LYMPHOCYTE SUBSETS AND CYTOKINES IN BLOOD AND CEREBROSPINAL FLUID IN CHILDREN WITH VIRAL AND BACTERIAL MENINGITIS

Cover Page

Cite item

Abstract

Introduction of flow cytometry caused an increase in the investigation of liquor lymphocyte pool phenotype in the case of different brain disorders, including viral and bacterial meningitis, however this type of research in children has been relatively rare. Phenotype and lymphocyte functions are under cytokine control system, therefore detection of interconnections between lymphocyte pool subpopulation composition and cytokine level in blood and liquor of the patients concerns a great interest. The purpose of this research was to study lymphocyte subpopulation composition and the level of cytokines IL-1β, IL-6, IL-8, IL-10, IFNα, IFNγ and IL-4, and also IgG in liquor and blood of children with viral and bacterial meningitis. There was performed blood and liquor investigation in 46 children aged from 1 to 16 years old with viral (n = 35) and bacterial (n = 11) meningitis. Immunophenotyping of blood and liquor cells was performed by the method of flow cytometry with the use of monoclonal antibodies to CD3, CD4, CD8, CD19, CD16, CD56, CD25 and CD95. The content of cytokines was detected in ELISA, and that of IgG — by the method of quantitative immunoturbodimetry. During an acute period of viral meningitis there was detected a decrease in NK portion and activated CD25+ cells in the blood of patients accompanied by the increase in B-lymphocytes number, along with cytokine IFNγ, IL-8 and IL-10 serum level rise. There was determined T-lymphocytes accumulation in liquor with the prevalence of CD4+ Т-cells and, to a lesser degree, CD25+ and CD95+ cells, NK and B-lymphocytes. Intrathecally there was noted the predominance of IL-6 response accompanied by the growth of IL-8 and IL-10 concentration as well. During an acute period of bacterial meningitis there was noted a decrease in percentage of CD3+, CD4+, CD8+ Т-lymphocytes, NK, CD25+ and CD95+ cells, along with, on the contrary, sharp increase in B-cells pool, simultaneously with an expressed system response of IL-8 and IL-10. Liquor T-lymphocyte content was relatively correlated with blood indicators whereas the fraction of NK exceeded it, and B-lymphocyte content was 3–4 times higher than in patients with viral meningitis. There was IL-6, IL-10, IFNγ and IL-4 response intrathecally, and 10-multiply-growth of IgG level. Thus, the redistribution of lymphocyte subpopulations, and system and local cytokine response in children with meningitis have both common and special features depending on the aetiology and severity of disease. Phenotyping of lymphocytes and determination of both cytokines and immunoglobulins simultaneously in two biologic fluid allow to clear up the pathogenetic value of immunologic abnormalities in blood and cerebrospinal fluid of the patients in the aspect of interactions between cell and humoral factors of system and local immune response in neuroinfections of various aetiology.

About the authors

L. A. Alekseeva

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Email: fake@neicon.ru

PhD, MD (Biology), Head and Leading Researcher, Department of Clinical Laboratory Diagnostics, Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Russian Federation

G. F. Zheleznikova

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Author for correspondence.
Email: zheleznikova.galina@gmail.com

PhD, MD (Medicine), Professor, Senior Researcher, Department of Clinical Laboratory Diagnostic, Scientific Research Institute of Children’s Infection, St. Petersburg, Russian Federation 197002, Russian Federation, St. Petersburg, Prof. Popova str., 9, Phone: +7 905 267-41-32 (mobile).

Russian Federation

A. A. Zhirkov

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Email: fake@neicon.ru

Junior Researcher, Department of Clinical Laboratory Diagnostics, Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Russian Federation

N. V. Skripchenko

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Email: fake@neicon.ru

PhD, MD (Medicine), Professor, Deputy Director of Science, Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Russian Federation

A. A. Vilnits

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Email: fake@neicon.ru

PhD, Senior Researcher, Department of Neuroinfections and Organic Pathology of Nervous System, Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Russian Federation

N. E. Monakhova

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Email: fake@neicon.ru

Researcher, Department of Clinical Laboratory Diagnostics, Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Russian Federation

T. V. Bessonova

Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Email: fake@neicon.ru

Researcher, Department of Clinical Laboratory Diagnostics, Scientific Research Institute of Children’s Infections, St. Petersburg, Russian Federation

