CYTOKINES AND HERPESVIRUSES IN CHILDREN WITH MULTIPLE SCLEROSIS
- Authors: Zheleznikova G.F.1, Skripchenko N.V.1, Ivanova G.P.1, Surovtseva A.V.1, Monakhova N.E.1
-
Affiliations:
- Scientific and Research Institute of Children’s Infections, St. Petersburg, Russian Federation
- Issue: Vol 5, No 4 (2015)
- Pages: 349-358
- Section: ORIGINAL ARTICLES
- Submitted: 15.02.2016
- Accepted: 15.02.2016
- Published: 16.12.2015
- URL: https://iimmun.ru/iimm/article/view/352
- DOI: https://doi.org/10.15789/2220-7619-2015-4-349-358
- ID: 352
Cite item
Full Text
Abstract
It was determined earlier (G.P. Ivanova, 2012) that a chronic course of leukoencephalitis in teenagers caused by inadequate response of cytokine system to the combination of two herpesviruses (HV) — EBV and HHV-6, leads to the development of multiple sclerosis (MS) in 44% of cases. The research objective was to characterize the cytokine response in children with MS with simultaneous screening of the presence of active HV infections. 39 children with the diagnosis “MS” were under observation, 34 of them had relapsing-remitting (RR) MS, and 5 children had a progressing course of MS (PMS). Concentration of cytokines IL-1β, IL-6, IL-8, IL-10, IFNα, IFNγ, and IL-4 was identified in blood serum and cerebrospinal liquid (CSF) by enzyme-linked immunosorbent assay, HV DNA was revealed by PCR. Cytokine status in children with MS had some differences depending on the phase of the disease, clinical severity of the relapse and the course of MS. The relapse phase of RRMS was associated with the accumulation of IL-8, IL-10, and IL-6 in the blood, and index IFNγ/IL-4 modulations in accordance with the clinical severity of the relapse. A severe aggravation of the disease in children with PMS was accompanied by the increase of IL-8 system response. HV DNA was revealed in 27 patients from 39 ones (69%) in blood and in 17 patients (44%) in CSF with the predominance of EBV (93%), frequently in combination with HHV-6. During an acute period the frequency of HV DNA identification increased 2–3 times to compare with the remission period. Unlike children with RRMS, a mixed-infection of 3–4 herpes viruses was revealed in all 5 patients with PMS. According to the results summary it is possible to make a conclusion that HV-infection has an important role in MS pathogenesis in teenagers, taking part in the aggravation and progression of the disease by its effect on the cytokine system response. EBV-infection dominates among HV, however the risk of MS development increases to a great extent in the case of EBV association with another lymphotropic virus — HHV-6.
About the authors
G. F. Zheleznikova
Scientific and 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, Institute of Children’s Infections, St. Petersburg, Russian Federation
РоссияN. V. Skripchenko
Scientific and Research Institute of Children’s Infections, St. Petersburg, Russian Federation
Email: fake@neicon.ru
PhD, MD (Medicine), Professor, Deputy Director on Science, Institute of Children’s Infections, St. Petersburg, Russian Federation
РоссияG. P. Ivanova
Scientific and Research Institute of Children’s Infections, St. Petersburg, Russian Federation
Email: fake@neicon.ru
PhD, MD (Medicine), Leading Researcher, Head of the Department of Intensive Therapy in Urgent Cases, Institute of Children’s Infections, St. Petersburg, Russian Federation
РоссияA. V. Surovtseva
Scientific and Research Institute of Children’s Infections, St. Petersburg, Russian Federation
Email: fake@neicon.ru
PhD Candidate, Department of Neuroinfections and Organic Pathology of Nervous System, Institute of Children’s Infections, St. Petersburg, Russian Federation
РоссияN. E. Monakhova
Scientific and Research Institute of Children’s Infections, St. Petersburg, Russian Federation
Email: fake@neicon.ru
Senior Researcher, Department of Clinical Laboratory Diagnostic, Institute of Children’s Infections, St. Petersburg, Russian Federation
РоссияReferences
- Горейко Т.В., Калинина Н.М., Дрыгина Л.Б. Современные представления об иммунопатогенезе инфекции, вызванной вирусом Эпштейна–Барр // Инфекция и иммунитет. 2011. Т. 1, № 2. С. 121–130. [Goreiko T.V., Kalinina N.M., Drygina L.B. The modern conceptions about immunopathogenesis of infection caused by the Epstein–Barr virus. Infektsiya i immunitet = RussianJournal of Infection and Immunity, 2011, vol. 1, no. 2, pp. 121–130. doi: 10.15789/2220-7619-2011-2-121-130 (In Russ.)]
- Железникова Г.Ф., Васякина Л.И., Монахова Н.Е., Павленко М.А., Новожилова Е.В., Попова Н.А., Родионова О.В. Апоптоз и иммунный ответ у детей с острым инфекционным мононуклеозом // Иммунопатология, аллергология, инфектология. 2000. № 4. C. 87–93. [Zheleznikova G.F., Vasjakina L.I., Monachova N.E., Pavlenko M.A., Novozhilova E.V., Popova N.A., Rodionova O.V. Apoptosis and immune response in children with acute infectious mononucleosis. Immunologiya, allergologiya, infektologiya = Immunology, Allergology, Infectology, 2000, no. 4, pp. 87–93. (In Russ.)]
- Железникова Г.Ф., Иванова В.В., Левина А.С., Монахова Н.Е., Керимова Л.В. Варианты иммунопатогенеза инфекционного мононуклеоза, вызванного вирусом Эпштейна–Барр, у детей // Инфекционные болезни. 2007. Т. 5, № 3. C. 20–27. [Zheleznikova G.F., Ivanova V.V., Levina A.S., Monakhova N.E., Kerimova L.V. Variants of immunopathogenesis of infectious mononucleosis caused by Epstein–Barr virus in children. Infektsionnye bolezni = Infectious Diseases, 2007, vol. 5, no. 3, pp. 20–27. (In Russ.)]
- Железникова Г.Ф., Иванова В.В., Монахова Н.Е. Варианты иммунопатогенеза острых инфекций у детей. СПб.: ООО «Издательство Фолиант», 2007. 256 с. [Zheleznikova G.F., Ivanova V.V., Monakhova N.E. Varianty immunopatogeneza ostrykh infektsii u detei [Variants of immunopathogenesis of acute infectious diseases in children]. St. Petersburg: Foliant, 2007. 256 p.]
- Иванова Г.П., Скрипченко Н.В., Железникова Г.Ф., Монахова Н.Е. Особенности иммунной защиты при лейко-энцефалитах у детей // Российский вестник перинатологии и педиатрии. 2012. № 3. С. 56–64. [Ivanova G.P., Skripchenko N.V., Zheleznikova G.F., Monakhova N.E. Specific features of immune protection in children with leukoencephalitis. Rossiiskii vestnik perinatologii i pediatrii = Russian Herald of Perinatology and Pediatrics, 2012, no. 3, pp. 56–64. (In Russ.)]
- Кудин А.П. Эта «безобидная» вирус Эпштейна–Барр инфекция. Часть 1. Характеристика возбудителя. Реакция иммунной системы на вирус // Медицинские новости. 2006. № 7. C. 14–22. [Kudin A.P. The “harmless” virus Epstein-Barr infection. Part 1. The description of agent. The responses of immune system to virus. Medizinskie novosti = Medical News, 2006, no. 7, pp. 14–22. (In Russ.)]
- Кудин А.П. Эта «безобидная» вирус Эпштейна–Барр инфекция. Часть 2. Острая ВЭБ-инфекция: эпидемиология, клиника, диагностика, лечение // Медицинские новости. 2006. № 8, Т. 1. C. 25–31. [Kudin A.P. The “harmless” virus Epstein-Barr infection. Part 2. Acute EBV-infection: epidemiology, clinic, diagnostic, treatment. Medizinskie novosti = Medical News, 2006, vol. 8, no. 1, pp. 25–31. (In Russ.)]
