The Role of the Cell-mediated Immunity in the Pathogenesis of Multiple Sclerosis with Focus on Th17 and Treg Lymfocytes

Authors: M. Svobodová 1;  P. Štourač 1,2
Authors‘ workplace: Neurologická klinika LF MU a FN Brno 1;  CEITEC – Středoevropský technologický institut, MU, Brno 2
Published in: Cesk Slov Neurol N 2017; 80/113(2): 173-179
Category: Review Article
doi: 10.14735/amcsnn2017173

Podpořeno grantem MZ ČR – RVO (FNBr, 65269705) a projektem specifického výzkumu č. MUNI/ A/ 1072/ 2015 z programu podpory studentských projektů na Masarykově univerzitě.


Multiple sclerosis is a serious autoimmune disease of the central nervous system. It occurs with relatively high prevalence, especially in young people. It is essential to understand the pathogenesis of this disease in order to develop new treatments. All components of immunity are involved in this process but current research mainly focuses on lymphocyte populations. Previously, imbalance between subtypes of helper lymphocytes Th1 and Th2 was considered as the main cause of multiple sclerosis. Recently, the influence of other cell elements, such as B lymphocytes, cytotoxic T lymphocytes, was shown. Moreover, new cell types, regulatory T lymphocytes and helper Th17 lymphocytes, have been discovered. The aim of this article is to describe the main roles of individual lymphocyte subtypes in multiple sclerosis pathogenesis, focusing first on regulatory T lymphocytes and helper Th17 lymphocytes.

Key words:
multiple sclerosis – B lymphocytes – T lymphocytes – regulatory T lymphocytes – Th17 lymphocytes

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.


1. Havrdová E. Neuroimunologie. 1. vyd. Praha: Maxdorf 2001.

2. Constantinescu CS, Farooqi N, O’Brien K, et al. Experimental autoim­mune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 2011;164(4):1079– 106. doi: 10.1111/ j.1476-5381.2011. 01302.x.

3. Kuhlmann T, Las­smann H, Brück W. Dia­gnosis of inflam­matory demyelination in bio­psy specimens: a practical approach. Acta Neuropathol 2008;115(3)275– 87. doi: 10.1007/ s00401-007-0320-8.

4. Lauerová L, Kocák I. Regulace protinádorové imunity pomocnými CD4+ TH1/ TH2 lymfocyty. Klin Onkol 2001;14(5):154– 6.

5. Noble A, Thomas MJ, Kemeny DM. Early Th1/ Th2 cell polarization in the absence of IL-4 and IL-12: T cell receptor signal­ing regulates the response to cytokines in CD4 and CD8 T cel­ls. Eur J Im­munol 2001;31(7):2227– 35.

6. Sal­lusto F, Geginat J, Lanzavecchia A. Central memory and ef­fector memory T cell subsets: function, generation, and maintenance. An­nu Rev Im­munol 2004;22:745– 63. doi: 10.1146/ an­­munol.22.012703.104702.

7. Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cel­ls and im­mune tolerance. Cell 2008;133(5):775– 87.doi: 10.1016/ j.cel­l.2008.05.009.

8. Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17 produc­ing T helper memory cel­ls. Nat Im­munol 2007;8(6):639– 46. doi: 10.1038/ ni1467.

9. Horejší V, Bartůňková J. Základy imunologie. 4. vyd. Praha: Triton 2009.

10. Chiba K, Adachi K. Discovery of fingolimod, the sphingosine 1 phosphate receptor modulator and its application for the therapy of multiple sclerosis. Future Med Chem 2012;4(6):771– 81. doi: 10.4155/ fmc.12.25.

11. Sato DK, Nakashima I, Bar-Or A, et al. Changes in Th17 and regulatory T cel­ls after fingolimod initiation to treat multiple sclerosis. J Neuroim­munol 2014;268(1– 2):95– 8. doi: 10.1016/ j.jneuroim.2014.01.008.

12. Yusuf-Makagiansar H, Anderson ME, Yakovleva TV, et al. Inhibition of LFA-1/ ICAM-1 and VLA-4/ VCAM-1 as a therapeutic approach to inflam­mation and autoim­mune diseases. Med Res Rev 2002;22(2):146– 67.

