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Multiple Sclerosis –  a Role of Regulatory T Cells in the Pathogenesis and Biological Treatment of the Disease


Authors: M. Buc
Authors‘ workplace: Imunologický ústav LF UK, Bratislava
Published in: Cesk Slov Neurol N 2013; 76/109(3): 293-299
Category: Review Article

Overview

Every bio­logical system has its executive as well as control mechanisms that, by the means of feed back, maintain homeostasis within the organism. Regulatory B cells (Breg) and especially regulatory T cells (Treg) are of paramount importance in preventing auto‑ aggressive (allergic and autoimmune) processes. Multiple sclerosis (MS) is an autoimmune disease driven by proinflammatory activities of various cell types led by TH1 and TH17 cells. Recently, it has been established that the over‑activity of the involved cells is enabled by insufficient activity of regulatory T cells. It is, therefore, natural that, in MS, therapy aims to re‑establish their physiological function. IFN‑β and glatiramer ace­tate, first line bio­logical agents, are able to do so. The second line agents, natalizumab and FTY720, influence the activity of Treg cells in various ways –  natalizumab does not affect T cells in any way, while FTY720 supports both, their proliferation and activity. It seems that it is an insufficient immunosuppressive activity after suspension of the 720 (FTY720) treatment that results in a development of the IRIS. With respect to the role of regulatory T cells in the development and therapy of MS it is worth mentioning that they can be induced and expanded in vitro and subsequently re‑introduced to the patient. Recently, monoclonal antibodies rituximab, alemtuzumab and daclizumab have entered clinical tests as the treatments of MS. Their mechanisms of action are different. Rituximab down‑ regulates antigen‑ presentation function of B cells, alemtuzumab profoundly depletes T cells, including auto‑ reactive lines, and daclizumab induces NK cells that enter the itrathecal compartment and kill autoreactive T cells. The paper also discusses the support that laboratory immunology has to offer to physicians in terms of the diagnosis and bio­logical treatment decision making.

Key words:
glatiramer acetate – interferon b –monoclonal antibodies – regulatory T cells – multiple sclerosis – TH1 cells – TH17 cells


Sources

1. Liu YJ. A unified theory of central tolerance in the thymus. Trends Immunol 2006; 27(5): 215– 221.

2. Lan RY, Ansari AA, Lian ZX, Gershwin ME. Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 2005; 4(6): 351– 363.

3. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10(7): 490– 500.

4. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531– 564.

5. Mizoguchi A, Bhan AK. A case for regulatory B cells. J. Immunol 2006; 176(2): 705– 710.

6. Park SG, Mathur R, Long M, Hosh N, Hao L, Hayden MS et al. T regulatory cells maintain intestinal homeostasis by suppressing gammadelta T cells. Immunity 2010; 33(5): 791– 803.

7. Ohkura N, Sakaguchi S. Maturation of effector regulatory T cells. Nat Immunol 2011; 12(4): 283– 284.

8. Ouyang W, Li MO. Foxo: in command of T lymphocyte homeostasis and tolerance. Trends Immunol 2011; 32(1): 26– 33.

9. Langier S, Sade K, Kivity S. Regulatory T cells: the suppressor arm of the immune system. Autoimmun Rev 2010; 10(2): 112– 115.

10. Shevach EM. Mechanisms of foxp3+ T regulatory cell‑ mediated suppression. Immunity 2009; 30(5): 636– 645.

11. Cvetanovich GL, Hafler DA. Human regulatory T cells in autoimmune diseases. Curr Opin Immunol 2010; 22(6): 753– 760.

12. Tejera‑ Alhambra M, Alonso B, Teijeiro R, Ramos‑ Medina R, Aristimuno C, Valor L et al. Perforin expression by CD4+ regulatory T cells increases at multiple sclerosis relapse: sex differences. Int J Mol Sci 2012; 13(6): 6698– 6710.

13. Hori S. Developmental plasticity of Foxp3+ regulatory T cells. Curr Opin Immunol 2010; 22(5): 575– 582.

14. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 2012; 482(7385): 395– 399.

15. Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012; 30: 733– 758.

16. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN et al. Neuropilin 1 is expressed on thymus‑ derived natural regulatory T cells, but not mucosa‑ generated induced Foxp3+ T reg cells. J Exp Med 2012; 209(10): 1723– 1742.

17. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4(+) T cell immunity. Nat Rev Immunol 2010; 10(4): 236– 247.