Russian Federation

References

  1. Алексеева Л.А., Мазаева Е.М., Скрипченко Н.В., Монахова Н.Е., Бессонова Т.В. Цитокины в цереброспинальной жидкости при менингитах у детей // Журнал инфектологии. 2014. Т. 6, № 1. С. 54–59. [Alekseyeva L.A., Mazayeva E.M., Skripchenko N.V., Monakhova N.E., Bessonova T.V. Cytokines in cerebrospinal fluid in the case of meningitis in children. Zhurnal infektologii = Journal of Infectology, 2014, vol. 6, no. 1, pp. 54–59. (In Russ.)]
  2. Железникова Г.Ф. Роль гамма-интерферона в иммунопатогенезе инфекций (обзор) // Клиническая лабораторная диагностика. 2008. № 4. С. 3–8. [Zheleznikova G.F. The role of gamma-interferon in immunopathogenesis of infections. Klinicheskaya laboratornaya diagnostika = Clinical Laboratory Diagnostics, 2008, no. 4, pp. 3–8. (In Russ.)]
  3. Железникова Г.Ф. Цитокины как предикторы течения и исхода инфекций (обзор) // Цитокины и воспаление. 2009. Т. 8, № 1. С. 10–17. [Zheleznikova G.F. Cytokines as predictors of infection course and outcome. Tsitokiny i vospalenie = Cytokines and Inflammation, 2009, vol. 8, no. 1, pp. 10–17. (In Russ.)]
  4. Железникова Г.Ф., Скрипченко Н.В. Иммунопатогенез инфекционно-воспалительных заболеваний ЦНС (обзор) // Журнал инфектологии. 2011. Т. 3, № 2. С. 28–32. [Zheleznikova G.F., Skripchenko N.V. Immunopathogenesis of infectiousinflammatory diseases of central nervous system. Zhurnal infektologii = Journal of Infectology, 2011, vol. 3, no. 2, pp. 28–32. (In Russ.)]
  5. Железникова Г.Ф., Скрипченко Н.В., Моргацкий Н.В., Монахова Н.Е., Керимова Л.В. Иммунопатогенетические особенности клещевого энцефалита у детей и эффект терапии // Нейроиммунология. 2008. Т. 6, № 1–2. С. 13–22. [Zheleznikova G.F., Skripchenko N.V., Morgatsky N.V., Monachova N.E., Kerimova L.V. Immunopathogenesis of tick-borne encephalitis (TBE) in children and effects of therapy. Neiroimmunologiya = Neuroimmunology, 2008, vol. 6, no. 1–2, pp. 13–22. (In Russ.)]
  6. Железникова Г.Ф., Иванова В.В., Васякина Л.И., Монахова Н.Е., Бехтерева М.К. Иммунный ответ при остром псевдотуберкулезе у детей // Медицинская иммунология. 2002. Т. 4, № 1. С. 45–58. [Zheleznikova G.F., Ivanova V.V., Vasjakina L.I., Monachova N.E., Bechtereva M.K. Immune response in children with acute pseudotuberculosis. Meditsinskaya immunologiya = Medical Immunology (Russia), 2002, vol. 4, no. 1, pp. 45–58. (In Russ.)]
  7. Железникова Г.Ф., Скрипченко Н.В. Факторы иммунной защиты в цереброспинальной жидкости при вирусных инфекциях ЦНС (обзор) // Журнал неврологии и психиатрии им. С.С. Корсакова. 2012. № 4. С. 61–66. [Geleznikova G.F., Skripchenko N.V. Factors of immune defense in the cerebrospinal fluid in viral infections of the central nervous system. Zhurnal nevrologii i psihiatrii im. S.S.Korsakova = Journal of Neurology and Psychiatry named after S.S. Korsakov, 2012, no. 4, pp. 61–66. (In Russ.)]
  8. Иванова В.В., Железникова Г.Ф., Аксенов О.А., Насыров Р.А., Александрова Н.В., Левина А.С., Монахова Н.Е. Инфекционный мононуклеоз: клиника, патогенез, новое в диагностике и терапии // Инфекционные болезни. 2004. Т. 2, № 4. С. 5–12. [Ivanova V.V., Zheleznikova G.F., Aksenov O.A., Nasyrov R.A., Aleksandrova N.V., Levina A.S., Monakhova N.E. Infectious mononucleosis: clinical course, pathogenesis, novel in diagnostics and therapy. Infektsionnye bolezni = Infectious Diseases, 2004, vol. 2, no. 4, pp. 5–12. (In Russ.)]
  9. Краснова Е.И., Васюнин А.В. Особенности иммунного ответа при инфекционном мононуклеозе у детей и подходы к иммуномодулирующей терапии циклофероном // Профилактическая и клиническая медицина. 2005. Т. 6, № 1. С. 76–82. [Krasnova E.I., Vasyunin A.V. Special features of immune responses in children with infectious mononucleosis and the approaches to immunomodulating therapy by cyclopheronum. Profilakticheskaya i klinicheskaya medicina = Preventive and Clinical Medicine, 2005, vol. 6, no. 1, pp. 76–82. (In Russ.)]
  10. Крылова Н.В., Леонова Г.Н., Павленко Е.В., Запорожец Т.С., Смолина Т.П., Гажа А.К., Новиков Д.В., Ченцова И.В. Комплексная оценка состояния иммунной системы при различных формах клещевого энцефалита в остром периоде // Медицинская иммунология. 2012. Т. 14, № 4–5. С. 313–320. [Krylova N.V., Leonova G.N., Pavlenko E.V., Zaporozhets T.S., Smolina T.P., Gazha A.K., Novikov D.V., Chenzova I.V. Comprehensive assessment of immune system in various forms of tick-borne encephalitis in acute phase. Meditsinskaya immunologiya = Medical Immunology (Russia), 2012, vol. 14, no. 4–5, pp. 313–320. doi: 10.15789/1563-0625-2012-4-5-313-320 (In Russ.)]
  11. Лагерева Ю.Г., Меньшиков С.В., Савинова Т.Л., Бейкин Я.Б., Черешнев В.А. Оценка содержания различных Т-эффекторных субпопуляций у детей и взрослых методом внутриклеточного окрашивания цитокинов // Медицинская иммунология. 2012. Т. 14, № 4–5. С. 295–304. [Lagereva Yu.G., Menshikov S.V., Savinova T.L., Beykin J.B., Chereshnev V.A. Evaluation of T-cell effector subpopulations distribution in children and adults by means of intracellular staining of cytokines. Meditsinskaya immunologiya = Medical Immunology (Russia), 2012, vol. 14, no. 4–5, pp. 295–304. doi: 10.15789/1563-0625-2012-
  12. -5-295-304 (In Russ.)]
  13. Литвинова Л.С., Гуцол А.А., Сохоневич Н.А., Кофанова К.А., Хазиахматова О.Г., Шуплецова В.В., Кайгородова Е.В., Гончаров А.Г. Основные поверхностные маркеры функциональной активности Т-лимфоцитов (обзор) // Медицинская иммунология. 2014. Т. 16, № 1. С. 7–26. [Litvinova L.S., Gutsol A.A., Sokhonevich N.A., Kofanova K.A., Khaziakhmatova O.G., Shupletsova V.V., Kaigorodova E.V., Goncharov A.G. Basic surface markers of functional activity T-lymphocytes. Meditsinskaya immunologiya = Medical Immunology (Russia), 2014, vol. 16, no. 1, pp. 7–26. doi: 10.15789/1563-0625-2014-1-7-26 (In Russ.)]
  14. Нейроинфекции у детей / Под ред. Н.В. Скрипченко. СПб.: Тактик-Студио, 2015. 856 с. [Nejroinfekcii u detej [Nervous system infections in children] / Ed. by Skripchenko N.V. St. Petersburg: Taktik-Studio, 2015. 856 p. (In Russ.)]
  15. De Graaf M., Smitt P., Luitwieler R., van Vetzen Z., van den Broek P.D., Kraan J., Gratama J.W. Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry Part B, 2011, vol. 80B, Iss. 1, pp. 43–50. doi: 10.1002/cyto.b.20542
  16. Han S., Lin Y., Wu T., Salgado A., Mexhitaj I., Wuest S., Romm E., Ohayon J., Goldbach-Mansky R., Vanderver A., Marques A., Toro C., Williamson P., Cortese I., Bielekova B. Comprehensive immunophenotyping of cerebrospinal fluid cells in patients with neuroimmunological diseases. J. Immunol., 2014, vol. 192, no. 6, pp. 2551–2563. doi: 10.4049/jimmunol.1302884
  17. Ichiyama T., Maeba S., Suenaga N., Saito K., Matsubara T., Furukawa S. Analysis of cytokine levels in cerebrospinal fluid in mumps meningitis: comparison with echovirus type 30 meningitis. Cytokine, 2005, vol. 30, no. 5, pp. 243–247.
  18. Ichiyama T., Kajimoto M., Matsushige T., Shiraishi M., Suzuki Y., Furukawa S. Mononuclear cell subpopulations in CSF and blood of children with bacterial meningitis. J. Infect., 2009, vol. 58, no. 1, pp. 28–31. doi: 10.1016/j.jinf.2008.10.012
