol., 2014, vol. 261, pp. 130-143. doi: 10.1007/s00415-013-7145-2
  23. Kumar V., Terry L. Different subsets of natural killer T cells may vary in their roles in health and disease. Immunology, 2014, vol. 142, no. 3, pp. 321-336. doi: 10.1111/imm.12247
  24. Ligocki A.J., Niederkorn J.Y. Advances on non-CD4+Foxp3+ T regulatory cells: CD8+, type 1, and double negative T regulatory cells in organ transplantation. Transplantation, 2015, vol. 20, no. 2, pp. 163-178. doi: 10.1097/TP.0000000000000813
  25. Lin H., Nieda M., Rozenkov V., Nicol A.J. Analysis of the effect of different NKT cell subpopulations on the activation of CD4 and CD8 T cells, NK cells, and B cells. Exp. Hematol., 2006, vol. 34, no. 3, pp. 289-295. doi: 10.1016/j.exphem.2005.12.008
  26. Marrero I., Ware R., Kumar V. Type II NKT cells in inflammation, autoimmunity, microbial immunity, and cancer. Front. Immunol., 2015, vol. 6, pp. 1-6. doi: 10.3389/fimmu.2015.00316
  27. Ouyang L., Li X., Liang Z., Yang D., Gong F. CD8low T-cell subpopulation is increased in patients with chronic hepatitis B virus infection. Mol. Immunol., 2013, vol. 56, no. 4, pp. 698-704. doi: 10.1016/j.molimm.2013.07.003
  28. Overgaard N.H., Jung J.-W., Steptoe R.J., Wells J.W. CD4+/CD8+ double-positive T cells: more than just a developmental stage? J. Leukoc. Biol., 2015, vol. 97, no. 1, pp. 31-38. doi: 10.1189/jlb.1RU0814-382
  29. Rhost S., Sedimbi S., Kadri N., Cardell S.L. immunomodulatory type II natural killer T Lymphocytes in health and disease. Scand. J. Immunol., 2012, vol. 76, no. 3, pp. 246-255. doi: 10.1111/j.1365-3083.2012.02750.x
  30. Schonrich G., Raftery M.J. CDl-restricted T cells during persistent virus infections: “sympathy for the devil”. Front Immunol., 2018, vol. 9, pp. 1-16. doi: 10.3389/fimmu.2018.00545
  31. Singh A.K., Tripathi P., Cardell S.L. Type II NKT cells: an elusive population with immunoregulatory properties. Front Immunol., 2018, vol. 9, pp. 1-8. doi: 10.3389/fimmu.2018.01969
  32. Torina A., Guggino G., Pio M., Manna L., Sireci G. The Janus face of NKT cell function in autoimmunity and infectious diseases. Int. J. Mol. Sci., 2018, vol. 19, no. 440, pp. 1-10. doi: 10.3390/ijms19020440
  33. Tosano F., Bucciol G., Pantano G., Putti M.C., Sanzari M.C., Basso G., Plebani M. Lymphocytes subsets reference value in childhood. Cytometry Part A, 2015, vol. 87, no. 1, pp. 81-85. doi: 10.1002/cyto.a.22520
  34. Trautmann A., Ruckert B., Schmid-Grendelmeier E., Niederery P., Blaser K., Akdis C.A. Human CD8 T cells of the peripheral blood contain a low CD8 expressing cytotoxic/effector subpopulation. Immunol., 2003, vol. 108, no. 3, pp. 305-312. doi: 10.1046/j.1365-2567.2003.01590.x
  35. Tsunoda I., Tanaka T., Fujinami R.S. Regulatory role of CD1d in neurotropic virus infection. J. Virol., 2008, vol. 82, no. 20, pp. 10279-10289. doi: 10.1128/JVI.00734-08
  36. Tupin E., Kinjo Y., Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat. Rev., 2007, vol. 5, no. 6, pp. 405-417. doi: 10.1038/nrmicro1657
  37. Zajonc D.M., Girardi E. Recognition of microbial glycolipids by natural killer T cells. Front. Immunol., 2015, vol. 6, pp. 1-11. doi: 10.3389/fimmu.2015.00400
  38. Zloza A., Al-Harthi L. Multiple populations of T lymphocytes are distinguished by the level of CD4 and CD8 coexpression and require individual consideration. J. Leukoc. Biol., 2006, vol. 79, no. 1, pp. 4-6. doi: 10.1189/jlb.0805455

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2020 Zhirkov A.A., Alekseeva L.A., Zheleznikova G.F., Sckripchenko N.V., Monakhova N.E., Bessonova T.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies