NF-κB, a potential therapeutic target for the treatment of multiple sclerosis

CNS and Neurological Disorders - Drug Targets

Volumn 7, Issue 6, 2008, Pages 536-557

  Yan, J ^a   Greer, J M ^a  

^a UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

Autoimmunity; I B; IKK; Multiple sclerosis; NF B; Therapeutic intervention; Therapy

Indexed keywords

AZATHIOPRINE; BETA INTERFERON; BETA1A INTERFERON; CLADRIBINE; CORTICOSTEROID DERIVATIVE; CURCUMIN; CYCLOPHOSPHAMIDE; CYCLOSPORIN; ESTRIOL; ESTROGEN; GLATIRAMER; GLUCOCORTICOID; HLA DR ANTIGEN; I KAPPA B; I KAPPA B KINASE ALPHA; I KAPPA B KINASE INHIBITOR; IMMUNOGLOBULIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERFERON BETA SERINE; LACTACYSTIN BETA LACTONE; METHOTREXATE; METHYLPREDNISOLONE; MITOXANTRONE; NATALIZUMAB; THYMOQUINONE; TUMOR NECROSIS FACTOR ALPHA;

ALLERGIC ENCEPHALOMYELITIS; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; AUTOIMMUNITY; B LYMPHOCYTE; BLOOD BRAIN BARRIER; BRAIN CELL; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL PROLIFERATION; DENDRITIC CELL; DISEASE COURSE; DRUG POTENCY; DRUG TARGETING; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; GENE DELIVERY SYSTEM; GENETIC POLYMORPHISM; GENETIC SUSCEPTIBILITY; HEREDITY; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOPATHOGENESIS; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATION; LYMPHOCYTE ACTIVATION; MACROPHAGE; MULTIPLE SCLEROSIS; NONHUMAN; PROTEIN DEGRADATION; REGULATORY T LYMPHOCYTE; RELAPSE; REMISSION; REVIEW; SIGNAL TRANSDUCTION; TH1 CELL; TH17 CELL;

ANIMALS; DRUG DELIVERY SYSTEMS; HUMANS; MULTIPLE SCLEROSIS; NF-KAPPA B;

EID: 70350011787     PISSN: 18715273     EISSN: None     Source Type: Journal    
DOI: 10.2174/187152708787122941     Document Type: Review

References (192)

1. Noseworthy, J.H.; Lucchinetti, C.; Rodriguez, M.; Weinshenker, B.G. Multiple sclerosis. N. Engl. J. Med., 2000, 343, 938-52.
2. Dyment, D.A.; Ebers, G.C.; Sadovnick, A.D. Genetics of multiple sclerosis. Lancet Neurol., 2004, 3, 104-10.
3. Weiner, H.L. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol., 2008, 255 (Suppl 1), 3-11.
4. Hafler, D.A. Multiple sclerosis. J. Clin. Invest., 2004, 113, 788-94.
5. Vukusic, S.; Confavreux, C. Primary and secondary progressive multiple sclerosis. J. Neurol. Sci., 2003, 206, 153-5.
6. Lublin, F.D.; Reingold, S.C. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology, 1996, 46, 907-11.
7. Confavreux, C.; Aimard, G.; Devic, M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain, 1980, 103, 281-300.
8. Trapp, B.D.; Nave, K.A. Multiple sclerosis: an immune or neurodegenerative disorder? Ann. Rev. Neurosci., 2008, 31, 247-69.
9. Martinelli, V.; Rodegher, M.; Moiola, L.; Comi, G. Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis. Neurol. Sci., 2004, 25 (Suppl 4), S350-55.
10. Thompson, A.J.; Kermode, A.G.; Wicks, D.; MacManus, D.G.; Kendall, B.E.; Kingsley, D.P.; McDonald, W.I. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann. Neurol., 1991, 29, 53-62.
11. Thompson, A.J.; Polman, C.H.; Miller, D.H.; McDonald, W.I.; Brochet, B.; Filippi, M.M.X.; De Sa, J. Primary progressive multiple sclerosis. Brain, 1997, 120, 1085-96.
12. Zaffaroni, M.; Ghezzi, A. The prognostic value of age, gender, pregnancy and endocrine factors in multiple sclerosis. Neurol. Sci., 2000, 21 (Suppl 2), S857-60.
13. Gayou, A.; Brochet, B.; Dousset, V.J. Transitional progressive multiple sclerosis: a clinical and imaging study. Neurol. Neurosurg. Psychiatry, 1997, 63, 396-8.
14. Foong, J.; Rozewicz, L.; Chong, W.K.; Thompson, A.J.; Miller, D.H.; Ron, M.A. A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis. J. Neurol., 2000, 247, 97-101.
15. Pender, M.P.; Greer, J.M. Immunology of multiple sclerosis. Curr. Allergy Asthma Rep., 2007, 7, 285-92.
16. Confavreux, C.; Vukusic, S. Natural history of multiple sclerosis: a unifying concept. Brain, 2006, 129, 606-16.
17. Tullman, M.J.; Oshinsky, R.J.; Lublin, F.D.; Cutter, G.R. Clinical characteristics of progressive relapsing multiple sclerosis. Mult. Scler., 2004, 10, 451-54.
18. Pender, M.P.; Csurhes, P.A.; Greer, J.M.; Mowat, P.D.; Henderson, R.D.; Cameron, K.D.; Purdie, D.M.; McCombe, P.A.; Good, M.F. Surges of increased T cell reactivity to an encephalitogenic region of myelin proteolipid protein occur more often in patients with multiple sclerosis than in healthy subjects. J. Immunol., 2000, 165, 5322-31.
19. Greer, J.M.; Csurhes, P.A.; Muller, D.M.; Pender, M.P. Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. J. Immunol., 2008, 180, 6402-10.
20. Das, M.P.; Nicholson, L.B.; Greer, J.M.; Kuchroo, V.K. Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein. J. Exp. Med., 1997, 186, 867-76.
21. Kroenke, M.A.; Carlson, T.J.; Andjelkovic, A.V.; Segal, B.M. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J. Exp. Med., 2008, 205, 1535-41.
22. Kebir, H.; Kreymborg, K.; Ifergan, I.; Dodelet-Devillers, A.; Cayrol, R.; Bernard, M.; Giuliani, F.; Arbour, N.; Becher, B.; Prat, A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med., 2007, 13, 1173-75.
23. Stromnes, I.M.; Cerretti, L.M.; Liggitt, D.; Harris, R.A.; Goverman, J.M. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat. Med., 2008, 14, 337-42.
24. McCandless, E.E.; Klein, R.S. Molecular targets for disrupting leukocyte trafficking during multiple sclerosis. Exp. Rev. Mol. Med., 2007, 9, 1-19.