  19. Kivisäkk P., Mahad D., Callahan M., Trebst C., Tucky B., Wei T., Wu L., Baekkevold E., Lassmann H., Staugaitis S., Campbell J., Ransohoff R. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl. Acad. Sci. USA, 2003, vol. 100, no. 14, pp. 8389–8394.
  20. Kowarik M., Grummel V., Vemlinger S., Buck D., Weber M., Berthele A., Hemmer B. Immune cell subtyping in the cerebrospinal fluid of patients with neurological diseases. J. Neurol., 2014, vol. 261, no. 1, pp. 130–143. doi: 10.1007/s00415-013-7145-2
  21. Lepej S., Tesovic G., Sternak S., Jeren T. Naive and memory CD4+ T-cells in the cerebrospinal fluid of children with aseptic meningitis following measles-mumps-rubella vaccination and enteroviral meningitis. Immunol. Invest., 2007, vol. 36, no. 3, pp. 321–335. doi: 10.1080/08820130601069855
  22. Matsubara T., Matsuoka T., Katayama K., Yoshitomi T., Nishikawa M., Ichiyama T., Furukawa S. Mononuclear cells and cytokines in the cerebrospinal fluid of echovirus 30 meningitis patients. Scand. J. Infect. Dis., 2000, vol. 32, no. 5, pp. 471–474.
  23. Maxeiner H., Rojewski M., Schmitt A., Tumani H., Bechter K., Schmitt M. Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders. Brain Behav. Immun., 2009, vol. 23, no. 1, pp. 134–142. doi: 10.1016/j.bbi.2008.08.003
  24. Reindl M., Kuenz B., Berger T. B cells and antibodies in MS. In: Molecular Basis of Multiple Sclerosis. Springer, 2009, pp. 99–113. (Series: Results Probl. Cell. Differ., vol. 51). doi: 10.1007/400_2008_16
  25. Sakatoku H., Inoue M., Kojima M., Azuma E., Komada Y., Zhou Y., Zhang S., Sakurai M. 2’,5’-oligoadenylate synthetase activity and T cell subset in the cerebrospinal fluid and peripheral blood of aseptic meningitis. Acta Paediatr. Jpn., 1997, vol. 39, no. 1, pp. 48–53.
  26. Schatorjé E., Gemen E., Driessen G., Leuvenink J., van Hout R., de Vries E. Paediatric reference values for the peripheral T cell compartment. Scand. J. Immunol., 2012, vol. 75, no. 4, pp. 436–444. doi: 10.1111/j.1365-3083.2012.02671.x
  27. Sulik A., Kroten A., Wojtkowska M., Oldak E. Increased levels of cytokines in cerebrospinal fluid of children with aseptic meningitis caused by mumps virus and echovirus 30. Scand. J. Immunol., 2014, vol. 79, no. 1, pp. 68–72. doi: 10.1111/sji.12131
  28. Svenningsson A., Andersen O., Edsbagge M., Stemme S. Lymphocyte phenotype and subset distribution in normal cerebrospinal fluid. J. Neuroimmunol., 1995, vol. 63, pp. 39–46.
  29. Svenningsson A., Hansson G., Andersen O., Andersson R., Patarroyo M., Stemme S. Adhesion molecule expression on cerebrospinal fluid T lymphocytes: evidence for common recruitment mechanisms in multiple sclerosis, aseptic meningitis, and normal controls. Ann. Neurol., 1993, vol. 34, no. 2, pp. 155–161.
  30. Tabata N., Oitani K., Morita K., Shogo Y., Sakurai N., Zhang S., Zhou Y., Komada Y. T cell subsets in peripheral blood and cerebrospinal fluid from children with aseptic meningitis. Acta Paediatr. Jpn., 1994, vol. 36, no. 6, pp. 632–636.
  31. Vrethem M., Dahle C., Ekerfelt C., Forsberg P., Danielsson O., Ernerudh J. CD4 and CD8 lymphocyte subsets in cerebrospinal fluid and peripheral blood from patients with multiple sclerosis, meningitis and normal controls. Acta Neurol. Scand., 1998, vol. 97, no. 4, pp. 215–220.
  32. Weber M., Hemmer B. Cooperation of B cells and T cells in the pathogenesis of multiple sclerosis. Results Probl. Cell Differ., 2010, vol. 51, pp. 115–126. doi: 10.1007/400_2009_21

Copyright (c) 2016 Alekseeva L.A., Zheleznikova G.F., Zhirkov A.A., Skripchenko N.V., Vilnits A.A., 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