18. Vitale G, Mion F, Pucillo C. Regulatory B cells: evidence, developmental origin and population diversity. Mol Immunol 2010; 48(1– 3): 1– 8.

19. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M, Kountikov EI et al. Regulatory B cells control T‑ cell autoimmunity through IL‑21– dependent cognate interactions. Nature 2012; 491(7423): 264– 268.

20. Haas J, Hug A, Viehöver A, Fritzsching B, Falk CS,Filser A et al. Reduced suppressive effect of CD4+CD25 high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 2005; 35(11): 3343– 3352.

21. Kumar M, Putzki N, Limmroth V, Remus R, Lindemann M, Knop D et al. CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein‑induced proliferation in patients with multiple sclerosis. J Neuroimmunol 2006; 180(1– 2): 178– 184.

22. Lowther DE, Hafler DA. Regulatory T cells in the central nervous system. Immunol Rev 2012; 248(1): 156– 169.

23. Praksova P, Stourac P, Bednarik J, Vlckova E, Mikulkova Z, Michalek J. Immunoregulatory T cells in multiple sclerosis and the effect of interferon beta and glatiramer acetate treatment on T cell subpopulations. J Neurol Sci 2012; 319(1– 2): 18– 23.

24. Joller N, Peters A, Anderson AC, Kuchroo VK. Immune checkpoints in central nervous system autoimmunity. Immunol Rev 2012; 248(1): 122– 139.

25. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683– 747.

26. Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood‑ brain barriers. Trends Immunol 2012; 33(12): 579– 589.

27. Krumbholz M, Theil D, Steinmeyer F, Cepok S, Hemmer B, Hofbauer M et al. CCL19 is constitutively expressed in the CNS, up‑ regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol 2007; 190(1– 2): 72– 79.

28. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest 2012; 122(4): 1180– 1188.

29. Peelen E, Damoiseaux J, Smolders J, Knippenberg S,Menheere P, Tervaert JW et al. Th17 expansion in MS patients is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. J Neuroimmunol 2011; 240– 241: 97– 103.

30. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004; 364(9451): 2106– 2112.

31. Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R et al. Mechanisms of disease: aquaporin‑4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol 2008; 4(4): 202– 214.

32. Wang HH, Dai YQ, Qiu W, Lu ZQ, Peng FH, Wang YGet al. Interleukin‑17- secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neurosci 2011; 18(10): 1313– 1317.

33. Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012; 11(6): 535– 544.

34. Palace J, Leite MI, Nairne A, Vincent A. Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol 2010; 67(8): 1016– 1017.

35. Tradtrantip L, Zhang H, Saadoun S, Phuan PW, Lam C, Papadopoulos MC et al. Anti‑aquaporin‑4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol 2012; 71(3): 314– 232.

36. Graber JJ, McGraw CA, Kimbrough D, Dhib‑ Jalbut S. Overlapping and distinct mechanisms of action of multiple sclerosis therapies. Clin Neurol Neurosurg 2010; 112(7): 583– 591.

37. Chen M, Chen G, Deng S, Liu X, Hutton GJ, Hong J. IFN‑beta induces the proliferation of CD4+CD25+Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis. J Neuroimmunol 2012; 242(1– 2): 39– 46.

38. Burger D, Molnarfi N, Weber MS, Brandt KJ, Benkhoucha M, Gruaz L et al. Glatiramer acetate increases IL‑1 receptor antagonist but decreases T cell‑induced IL‑1beta in human monocytes and multiple sclerosis. Proc Natl Acad Sci USA 2009; 106(11): 4355– 4359.

39. Lalive PH, Neuhaus O, Benkhoucha M, Burger D, Hohlfeld R, Zamvil SS et al. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 2011; 25(5): 401– 414.

40. Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T‑ cell function by expansion of naive CD4(+)CD25(+) FOXP3(+) CD31(+) T‑ cells in patients with multiple sclerosis. J Neuroimmunol 2009; 216(1– 2): 113– 117.

41. Martelli AM, Tabellini G, Bressanin D, Ognibene A,Goto K, Cocco L et al. The emerging multiple roles of nuclear Akt. Biochim Biophys Acta 2012; 1823(12): 2168– 2178.

42. Rossi S, Motta C, Studer V, Monteleone F, De Chiara V, Buttari F et al. A genetic variant of the anti‑apoptotic protein Akt predicts natalizumab‑induced lymphocytosis and post‑natalizumab multiple sclerosis reactivation. Mult Scler 2013; 19(1): 59– 68.

43. Mancini N, Clementi M, Burioni R. Natalizumab‑associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 367(9): 871– 872.