25. Crawford, M.P.; Yan, S.X.; Ortega, S.B.; Mehta, R.S.; Hewitt, R.E.; Price, D.A.; Stastny, P.; Douek, D.C.; Koup, R.A.; Racke, M.K.; Karandikar, N.J. High prevalence of autoreactive, neuroantigenspecific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood, 2004, 103, 4222-31.
26. Berthelot, L.; Laplaud, D.-A.; Pettré, S.; Ballet, C.; Michel, L.; Hillion, S.; Braudeau, C.; Connan, F.; Lefrère, F.; Wiertlewski, S.; Guillet, J.-G.; Brouard, S.; Choppin, J.; Soulillou, J.-P. Blood CD8+ T cell responses against myelin determinants in multiple sclerosis and healthy individuals. Eur. J. Immunol., 2008, 38, 1889-99.
27. Zozulya, A.L.; Wiendl, H. The role of regulatory T cells in multiple sclerosis. Nat. Clin. Pract. Neurol., 2008, 4, 384-98.
28. Haas, J.; Hug, A.; Viehover, A.; Fritzsching, B.; Falk, C.S.; Filser, A.; Vetter, T.; Milkova, L.; Korporal, M.; Fritz, B.; Storch-Hagenlocher, B.; Krammer, P.H.; Suri-Payer, E.; Wildemann, B. 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, 3343-52.
29. Feger, U.; Luther, C.; Poeschel, S.; Melms, A.; Tolosa, E.; Wiendl, H. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin. Exp. Immunol., 2007, 147, 412-18.
30. Vyshkina, T.; Kalman, B. Autoantibodies and neurodegeneration in multiple sclerosis. Lab. Invest., 2008, 88, 796-807.
31. Baeuerle, P.A.; Henkel, T. Function and activation of NF-kappa B in the immune system. Ann. Rev. Immunol., 1994, 12, 141-79.
32. Comabella, M.; Martin, R. Genomics in multiple sclerosis - current state and future directions. J. Neuroimmunol., 2007, 187, 1-8.
33. Li, Q.; Verma, I.M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol., 2002, 2, 725-34.
34. Karin, M.; Greten, F.R. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol., 2005, 5, 749-59.
35. Siebenlist, U.; Franzoso, G.; Brown, K. Structure, regulation and function of NF-kappa B. Ann. Rev. Cell Biol., 1994, 10, 405-55.
36. Baeuerle, P.A.; Baltimore, D. NF-kappa B: ten years after. Cell, 1996, 87, 13-20.
37. Karin, M.; Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-[kappa] B activity. Ann. Rev. Immunol., 2000, 18, 621-63.
38. Perkins, N.D. Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene, 2006, 25, 6717-30.
39. Hoffmann, A.; Natoli, G.; Ghosh, G. Transcriptional regulation via the NF-kappaB signaling module. Oncogene, 2006, 25, 6706-16.
40. Whiteside, S.T.; Israel, A. I kappa B proteins: structure, function and regulation. Semin. Cancer Biol., 1997, 8, 75-82.
41. Yamazaki, S.; Muta, T.; Takeshige, K. A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factorkappaB in the nuclei. J. Biol. Chem., 2001, 276, 27657-62.
42. Yamamoto, Y.; Gaynor, R.B. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem. Sci., 2004, 29, 72-79.
43. Barnes, P.J.; Karin, M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med., 1997, 336, 1066-71.
44. Ghosh, S.; May, M.J.; Kopp, E.B. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Ann. Rev. Immunol., 1998, 16, 225-60.
45. Viatour, P.; Merville, M.P.; Bours, V. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem. Sci., 2005, 30, 43-52.
46. Hsu, H.; Xiong, J.; Goeddel, D.V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell, 1995, 81, 495-504.
47. Brown, K.; Gerstberger, S.; Carlson, L.; Franzoso, G.; Siebenlist, U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science, 1995, 267, 1485-88.
48. Gilmore, T.D.; Herscovitch, M. Inhibitors of NFkappaB signaling: 785 and counting. Oncogene, 2006, 25, 6887-99.
49. Baldwin, A.S., Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Ann. Rev. Immunol., 1996, 14, 649-83.
50. Pahl, H.L. Activators and target genes of Rel/NFkappaB transcription factors. Oncogene, 1999, 18, 6853-66.
51. Bonizzi, G.; Karin, M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol., 2004, 25, 280-88.
52. Birbach, A.; Gold, P.; Binder, B.R.; Hofer, E.; de Martin, R.; Schmid, J.A. Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus. J. Biol. Chem., 2002, 277, 10842-51.
53. Dejardin, E.; Droin, N.M.; Delhase, M.; Haas, E.; Cao, Y.; Makris, C.; Li, Z.W.; Karin, M.; Ware, C.F.; Green, D.R. The lymphotoxin-beta receptor induces different patterns of gene expression via two NFkappaB pathways. Immunity, 2002, 17, 525-35.
54. Claudio, E.; Brown, K.; Park, S.; Wang, H.; Siebenlist, U. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat. Immunol., 2002, 3, 958-65.
55. Coope, H.J.; Atkinson, P.G.; Huhse, B.; Belich, M.; Janzen, J.; Holman, M.J.; Klaus, G.G.; Johnston, L.H.; Ley, S.C. CD40 regulates the processing of NFkappaB2 p100 to p52. EMBO J., 2002, 21, 5375-85.
56. Eliopoulos, A.G.; Caamano, J.H.; Flavell, J.; Reynolds, G.M.; Murray, P.G.; Poyet, J.L.; Young, L.S. Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NFkappaB2 to p52 via an IKKgamma/NEMOindependent signalling pathway. Oncogene, 2003, 22, 7557-69.
57. Dejardin, E. The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem. Pharmacol., 2006, 72, 1161-79.
58. Lawrence, T.; Bebien, M.; Liu, G.Y.; Nizet, V.; Karin, M. IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature, 2005, 434, 1138-43.
59. Kinoshita, D.; Hirota, F.; Kaisho, T.; Kasai, M.; Izumi, K.; Bando, Y.; Mouri, Y.; Matsushima, A.; Niki, S.; Han, H.; Oshikawa, K.; Kuroda, N.; Maegawa, M.; Irahara, M.; Takeda, K.; Akira, S.; Matsumoto, M. Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J. Immunol., 2006, 176, 3995-4002.
60. Tas, S.W.; Vervoordeldonk, M.J.; Hajji, N.; Schuitemaker, J.H.; van der Sluijs, K.F.; May, M.J.; Ghosh, S.; Kapsenberg, M.L.; Tak, P.P.; de Jong, E.C. Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood, 2007, 110, 1540-49.
61. Tergaonkar, V.; Bottero, V.; Ikawa, M.; Li, Q.; Verma, I.M. IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Mol. Cell. Biol., 2003, 23, 8070-83.
62. Imbert, V.; Rupec, R.A.; Livolsi, A.; Pahl, H.L.; Traenckner, E.B.; Mueller-Dieckmann, C.; Farahifar, D.; Rossi, B.; Auberger, P.; Baeuerle, P.A.; Peyron, J.F. Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha. Cell, 1996, 86, 787-98.
63. Kato, T., Jr.; Delhase, M.; Hoffmann, A.; Karin, M. CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response. Mol. Cell, 2003, 12, 829-39.
64. Takada, Y.; Mukhopadhyay, A.; Kundu, G.C.; Mahabeleshwar, G.H.; Singh, S.; Aggarwal, B.B. Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J. Biol. Chem., 2003, 278, 24233-41.
65. Thompson, J.E.; Phillips, R.J.; Erdjument-Bromage, H.; Tempst, P.; Ghosh, S. I kappa B-beta regulates the persistent response in a biphasic activation of NFkappa B. Cell, 1995, 80, 573-82.
66. Tergaonkar, V.; Correa, R.G.; Ikawa, M.; Verma, I.M. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity. Nat. Cell Biol., 2005, 7, 921-23.
67. Siebenlist, U.; Brown, K.; Claudio, E. Control of lymphocyte development by nuclear factor-kappaB. Nat. Rev. Immunol., 2005, 5, 435-45.
68. Hayden, M.S.; West, A.P.; Ghosh, S. NF-kappaB and the immune response. Oncogene, 2006, 25, 6758-80.
69. Pasparakis, M.; Schmidt-Supprian, M.; Rajewsky, K. IkappaB kinase signaling is essential for maintenance of mature B cells. J. Exp. Med., 2002, 196, 743-52.
70. Li, Z.-W.; Omori, S.A.; Labuda, T.; Karin, M.; Rickert, R.C. IKK beta is required for peripheral B cell survival and proliferation. J. Immunol., 2003, 170, 4630-37.
