Multiple sclerosis: The role of cytokines in pathogenesis and in therapies

International Journal of Molecular Sciences

Volumn 13, Issue 10, 2012, Pages 13438-13460

  Amedei, Amedeo ^a,b   Prisco, Domenico ^a,b   D'Elios, Mario Milco ^a,b  

^a UNIVERSITY OF FLORENCE   (Italy)

^b CAREGGI UNIVERSITY HOSPITAL   (Italy)

Author keywords

Cytokines; Interferons (IFNS); Interleukin 17 (IL 17); Multiple sclerosis; T helper cells (TH)

Indexed keywords

ALEMTUZUMAB; BETA INTERFERON; CLADRIBINE; CYTOKINE; DACLIZUMAB; FINGOLIMOD; FUMARIC ACID; GEMFIBROZIL; GLATIRAMER; INTERLEUKIN 7; LAQUINIMOD; MINOCYCLINE; MITOXANTRONE; PIOGLITAZONE; TERIFLUNOMIDE; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 17;

ADAPTIVE IMMUNITY; DISEASE ASSOCIATION; DRUG MECHANISM; HUMAN; INNATE IMMUNITY; LYMPHOCYTE FUNCTION; MULTIPLE SCLEROSIS; NEUROPROTECTION; PATHOGENESIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; T LYMPHOCYTE; TREATMENT INDICATION; ANIMAL; GENETICS; HELPER CELL; IMMUNOLOGY; METABOLISM; PATHOLOGY;

ANIMALS; CYTOKINES; HUMANS; IMMUNITY, INNATE; IMMUNOSUPPRESSIVE AGENTS; INTERLEUKIN-17; MULTIPLE SCLEROSIS; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 84870659860     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms131013438     Document Type: Review

References (144)

1. Noseworthy, J.H. Progress in determining the causes and treatment of multiple sclerosis. Nature 1999, 399, A40-A47.
2. Giraudon, P.; Bernard, A. Chronic viral infections of the central nervous system: Aspects specific to multiple sclerosis. Rev. Neurol. (Paris) 2009, 165, 789-795.
3. Billiau, A.; Edy, V.G.; Heremans, H.; van Damme, J.; Desmyter, J.; Georgiades, J.A.; de Somer, P. Human interferon: Mass production in a newly established cell line, MG-63. Antimicrob. Agents Chemother. 1977, 12, 11-15.
4. Weinstock-Guttman, B.; Ramanathan, M.; Zivadinov, R. Interferon-beta treatment for relapsing multiple sclerosis. Expert Opin. Biol. Ther. 2008, 8, 1435-1447.
5. Ebers, G.C.; Sadovnick, A.D. The geographic distribution of multiple sclerosis: A review. Neuroepidemiology 1993, 12, 1-5.
6. Goris, A.; Epplen, C; Fiten, P.; Andersson, M.; Murru, R.; Sciacca, F.L.; Ronsse, I.; Jäckel, S.; Epplen, J.T.; Marrosu, M.G. et al. Analysis of an IFN-γ gene (IFNG) polymorphism in multiple sclerosis in Europe: Effect of population structure on association with disease. J. Interferon Cytokine Res. 1999, 19, 1037-1046.
7. Ebers, G.C.; Bulman, D.E.; Sadovnick, A.D.; Paty, D.W.; Warren, S.; Hader, W.; Murray, T.J.; Seland, T.P.; Duquette, P.; Grey, T. et al. A population-based study of multiple sclerosis in twins. N Engl. J. Med. 1986, 315, 1638-1642.
8. Murray, T.J. Multiple Sclerosis, the History of a Disease; Demos Medical Publishing: New York, NY, USA, 2005.
9. Compston, A.; McDonald, I.; Noseworthy, J.; Lassmann, H.; Miller, D.; Smith, K.; Wekerle, H.; Confavreux, C. McAlpine's Multiple Sclerosis, 4th ed.; Churchill Livingstone: London, UK, 2005.
10. Zuvich, R.L.; McCauley, J.L.; Pericak-Vance, M.A.; Haines, J.L. Genetics and pathogenesis of multiple sclerosis. Semin. Immunol. 2009, 21, 328-333.
11. Oksenberg, J.R.; Baranzini, S.E. Multiple sclerosis genetics-Is the glass half full, or half empty? Nat. Rev. Neurol. 2010, 6, 429-437.
12. Steinman, L.; Zamvil, S. Transcriptional analysis of targets in multiple sclerosis. Nat. Rev. Immunol. 2003, 3, 483-492.
13. Mariño, K.; Bones, J.; Kattla, J.J.; Rudd, P.M. A systematic approach to protein glycosylation analysis: A path through the maze. Nat. Chem. Biol. 2010, 6, 713-723.
14. Opdenakker, G; van Damme, J. Cytokine-regulated proteases in autoimmune diseases. Immunol. Today 1994, 15, 103-107.
15. Gijbels, K.; Masure, S.; Carton, H.; Opdenakker, G. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J. Neuroimmunol. 1992, 41, 29-34.
16. Paemen, L.; Olsson, T.; Söderström, M.; van Damme, J.; Opdenakker, G. Evaluation of gelatinases and IL-6 in the cerebrospinal fluid of patients with optic neuritis, multiple sclerosis and other inflammatory neurological diseases. Eur. J. Neurol. 1994, 1, 55-63.
17. Pette, M.; Fujita K.; Kitze, B.; Whitaker, J.N.; Albert, E.; Kappos, L.; Wekerle, H. Myelin basic protein specific T lymphocyte lines from MS patients and healthy individuals. Neurology 1990, 40, 1770-1776.
18. Schluesener, H.J.; Wekerle, H. Autoaggressive T lymphocyte lines recognizing the encephalitogenic region of myelin basic protein: In vitro selection from unprimed rat T lymphocyte populations. J. Immunol. 1985, 135, 3128-3133.
19. Genain, C.P.; Lee-Parritz, D.; Nguyen, M.H.; Massacesi, L.; Joshi, N.; Ferrante, R.; Hoffman, K.; Moseley, M.; Letvin, N.L.; Hauser, S.L. In healthy primates, circulating autoreactive T cells mediate autoimmune disease. J. Clin. Invest. 1994, 94, 1339-1345.
20. Ben-Nun, A.; Wekerle, H.; Cohen, I.R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur. J. Immunol. 1981, 11, 195-199.
21. Anderson, A.C.; Nicholson, L.B.; Legge, K.L.; Turchin, V.; Zaghouani, H.; Kuchroo, V.K. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the selfreactive repertoire. J. Exp. Med. 2000, 191, 761-770.
22. Fort, M.M.; Cheung, J.; Yen, D.; Li, J.; Zurawski, S.M.; Lo, S.; Menon, S.; Clifford, T.; Hunte, B.; Lesley, R. et al. IL-25 Induces IL- 4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001, 15, 985-995.
23. Kuchroo, V.K.; Anderson, A.C.; Waldner, H.; Munder, M.; Bettelli, E.; Nicholson, L.B. T cell response in experimental autoimmune encephalomyelitis (EAE): Role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Ann. Rev. Immunol. 2002, 20, 101-123.
24. Imam, S.A.; Guyton, M.K.; Haque, A.; Vandenbark, A.; Tyor, W.R.; Ray, S.K.; Banik, N.L. Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients. J. Neuroimmunol. 2007, 190, 139-145.
25. Panitch, H.S.; Hirsch, R.L.; Schindler, J.; Johnson, K.P. Treatment of multiple sclerosis with gamma interferon: Exacerbations associated with activation of the immune system. Neurology 1987, 37, 1097-1102.
26. Neukirch, F.; Lyon-Caen, O.; Clanet, M.; Bousquet, J.; Feingold, J.; Druet, P. Asthma, nasal allergies, andmultiple sclerosis. J. Allergy Clin. Immunol. 1997, 99, 270-271.
27. Ando, D.G.; Clayton, J.; Kono, D.; Urban, J.L.; Sercarz, E.E. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell. Immunol. 1989, 124, 132-143.
28. Zamvil, S.S.; Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Ann. Rev. Immunol. 1990, 8, 579-621.
29. Yura, M.; Takahashi, I.; Serada, M.; Koshio, T.; Nakagami, K.; Yuki, Y.; Kiyono, H. Role of MOG stimulated th1 type "light up" (GFP+) CD4+ T cells for the development of experimental autoimmune encephalomyelitis (EAE). J. Autoimmun. 2001, 17, 17-25.
30. Mosmann, T.R.; Coffman, R.L. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol. 1989, 7, 145-173.
31. Adorini, L.; Guéry, J.C.; Trembleau, S. Manipulation of the Th1/Th2 cell balance: An approach to treat human autoimmune diseases? Autoimmunity 1996, 23, 53-68.
32. Krakowski, M.; Owens, T. Interferon-γ confers resistance to experimental allergic encephalomyelitis. Eur. J. Immunol. 1996, 26, 1641-1646.
33. Tran, E.H.; Prince, E.N.; Owens, T. IFN-γ shapes immune invasion of the central nervous system via regulation of chemokines. J. Immunol. 2000, 164, 2759-2768.
34. Gran, B.; Zhang, G.X.; Yu, S.; Li, J.; Chen, X.H.; Ventura, E.S.; Kamoun, M.; Rostami, A. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: Evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J. Immunol. 2002, 169, 7104-7110.
35. Zhang, G.X.; Gran, B.; Yu, S.; Li, J.; Siglienti, I.; Chen, X.; Kamoun, M.; Rostami, A. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor- β2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J. Immunol. 2003, 170, 2153-2160.
36. Gutcher, I.; Urich, E.; Wolter, K.; Prinz, M.; Becher, B. Interleukin 18-independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation. Nat. Immunol. 2006, 7, 946-953.
37. Ferber, I.A.; Brocke, S.; Taylor-Edwards, C; Ridgway, W.; Dinisco, C; Steinman, L.; Dalton, D.; Fathman, C.G. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 1996, 156, 5-7.
38. Cua, D.J.; Sherlock, J.; Chen, Y.; Murphy, C.A.; Joyce, B.; Seymour, B.; Lucian, L.; To, W.; Kwan, S.; Churakova, T. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421, 744-748.
39. Aggarwal, S.; Ghilardi, N.; Xie, M.H.; de Sauvage, F.J.; Gurney, A.L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 2003, 278, 1910-1914.
40. Langrish, C.L.; Chen, Y.; Blumenschein, W.M.; Mattson, J.; Basham, B.; Sedgwick, J.D.; McClanahan, T.; Kastelein, R.A.; Cua, D.J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 2005, 201, 233-240.
41. Park, H.; Li, Z.; Yang, X.O.; Chang, S.H.; Nurieva, R.; Wang, Y.H.; Wang, Y.; Hood, L.; Zhu, Z.; Tian, Q. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 2005, 6, 1133-1141.
42. Harrington, L.E.; Hatton, R.D.; Mangan, P.R.; Turner, H.; Murphy, T.L.; Murphy, K.M.; Weaver, C.T. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 2005, 6, 1123-1132.
43. Annunziato, F.; Cosmi, L.; Santarlasci, V.; Maggi, L.; Liotta, F.; Mazzinghi, B.; Parente, E.; Filì, L.; Ferri, S.; Frosali, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 2007, 204, 1849-1861.
44. Hedegaard, C.J.; Krakauer, M.; Bendtzen, K.; Lund, H.; Sellebjerg, F.; Nielsen, C.H. T helper cell type 1 (Th1, Th2 and Th17 responses to myelin basic protein and disease activity inmultiple sclerosis. Immunology 2008, 125, 161-169.
45. Parham, C; Chirica, M.; Timans, J.; Vaisberg, E.; Travis, M.; Cheung, J.; Pflanz, S.; Zhang, R.; Singh, K.P.; Vega, F. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 2002, 168, 5699-5708.
46. Mangan, P.R.; Harrington, L.E.; O'Quinn, D.B.; Helms, W.S.; Bullard, D.C.; Elson, CO.; Hatton, R.D.; Wahl, S.M.; Schoeb, T.R.; Weaver, C.T. Transforming growth factor-β induces development of the TH17 lineage. Nature 2006, 441, 231-234.
47. Bettelli, E.; Carrier, Y.; Gao, W.; Korn, T.; Strom, T.B.; Oukka, M.; Weiner, H.L.; Kuchroo, V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006, 441, 235-238.
48. Yang, L.; Anderson, D.E.; Baecher-Allan, C; Hastings, W.D.; Bettelli, E.; Oukka, M.; Kuchroo, V.K.; Hafler, D.A. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 2008, 454, 350-352.
49. Korn, T.; Bettelli, E.; Gao, W.; Awasthi, A.; Jäger, A.; Strom, T.B.; Oukka, M.; Kuchroo, V.K. IL-21 initiates an alternative pathway to induce proinflammatory T H17 cells. Nature 2007, 448, 484-487.
50. Lock, C; Hermans, G; Pedotti, R.; Brendolan, A.; Schadt, E.; Garren, H.; Langer-Gould, A.; Strober, S.; Cannella, B.; Allard, J. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 2002, 8, 500-508.
51. Korn, T.; Bettelli, E.; Oukka, M.; Kuchroo, V.K. IL-17 and Th17 cells. Ann. Rev. Immunol. 2009, 27, 485-517.
52. Matusevicius, D.; Kivisäkk, P.; He, B.; Kostulas, N.; Ozenci, V.; Fredrikson, S.; Link, H. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented inmultiple sclerosis. Mult. Scler. 1999, 5, 101-104.
53. Lees, J.R.; Iwakura, Y.; Russell, J.H. Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis induced by adoptive transfer of Th1 cell lines. J. Immunol. 2008, 180, 8066-8072.
54. Sutton, C; Brereton, C; Keogh, B.; Mills, K.H.G.; Lavelle, E.C. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J. Exp. Med. 2006, 203, 1685-1691.
55. De Jonga, B.A.; Huizingab, T.W.J.; Bollenc, E.L.E.M.; Uitdehaagd, B.M.J.; Bosmae, G.P.Th.; van Bucheme, M.A.; Remarquef, E.J.; Burgmansa, A.C.S.; Kalkersg, N.F.; Polmand, C.H. et al. Production of IL-1β and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis. J. Neuroimmunol. 2006, 126, 172-179.
56. Broberg, E.K.; Salmi, A.A.; Hukkanen, V. IL-4 is the key regulator in herpes simplex virus-based gene therapy of BALB/c experimental autoimmune encephalomyelitis. Neurosci. Lett. 2004, 364, 173-178.
57. Haas, J.; Hug, A.; Viehöver, A.; Fritzsching, B.; Falk, C.S.; Filser, A.; Vetter, T.; Milkova, L.; Korporal, M.; Fritz, B. et al. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur. J. Immunol. 2005, 35, 3343-3352.
58. Singh, S.P.; Zhang, H.H.; Foley, J.F.; Hedrick, M.N.; Farber, J.M. Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J. Immunol. 2008, 180, 214-221.
59. Haak, S.; Croxford, A.L.; Kreymborg, K.; Heppner, F.L.; Pouly, S.; Becher, B.; Waisman, A. IL-17A and IL-17F do not contribute vitally to autoimmune neuroinflammation in mice. J. Clin. Invest. 2009, 119, 61-69.
60. Liu, X.; Yun, S.L.; Yu, C.R.; Egwuagu, C.E. Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J. Immunol. 2008, 180, 6070-6076.
61. Stromnes, I.M.; Cerretti, L.M.; Liggitt, D.; Harris, R.A.; Goverman, J.M. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat. Med. 2008, 14, 337-342.
62. Zhou, L.; Ivanov, I.I.; Spolski, R.; Min, R.; Shenderov, K.; Egawa, T.; Levy, D.E.; Leonard, W.J.; Littman, D.R. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 2007, 8, 967-974.
63. Zhang, Z.; Rosenbaum, J.T.; Zhong, W.; Lim, C.; Hinrichs, D.J. Costimulation of Th17 cells: Adding fuel or putting out the fire in the inflamed gut? Semin. Immunopathol. 2010, 32, 55-70.
64. Vollmer, T.L.; Liu, R.; Price, M.; Rhodes, S.; La Cava, A.; Shi, F.D. Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J. Immunol. 2005, 174, 2696-2701.
65. Chen, Z.; O'Shea, J.J. Th17 cells: A new fate for differentiating helper T cells. Immunol. Res. 2008, 41, 87-102.
66. Pot, C.; Jin, H.; Awasthi, A.; Liu, S.M.; Lai, C.Y.; Madan, R.; Sharpe, A.H.; Karp, C.L.; Miaw, S.C.; Ho, I.C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 2009, 183, 797-801.
67. Fitzgerald, D.C.; Ciric, B.; Touil, T.; Harle, H.; Grammatikopolou, J.; Das Sarma, J.; Gran, B.; Zhang, G.X.; Rostami, A. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 2007, 179, 3268-3275.
68. Jäger, A.; Dardalhon, V.; Sobel, R.A.; Bettelli, E.; Kuchroo, V.K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 2009, 183, 7169-7177.
69. Mueller, A.M.; Pedré, X.; Killian, S.; David, M.; Steinbrecher, A. The Decoy Receptor 3 (DcR3, TNFRSF6B) suppresses Th17 immune responses and is abundant in human cerebrospinal fluid. J. Neuroimmunol. 2009, 209, 57-64.
70. Nowak, E.C.; Weaver, C.T.; Turner, H.; Begum-Haque, S.; Becher, B.; Schreiner, B.; Coyle, A.J.; Kasper, L.H.; Noelle, R.J. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 2009, 206, 1653-1660.
71. Ransohoff, R.M.; Kivisäkk, P.; Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 2003, 3, 569-581.
72. Xiao, B.G.; Diab, A.; Zhu, J.; van der Meide, P.; Link, H. Astrocytes induce hyporesponses of myelin basic proteinreactive T and B cell function. J. Neuroimmunol. 1998, 89, 113-121.
73. Dijkstra, C.D.; De Groot, C.J. A.; Huitinga, I. The role of macrophages in demyelination. J. Neuroimmunol. 1992, 40, 183-188.
74. Deshpande, P.; King, I.L.; Segal, B.M. Cutting edge: CNS CD11c+ cells, from mice with encephalomyelitis polarize Th17 cells, and support CD25+CD4+ T cell-mediated immunosuppression, suggesting dual roles in the disease process. J. Immunol. 2007, 178, 6695-6699.
75. Hemmer, B.; Nessler, S.; Zhou, D.; Kieseier, B.; Hartung, H.P. Immunopathogenesis and immunotherapy of multiple sclerosis. Nat. Clin. Pract. Neurol. 2006, 2, 201-211.
76. Neumann, H.; Cavalie, A.; Jenne, D.E.; Wekerle, H. Induction of MHC class I genes in neurons. Science 1995, 269, 549-552.
77. Dandekar, A.A.; Wu, G.F.; Pewe, L.; Perlman, S. Axonal damage is T cell mediated and occurs concomitantly with demyelination in mice infected with a neurotropic coronavirus. J. Virol. 2001, 75, 6115-6120.
78. Probert, L.; Eugster, H.P.; Akassoglou, K.; Bauer, J.; Frei, K.; Lassmann, H.; Fontana, A. TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immunemediated CNS disease. Brain 2000, 123, 2005-2019.
79. Tzartos, J.S.; Friese, M.A.; Craner, M.J.; Palace, J.; Newcombe, J.; Esiri, M.M.; Fugger, L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 2008, 172, 146-155.
80. Li, Y.; Chu, N.; Hu, A.; Gran, B.; Rostami, A.; Zhang, G.X. Increased IL-23p19 expression in multiple sclerosis lesionsand its induction in microglia. Brain 2007, 130, 490-501.
81. Larochelle, C; Alvarez, J.I. Prat A. How do immune cells overcome the blood-brain barrier in multiple sclerosis? FEBS Lett. 2011, 585, 3770-3780.
82. Linker, R.A.; Lühder, F.; Kallen, K.J.; Lee, D.H.; Engelhardt, B.; Rose-John, S.; Gold, R. IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier. J. Neuroimmunol. 2008, 205, 64-72.
83. Ifergan, I.; Kébir, H.; Bernard, M.; Wosik, K.; Dodelet-Devillers, A.; Cayrol, R.; Arbour, N.; Prat, A. The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 2008, 131, 785-799.
84. Miljkovic, D.; Momcilovic, M.; Stojanovic, I.; Stosic-Grujicic, S.; Ramic, Z.; Mostarica-Stojkovic, M. Astrocytes stimulate interleukin-17 and interferon-γ production in vitro. J. Neurosci. Res. 2007, 85, 3598-3606.
85. Das Sarma, J.; Ciric, B.; Marek, R.; Sadhukhan, S.; Caruso, M.L.; Shafagh, J.; Fitzgerald, D.C.; Shindler, K.S.; Rostami, A. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J. Neuroinflamm. 2009, 6, doi: 10.1186/1742-2094-6-14.
86. Ma, X.; Reynolds, S.L.; Baker, B.J.; Li, X.; Benveniste, E.N.; Qin, H. IL-17 enhancement of the IL-6 signaling cascade in astrocytes. J. Immunol. 2010, 184, 4898-4906.
87. Kang, Z.; Altuntas, C.Z.; Gulen, M.F.; Liu, C; Giltiay, N.; Qin, H.; Liu, L.; Qian, W.; Ransohoff, R.M.; Bergmann, C; et al. Astrocyte restricted ablation of interleukin-17-induced act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 2010, 32, 414-425.
88. Merkler, D.; Böscke, R.; Schmelting, B.; Czéh, B.; Fuchs, E.; Brück, W.; Stadelmann, C. Differential macrophage/microglia activation in neocortical EAE lesions in the marmoset monkey. Brain Pathol. 2006, 16, 117-123.
89. Wiendl, H.; Toyka, K.V.; Rieckmann, P.; Gold, R.; Hartung, H.P.; Hohlfeld, R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J. Neurol. 2008, 255, 1449-1463.
90. Bielekova, B.; Becker, B.L. Monoclonal antibodies in MS: Mechanisms of action. Neurology 2010, 74, S31-S40.
91. Bates, D. Alemtuzumab. Int. MS J. MS Forum 2009, 16, 75-76.
92. Hawker, K.; O'Connor, P.; Freedman, M.S.; Calabresi, P.A.; Antel, J.; Simon, J.; Hauser, S.; Waubant, E.; Vollmer, T.; Panitch, H. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 2009, 66, 460-471.
93. Bielekova, B.; Howard, T.; Packer, A.N.; Richert, N.; Blevins, G.; Ohayon, J.; Waldmann, T.A.; McFarland, H.F.; Martin, R. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch. Neurol. 2009, 66, 483-489.
94. Dhib-Jalbut, S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 2002, 58, S3-S9.
95. Krakauer, M.; Sorensen, P.; Khademi, M.; Olsson, T.; Sellebjerg, F. Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: Interferon-β treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression. Mult. Scler. 2008, 14, 622-630.
96. Ramgolam, V.S.; Sha, Y.; Jin, J.; Zhang, X.; Markovic-Plese, S. IFN-β inhibits human Th17 cell differentiation. J. Immunol. 2009, 183, 5418-5427.
97. Sweeney, CM.; Lonergan, R.; Basdeo, S.A.; Kinsella, K.; Dungan, L.S.; Higgins, S.C.; Kelly, P.J.; Costelloe, L.; Tubridy, N.; Mills, K.H.; et al. IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav. Immun. 2011, 25, 1170-1181.
98. Axtell, R.C.; Raman, C; Steinman, L. Interferon-β exacerbates Th17-mediated inflammatory disease. Trends Immunol. 2011, 32, 272-277.
99. Conti, L.; de Palma, R.; Rolla, S.; Boselli, D.; Rodolico, G.; Kaur, S.; Silvennoinen, O.; Niccolai, E.; Amedei, A.; Ivaldi, F.; et al. Th17 cells in multiple sclerosis express higher levels of JAK2, which increases their surface expression of IFN-γR2. J. Immunol. 2012, 188, 1011-1018.
100. Antel, J.; Bar-Or, A. Roles of immunoglobulins and B cells in multiple sclerosis: From pathogenesis to treatment. J. Neuroimmunol. 2006, 180, 3-8.
101. Fillatreau, S.; Gray, D.; Anderton S.M. Not always the bad guys: B cells as regulators of autoimmune pathology. Nat. Rev. Immunol. 2008, 8, 391-397.
102. Valenzuela, R.M.; Costello, K.; Chen, M.; Said, A.; Johnson, K.P.; Dhib-Jalbut, S. Clinical response to glatirameracetate correlates with modulation of IFN-γ and IL-4 expression in multiple sclerosis. Mult. Scler. 2007, 13, 754-762.
103. Ramgolam, V.S.; Sha, Y.; Marcus, K.L.; Choudhary, N.; Troiani, L.; Chopra, M.; Markovic-Plese, S. B cells as a therapeutic target for IFN-β in relapsing-remitting multiple sclerosis. J. Immunol. 2011, 186, 4518-4526.
104. Hong, J.; Li, N.; Zhang, X.; Zheng, B.; Zhang, J.Z. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc. Natl. Acad. Sci. USA 2005, 102, 6449-6454.
105. Vieira, P.L.; Heystek, H.C.; Wormmeester, J.; Wierenga, E.A.; Kapsenberg, M.L. Glatiramer acetate (copolymer-1,copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J. Immunol. 2003, 170, 4483-4488.
106. Jung, S.; Siglienti, I.; Grauer, O.; Magnus, T.; Scarlato, G.; Toyka, K. Induction of IL-10 in rat peritoneal macrophages and dendritic cells by glatiramer acetate. J. Neuroimmunol. 2004, 148, 63-73.
107. Hartung, H.P.; Gonsette, R.; König, N.; Kwiecinski, H.; Guseo, A.; Morrissey, S.P.; Krapf, H.; Zwingers, T. Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, doubleblind, randomised, multicentre trial. Lancet 2002, 360, 2018-2025.
108. Vogelgesang, A.; Rosenberg, S.; Skrzipek, S.; Broker, B.M.; Dressel, A. Mitoxantrone treatment in multiple sclerosis induces TH2-type cytokines. Acta Neurol. Scand. 2010, 122, 237-243.
109. Hohlfeld, R. Multiple sclerosis: Cladribine-a contentious therapeutic contender for MS. Nat. Rev. Neurol. 2011, 7, 425-427.
110. Matloubian, M.; Lo, C.G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.L.; Proia, R.L.; Cyster, J.G. Lymphocyte egress from thymus and peripheral lymphoid organs isdependent on S1P receptor 1. Nature 2004, 427, 355-360.
111. Ehling, R.; Berger, T.; Reindl, M. Multiple sclerosis-Established and novel therapeutic approaches. Cent. Nerv. Syst. Agents Med. Chem. 2010, 10, 3-15.
112. Strader, C.R.; Pearce, C.J.; Oberlies, N.H. Fingolimod FTY720: A recently approved multiple sclerosis drug based on a fungal secondary metabolite. J. Nat. Prod. 2011, 74, 900-907.
113. Lim, S.Y.; Constantinescu, C.S. Current and future disease-modifying therapies in multiple sclerosis. Int. J. Clin. Pract. 2010, 64, 637-650.
114. Harada J.; Foley, M.; Moskowitz, M.A.; Waeber, C. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J. Neurochem. 2004, 88, 1026-1039.
115. Allende, M.L.; Proia, R.L. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim. Biophys. Acta 2002, 1582, 222-227.
116. Jolly, P.S.; Bektas, M.; Olivera, A.; Gonzalez-Espinosa, C.; Proia, R.L.; Rivera, J.; Milstien, S.; Spiegel, S. Transactivation of sphingosine-1-phosphate receptors by FcεRI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 2004, 199, 959-970.
117. Donati, C.; Meacci, E.; Nuti, F.; Becciolini, L.; Farnararo, M.; Bruni, P. Sphingosine 1-phosphate regulates myogenic differentiation: A major role for S1P2 receptor. FASEB J. 2005, 19, 449-451.
118. Krump-Konvalinkova, V.; Yasuda, S.; Rubic, T.; Makarova, N.; Mages, J.; Erl, W.; Vosseler, C.; Kirkpatrick, C.J.; Tigyi, G.; Siess, W. Stable knock-down of the sphingosine 1-phosphate receptor S1P1 influences multiple functions of human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 546-552.
119. Halin, C.; Scimone, M.L.; Bonasio, R.; Gauguet J.M.; Mempel, T.R.; Quackenbush, E.; Proia, R.L.; Mandala, S.; von Andrian, U.H. The S1Panalog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches. Blood 2005, 106, 1314-1322.
120. Tao, R.; Hoover, H.E.; Zhang, J.; Honbo, N.; Alano, C.C.; Karliner, J.S. Cardiomyocyte S1P1 receptor-mediated extracellular signal-related kinase signaling and desensitization. J. Cardiovasc. Pharmacol. 2009, 53, 486-494.
121. Brinkmann, V.; Davis, M.D.; Heise, C.E.; Albert, R.; Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 2002, 277, 21453-21457.
122. Kataoka, H.; Sugahara, K.; Shimano, K.; Teshima, K.; Koyama, M.; Fukunari, A.; Chiba, K. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell. Mol. Immunol. 2005, 2, 439-448.
123. Brinkmann, V. FTY720 (fingolimod) in multiple sclerosis: Therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol. 2009, 158, 1173-1182.
124. Mehling, M.; Lindberg, R.; Raulf, F.; Kuhle, J.; Hess, C.; Kappos, L.; Brinkmann, V. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 2010, 75, 403-410.