13. Mehl­ing M, Johnson TA, Antel J, et al. Clinical im­munology of the sphingosine 1 phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis. Neurology 2011;76(Suppl 3):S20– 7. doi: 10.1212/ WNL.0b013e31820db341.

14. Cao Y, Goods BA, Raddas­si K, et al. Functional inflam­matory profiles distinguish myelin-reactive T cel­lsfrom patients with multiple sclerosis. Sci Transl Med2015;7(287):287ra74. doi: 10.1126/ scitranslmed.aaa8038.

15. Vil­lar LM, Masterman T, Casanova B, et al. CSF oligoclonal band patterns reveal disease heterogeneity in multiple sclerosis. J Neuroim­munol 2009;211(1– 2):101– 4. doi: 10.1016/ j.jneuroim.2009.03.003.

16. Ireland S, Monson N. Potential impact of B cel­ls on T cell function in multiple sclerosis. Mult Scler Int 2011;2011:423971. doi: 10.1155/ 2011/ 423971.

17. Buc M. Role of regulatory T cel­ls in pathogenesis and bio­logical therapy of multiple sclerosis. Mediators Inflamm 2013;2013:963748. doi: 10.1155/ 2013/ 963748.

18. Tobón GJ, Izquierdo JH, Cañas CA. B lymphocytes: development, tolerance, and their role in autoim­munity-focus on systemic lupus erythematosus. Autoim­mune Dis 2013;2013:827254. doi: 10.1155/ 2013/ 827254.

19. Cross AH, Klein RS, Piccio L. Rituximab combination therapy in relaps­ing multiple sclerosis. Ther Adv Neurol Disord 2012;5(6):311– 9. doi: 10.1177/ 1756285612461165.

20. Krumbholz M, Meinl E. B cel­ls in MS and NMO: pathogenesis and therapy. Semin Im­munopathol 2014;36(3):339– 50. doi: 10.1007/ s00281-014-0424-x.

21. Scol­lay R, Smith J, Stauf­fer V. Dynamics of early T cel­ls:prothymocyte migration and proliferation in the adult mouse thymus. Im­munol Rev 1986;91:129– 57.

22. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cel­ls. An­nu Rev Im­munol 2003; 21:139– 76. doi: 10.1146/ an­­munol.21.120601.141107.

23. Brucklacher-Waldert V, Stuerner K, Kolster M, et al. Phenotypical and functional characterization of T helper 17 cel­ls in multiple sclerosis. Brain 2009;132(12):3329– 41. doi: 10.1093/ brain/ awp289.

24. Neumann H, Medana IM, Bauer J, et al. Cytotoxic T lymphocytes in autoim­mune and degenerative CNS diseases. Trends Neurosci 2002;25(6):313– 9.

25. Las­smann H, Ransohoff RM. The CD4-Th1 model for multiple sclerosis: a critical [cor­rection of crucial] re-appraisal. Trends Im­munol 2004;25(3):132– 7. doi: 10.1016/

26. Denic A, Wootla B, Rodriguez M. CD8+ T Cel­lsin Multiple Sclerosis. Expert Opin Ther Targets 2013;17(9):1053– 66. doi: 10.1517/ 14728222.2013.815726.

27. Lake DB, Poole TR. Tacrolimus. Br J Ophthalmol 2003;87(1):121– 2.

28. Zheng SG. Regulatory T cel­ls vs Th17: dif­ferentiation of Th17 versus Treg, are the mutual­ly exclusive? Am J Clin Exp Im­munol 2013;2(1):94– 106.

29. Lovett-Racke AE, Yang Y, Racke MK. Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim Biophys Acta 2011;1812(2):246– 51. doi: 10.1016/ j.bbadis.2010.05.012.

30. Zhang J, Cheng Y, Cui W, et al. MicroRNA-155 modulates Th1 and Th17 cell dif­ferentiation and is as­sociated with multiple sclerosis and experimental autoim­mune encephalomyelitis. J Neuroim­munol 2014;266(1– 2):56– 63. doi: 10.1016/ j.jneuroim.2013.09.019.

31. Kebir H, Ifergan I, Alvarez JI, et al. Preferential recruitment of interferon-gam­ma-expres­s­ing TH17 cel­ls in multiple sclerosis. Ann Neurol 2009;66(3):390– 402. doi: 10.1002/ ana.21748.

32. Rostami A, Ciric B. Role of Th17 cel­ls in the pathogenesis of CNS inflam­matory demyelination. J Neurol Sci 2013;333(1– 2):76– 87. doi: 10.1016/ j.jns.2013.03.002.

33. Krejsek J, Holman­nová D. Imunopatogeneze roztroušené sklerózy mozkomíšní. Postgrad Med 2012;14:933– 8.

34. Maier E, Duschl A, Horejs-Hoeck J. STAT6-dependent and -independent mechanisms in Th2 polarization. Eur J Im­munol 2012;42(11):2827– 33. doi: 10.1002/ eji.201242433.

35. Krejsek J, Kopecký O. Klinická imunologie. 1. vyd. Hradec Králové: NUCLEUS HK 2004.

36. Liblau R. Glatiramer acetate for the treatment of multiple sclerosis: evidence for a dual anti-inflam­matory and neuroprotective role. J Neurol Sci 2009;287(Suppl 1):S17– 23. doi: 10.1016/ S0022-510X(09)71296-1.

37. Schrempf W, Ziems­sen T. Glatiramer acetate: mechanisms of action in multiple sclerosis. Autoim­mun Rev 2007;6(7):469– 75. doi: 10.1016/ j.autrev.2007.02.003.

38. Bettel­li E, Korn T, Kuchroo VK. Th17: the third member of the ef­fector T cell trilogy. Curr Opin Im­munol 2007;19(6):652– 7. doi: 10.1016/ j.coi.2007.07.020.

39. Mios­sec P. IL-17 and Th17 cel­ls in human inflam­matory diseases. Microbes Infect 2009;11(5):625– 30. doi: 10.1016/ j.micinf.2009.04.003.

40. Lee YK, Mukasa R, Hatton RD, et al. Developmental plasticity of Th17 and Treg cel­ls. Curr OpinIm­munol 2009;21(3):274– 80. doi: 10.1016/ j.coi.2009.05.021.

41. Zambrano-Zaragoza JF, Romo-Martínez EJ, Durán-Avelar MJ, et al. Th17 cel­ls in autoim­mune and infectious diseases. Int J Inflamm 2014;2014:651503. doi: 10.1155/ 2014/ 651503.

42. Babaloo Z, Aliparasti MR, Babaiea F, et al. The role of Th17 cel­ls in patients with relapsing-remitt­ing multiple sclerosis: interleukin-17A and interleukin-17F serum levels. Im­munol Lett 2015;164(2):76– 80. doi: 10.1016/ j.imlet.2015.01.001.

43. Li Y, Wang H, Long Y, et al. Increased memory Th17 cel­ls in patients with neuromyelitis optica and multiple sclerosis. J Neuroim­munol 2011;234(1– 2):155– 60. doi: 10.1016/ j.jneuroim.2011.03.009.

44. Di Mitri D, Sambucci M, Loiar­ro M, et al. The p38 mitogen-activated protein kinase cascade modulates T helper type 17 dif­ferentiation and functionality in multiple sclerosis. Im­munology 2015;146(2):251– 63. doi: 10.1111/ im­m.12497.

45. Jamshidian A, Shaygan­nejad V, Pourazar A, et al. Biased Treg/ Th17 balance away from regulatory toward inflam­matory phenotype in relapsed multiple sclerosis and its cor­relation with severity of symp­toms. J Neuroim­munol 2013;262(1– 2):106– 12. doi: 10.1016/ j.jneuroim.2013.06.007.

46. Poojary KV, Kong YM, Far­rar MA. Control of Th2-mediated inflam­mation by regulatory T cel­ls. Am J Pathol 2010;177(2):525– 31. doi: 10.2353/ ajpath.2010.090936.

47. Dejaco C, Duftner C, Grubeck-Loebenstein B, et al. Imbalance of regulatory T cel­ls in human autoim­mune diseases. Im­munology 2006;117(3):289– 300. doi: 10.1111/ j.1365-2567.2005.02317.x.

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 2

2017 Issue 2

Most read in this issue
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account