44. Girkontaite I, Sakk V, Wagner M, Borggrefe T, Tedford K, Chun J et al. The sphingosine‑ 1- phosphate (S1P) lysophospholipid receptor S1P3 regulates MAdCAM‑ 1+ endothelial cells in splenic marginal sinus organization. J Exp Med 2004; 200(11): 1491– 1501.

45. Cinamon G, Matloubian M, Lesneski MJ, Xu Y, Low C, Lu T et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat Immunol 2004; 5(7): 713– 720.

46. Sawicka E, Dubois G, Jarai G, Edwards M, Thomas M, Nicholls A et al. The sphingosine 1- phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/ CD25+ T‑ regulatory cells and enhances their functional activity. J Immunol 2005; 175(12): 7973– 7980.

47. Havla JB, Pellkofer HL, Meinl L, Gerdes LA, Hohlfeld R, Kümpfel T. Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol 2012; 69(2): 262– 264.

48. Gross CM, Baumgartner A, Rauer S, Stich O. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 2012; 79(19): 2006– 2007.

49. Rigau V, Mania A, Béfort P, Carlander B, Jonquet O,Lassmann H et al. Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology 2012; 79(22): 2214– 2216.

50. Marousi S, Travasarou M, Karageorgiou CE, Gheuens S, Koralnik IJ. Simultaneous PML‑IRIS after discontinuation of natalizumab in a patient with MS. Neurology 2012; 79(21): 2160.

51. Wolf AM, Eller K, Zeiser R, Dürr C, Gerlach UV, Sixt M et al. The sphingosine 1- phosphate receptor agonist FTY720 potently inhibits regulatory T cell proliferation in vitro and in vivo. J Immunol 2009; 183(6): 3751– 3760.

52. Suntharalingam G, Perry MR, Ward S, Brett SJ,Castello‑ Cortes A, Brunner MD et al. Cytokine storm in a phase 1 trial of the anti‑CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355(10): 1018– 1028.

53. Barun B, Bar‑ Or A. Treatment of multiple sclerosis with anti‑CD20 antibodies. Clin Immunol 2012; 142(1): 31– 37.

54. Ray A, Basu S, Williams CB, Salzman NH, Dittel BN.A novel IL‑10– independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J Immunol 2012; 188(7): 3188– 3198.

55. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte‑ specific antigen. J Immunol 1980; 125(4): 1678– 1685.

56. Saidha S, Eckstein C, Calabresi PA. New and emerging disease modifying therapies for multiple sclerosis. Ann N Y Acad Sci 2012; 1247: 117– 1137.

57. Yamamura T, Miyake S. B‑ cell‑ directed therapy: which B cells should be targeted and how? Immunotherapy 2012; 4(5): 455– 457.

58. Thompson SA, Jones JL, Cox AL, Compston DA, Coles AJ. B‑ cell reconstitution and BAFF after alemtuzumab (Campath‑ 1H) treatment of multiple sclerosis. J Clin Immunol 2010; 30(1): 99– 105.

59. Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999; 354(9191): 1691– 1695.

60. Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10(1): 55– 67.

61. Brusko T, Bluestone J. Clinical application of regulatory T cells for treatment of type 1 diabetes and transplantation. Eur J Immunol 2008; 38(4): 931– 934.

62. Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen‑ specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 2002; 169(9): 4712– 4716.

63. Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ. Helper T cell diversity and plasticity. Curr Opin Immunol 2012; 24(3): 297– 302.

64. Graber JJ, Dhib‑ Jalbut S. Biomarkers of disease activity in multiple sclerosis. J Neurol Sci 2011; 305(1– 2): 1– 10.

65. Krejsek J, Kopecký O. Klinická imunologie. Nucleus: Hradec Králové 2004.

66. Buc M. Základná a klinická imunológia. Veda: Bratislava 2012.

67. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 7th ed. Philadelphia: Saunders, Elsevier 2012.

68. Schoenfeld Y, Fučíková T, Bartůňková J. Autoimunita – vnitřní nepřítel. Grada Publishing: Praha 2007.

69. Buc M. Autoimunita a autoimunitné choroby. Veda: Bratislava 2007.

70. Rich RR. Clinical Immunology. Principles and Practice. 3rd ed. Philadelphia: Mosby, Elsevier 2008.

71. Havrdová E. Neuroimunologie. Praha: Maxdorf 2001.

Labels
Paediatric neurology Neurosurgery Neurology

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Czech and Slovak Neurology and Neurosurgery

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