125. Webb, M.; Tham, C.S.; Lin, F.F.; Lariosa-Willingham, K.; Yu, N.; Hale, J.; Mandala, S.; Chun, J.; Rao, T.S. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol. 2004, 153, 108-121.
126. Van Doorn, R.; van Horssen, J.; Verzijl, D.; Witte, M.; Ronken, E.; van Het Hof, B.; Lakeman, K.; Dijkstra, C.D.; van der Valk, P.; Reijerkerk, A.; et al. Phingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. GLIA 2010, 58, 1465-1476.
127. Rouach, N.; Pébay, A.; Même, W.; Cordier, J.; Ezan, P.; Etienne, E.; Giaume, C.; Tencé, M. S1P inhibits gap junctions in astrocytes: Involvement of G and Rho GTPase/ROCK. Eur. J. Neurosci. 2006, 23, 1453-1464.
128. Beutler, E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992, 340, 952-956.
129. Carson, D.A.; Wasson, D.B.; Taetle, R.; Yu, A. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood 1983, 62, 737-743.
130. Yates, D. Multiple sclerosis: Orally administered cladribine displays efficacy in multiple sclerosis trial. Nat. Rev. Neurol. 2010, 6, 182.
131. Giovannoni, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Sørensen, P.S.; Vermersch, P.; Hamlett, A.; Viglietta, V.; Greenberg, S. CLARITY study group. Sustained disease-activity-free status in patients with relapsingremitting multiple sclerosis treated with cladribine tablets in the CLARITY study: A post-hoc and subgroup analysis. Lancet Neurol. 2011, 10, 329-337.
132. Giovannoni, G.; Comi, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Soelberg Sørensen, P.; Vermersch, P.; Chang, P.; Hamlett, A.; Musch, B.; et al. A placebocontrolled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 416-426.
133. Barten, L.J.; Allington, D.R.; Procacci, K.A.; Rivey, M.P. New approaches in the management of multiple sclerosis. Drug Des. Dev. Ther. 2010, 4, 343-366.
134. Minagar, A.; Alexander, J.S.; Sahraian, M.A.; Zivadinov, R. Alemtuzumab and multiple sclerosis: Therapeutic application. Expert Opin. Biol. Ther. 2010, 10, 421-429.
135. Lopez-Diego, R.S.; Weiner, H.L. Novel therapeutic strategies for multiple sclerosis-A multifaceted adversary. Nat. Rev. Drug Discovery 2008, 7, 909-925.
136. Zabad, R.K.; Metz, L.M.; Todoruk, T.R.; Zhang, Y.; Mitchell, J.R.; Yeung, M.; Patry, D.G.; Bell, R.B.; Yong, V.W. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: A pilot study. Mult. Scler. 2007, 13, 517-526.
137. Korn, T. Pathophysiology of multiple sclerosis. J. Neurol. 2008, 255, 2-6.
138. Komiyama, Y.; Nakae, S.; Matsuki, T.; Nambu, A.; Ishigame, H.; Kakuta, S.; Sudo, K.; Iwakura, Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 2006, 177, 566-573.
139. Steinman, L. Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat. Immunol. 2010, 11, 41-44.
140. Edwards, L.J.; Robins, R.A.; Constantinescu, C.S. Th17/Th1 phenotype in demyelinating disease. Cytokine 2010, 50, 19-23.
141. Murphy, A.C.; Lalor, S.J.; Lynch, M.A.; Mills, K.H.G. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav. Immun. 2010, 24, 641-651.
142. Fletcher, J.M.; Lalor, S.J.; Sweeney, C.M.; Tubridy, N.; Mills, K.H.G. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis, Clin. Exp. Immunol. 2010, 162, 1-11.
143. Lovett-Racke, A.E.; Yang, Y.; Racke, M.K. Th1 versus Th17: Are T cell cytokines relevant in multiple sclerosis? Biochim. Biophys. Acta 2011, 1812, 246-251.
144. Naismith, R.T.; Piccio, L.; Lyons, J.A.; Lauber, J.; Tutlam, N.T.; Parks, B.J.; Trinkaus, K.; Song, S.K.; Cross, A.H. Rituximab addon therapy for breakthrough relapsing multiple sclerosis: A 52-week phase II trial. Neurology 2010, 74, 1860-1867.