- Левина А.С., Железникова Г.Ф., Бабаченко И.В., Монахова Н.Е., Мурина Е.А. Цитокины в прогнозе рецидивирующего течения инфекционного мононуклеоза у детей // Российский иммунологический журнал. 2009. Т. 3 (12), № 2. С. 184–186. [Levina A.S., Zheleznikova G.F., Babachenko I.V., Monachova N.E., Murina E.A. Cytokines in the prognosis of recurrent course of infectious mononucleosis in children. Rossiiskii immunologicheskii zhurnal = Russian Journal of Immunology, 2009, vol. 3 (12), no. 2, pp. 184–186. (In Russ.)]
- Попова Е.В., Бойко А.Н., Хачанова Н.В., Шаранова С.Н. Вирус Эпштейна–Барр в патогенезе рассеянного склероза (обзор) // Журнал неврологии и психиатрии. 2014. № 2, вып. 2. С. 29–34. [Popova E.V., Boyko A.N., Hachanova N.V., Sharanova S.N. Epstein–Barr virus in the pathogenesis of multiple sclerosis (a reviev). Zhurnal nevrologii i psikhiatrii = Journal of Neurology and Psychiatry, 2014, no. 2, Iss. 2, pp. 29–34. (In Russ.)]
- Скрипченко Н.В., Иванова Г.П., Железникова Г.Ф., Алексеева Л.А., Говорова Л.В. Патогенетические аспекты течения и исходов лейкоэнцефалитов у детей // Нейрохирургия и неврология детского возраста. 2012. № 2–3. С. 58–70 [Skripchenko N.V., Ivanova G.P., Zheleznikova G.F., Alekseeva L.A., Govorova L.V. The pathogenetical aspects of course and outcome of leukoencephalitis in children. Neirochirurgiya i nevrologiya detskogo vozrasta = Neurosurgery and Pediatric Neurology, 2012, no. 2–3, pp. 58–70. (In Russ.)]
- Angelini D., Serafini B., Piras E., Severa M., Coccia E., Rosicarelli B., Ruggieri S., Gasperini C., Buttari F., Centonze D., Mechelli R., Salvetti M., Borsellino G., Aloisi F., Battistini L. Increased CD8+ T cell response to Epstein–Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog., 2013, vol. 9, no. 4, e1003220. doi: 10.1371/journal.ppat.1003220
- Cheng W., Ma Y., Gong F., Hu C., Qian L., Huang Q., Yu Q., Zhang J., Chen S., Liu Z., Chen X., Zhou T., Zhang D. Cross-reactivity of autoreactive T cells with MBP and viral antigens in patients with MS. Front. Biosci. (Landmark Ed.), 2012, vol. 17, pp. 1648–1658.
- Christensen R., Bürnsen L., Hesse D., Krakauer M., Sörensen P., Söndergaard H., Sellebjerg F. Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis. J. Neuroinflammation, 2012, vol. 9, p. 215. doi: 10.1186/1742-2094-9-215
- Djelilovic-Vranic J., Alajbegovic A. Role of early viral infections in development of multiple sclerosis. Med. Arch., 2012, vol. 66, no. 3, suppl. 1, pp. 37–40.
- Garcia-Montojo M., De Las Heras V., Dominguez-Mozo M., Bartolome M., Garcia-Martinez M., Arroyo R., Alvarez-Lafuente R. Human herpesvirus 6 and effectiveness of interferon β1b in multiple sclerosis patients. Eur. J. Neurol., 2011, vol. 18, no. 8, pp. 1027–1035. doi: 10.1111/j.1468-1331.2011.03410.x
- Gustavsen M., Page C., Moen S., Bjølgerud A., Berg-Hansen P., Nygaard G., Sandvik L., Lie B., Celius E., Harbo H. Environmental exposures and the risk of multiple sclerosis investigated in a Norwegian case-control study. BMC Neurol., 2014, vol. 14 p. 196. doi: 10.1186/s12883-014-0196-x
- Hedegaard C., Krakauer M., Bendtzen K., Lund H., Sellebjerg F. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology, 2008, vol. 125, no. 2, pp. 161–169. doi: 10.1111/j.1365-2567.2008.02837.x
- Jaquiery E., Jilek S., Schluep M., Le Goff G., Garcia M., Pantaleo G., Du Pasquier R. Cytokine mRNA profile of Epstein-Barr virus-stimulated highly differentiated T cells in multiple sclerosis: a pilot study. J. Neuroimmunol., 2010, vol. 225, no. 1–2, pp. 167–170. doi: 10.1016/j.jneuroim.2010.04.011
- Jilek S., Schluep M., Meylan P., Vingerhoets F., Guignard L., Monney A., Kleeberg J., Le Goff G., Pantaleo G.. Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain, 2008, vol. 131, pt. 7, pp. 1712–1721. doi: 10.1093/brain/awn108
- Kallaur A., Oliveira S., Colado Simão A., Delicato de Almeida E., Kaminami Morimoto H., Lopes J., de Carvalho Jennings Pereira W., Marques Andrade R., Muliterno Pelegrino L., Donizete Borelli S., Kaimen-Maciel D., Reiche E. Cytokine profile in relapsing-remitting multiple sclerosis patients and the association between progression and activity of the disease. Mol. Med. Rep., 2013, vol. 7, no. 3, pp. 1010–1020. doi: 10.1093/brain/awn108
- Libbey J., Cusick M., Fujinami R. Role of pathogens in multiple sclerosis. Int. Rev. Immunol., 2014, vol. 33, no. 4, pp. 266–283. doi: 10.3109/08830185.2013.823422
- Lünemann J., Jelcić I., Roberts S., Lutterotti A., Tackenberg B., Martin R., Münz C. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J. Exp. Med., 2008, vol. 205, no. 8, pp. 1763–1773. doi: 10.1084/jem.20072397
- Pender M., Burrows S. Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy. Clin. Transl. Immunology, 2014, vol. 3, no. 10, e27. doi: 10.1038/cti.2014.25
- Rossi S., Motta C., Studer V., Barbieri F., Buttari F., Bergami A., Sancesario G., Bernardini S., De Angelis G., Martino G., Furlan R., Centonze D. Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration. Mult. Scler., 2014, vol. 20, no. 3, pp. 304–312. doi: 10.1177/1352458513498128
- Sundqvist E., Bergström T., Daialhosein H., Nyström M., Sundström P., Hillert J., Alfredsson L., Kockum I., Olsson T. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult. Scler., 2014, vol. 20, no. 2, pp. 165–173. doi: 10.1177/1352458513494489
- Trenova A., Manova M., Kostadinova I., Murdjeva M., Hristova D., Vasileva T., Zahariev Z. Clinical and laboratory study of proinflammatory and antiinflammatory cytokines in women with multiple sclerosis. Folia Med. (Plovdiv), 2011, vol. 53, no. 2, pp. 29–35.
- Tzartos J., Khan G., Vossenkamper A., Cruz-Sadaba M., Lonardi S., Sefia E., Meager A., Elia A., Middeldorp J., Clemens M., Farrell P., Giovannoni G., Meier U. Association of innate immune activation with latent Epstein–Barr virus in active MS lesions. Neurology, 2012, vol. 78, no. 1, pp. 15–23. doi: 10.1212/WNL.0b013e31823ed057
- Waubant E., Mowry E., Krupp L., Chitnis T., Yeh E., Kuntz N., Ness J., Chabas D., Strober J., McDonald J., Belman A., Milazzo M., Gorman M., Weinstock-Guttman B., Rodriguez M., Oksenberg J., James J. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology, 2011, vol. 76, no. 23, pp. 1989–1995. doi: 10.1212/WNL.0b013e31821e552a