71. Souto-Carneiro, M.M.; Fritsch, R.; Sepulveda, N.; Lagareiro, M.J.; Morgado, N.; Longo, N.S.; Lipsky, P.E. The NF-kappaB canonical pathway is involved in the control of the exonucleolytic processing of coding ends during V(D)J recombination. J. Immunol., 2008, 180, 1040-49.
72. Schmidt-Supprian, M.; Courtois, G.; Tian, J.; Coyle, A.J.; Israel, A.; Rajewsky, K.; Pasparakis, M. Mature T cells depend on signaling through the IKK complex. Immunity, 2003, 19, 377-89.
73. Schmidt-Supprian, M.; Tian, J.; Grant, E.P.; Pasparakis, M.; Maehr, R.; Ovaa, H.; Ploegh, H.L.; Coyle, A.J.; Rajewsky, K. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc. Natl. Acad. Sci. USA, 2004, 101, 4566-71.
74. Shen, F.; Gaffen, S.L. Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine, 2008, 41, 92-104.
75. Munn, D.H.; Sharma, M.D.; Lee, J.R.; Jhaver, K.G.; Johnson, T.S.; Keskin, D.B.; Marshall, B.; Chandler, P.; Antonia, S.J.; Burgess, R.; Slingluff, C.L., Jr.; Mellor, A.L. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science, 2002, 297, 1867-70.
76. Grohmann, U.; Volpi, C.; Fallarino, F.; Bozza, S.; Bianchi, R.; Vacca, C.; Orabona, C.; Belladonna, M.L.; Ayroldi, E.; Nocentini, G.; Boon, L.; Bistoni, F.; Fioretti, M.C.; Romani, L.; Riccardi, C.; Puccetti, P. Links Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med., 2007, 13, 579-86.
77. Puccetti, P.; Fallarino, F. Generation of T cell regulatory activity by plasmacytoid dendritic cells and tryptophan catabolism. Blood Cells. Mol. Dis., 2008, 40, 101-05.
78. Puccetti, P.; Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat. Rev. Immunol., 2007, 7, 817-23.
79. Groesdonk, H.V.; Schlottmann, S.; Richter, F.; Georgieff, M.; Senftleben, U. Escherichia coli prevents phagocytosis-induced death of macrophages via classical NF-kappaB signaling, a link to T-cell activation. Infect. Immun., 2006, 74, 5989-6000.
80. Chu, W.; Gong, X.; Li, Z.; Takabayashi, K.; Ouyang, H.; Chen, Y.; Lois, A.; Chen, D.J.; Li, G.C.; Karin, M.; Raz, E. DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA. Cell, 2000, 103, 909-18.
81. Greten, F.R.; Eckmann, L.; Greten, T.F.; Park, J.M.; Li, Z.W.; Egan, L.J.; Kagnoff, M.F.; Karin, M. IKK-beta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 2004, 118, 285-90.
82. Mattson, M.P.; Camandola, S. NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest., 2001, 107, 247-54.
83. Memet, S. NF-kappaB functions in the nervous system: from development to disease. Biochem. Pharmacol., 2006, 72, 1180-95.
84. O'Neill, L.A.; Kaltschmidt, C. NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci., 1997, 20, 252-58.
85. Kaltschmidt, C.; Kaltschmidt, B.; Baeuerle, P.A. Brain synapses contain inducible forms of the transcription factor NF-kappa B. Mech. Dev., 1993, 43, 135-47.
86. Schneider, A.; Martin-Villalba, A.; Weih, F.; Vogel, J.; Wirth, T.; Schwaninger, M. NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat. Med., 1999, 5, 554-59.
87. Ullrich, O.; Diestel, A.; Bechmann, I.; Homberg, M.; Grune, T.; Hass, R.; Nitsch, R. Turnover of oxidatively damaged nuclear proteins in BV-2 microglial cells is linked to their activation state by poly-ADP-ribose polymerase. FASEB J., 2001, 15, 1460-62.
88. Gveric, D.; Kaltschmidt, C.; Cuzner, M.L.; Newcombe, J. Transcription factor NF-kappaB and inhibitor I kappaBalpha are localized in macrophages in active multiple sclerosis lesions. J. Neuropathol. Exp. Neurol., 1998, 57, 168-78.
89. Nicholas, R.S.; Wing, M.G.; Compston, A. Nonactivated microglia promote oligodendrocyte precursor survival and maturation through the transcription factor NF-kappa B. Eur. J. Neurosci., 2001, 13, 959-67.
90. Vollgraf, U.; Wegner, M.; Richter-Landsberg, C. Activation of AP-1 and nuclear factor-kappaB transcription factors is involved in hydrogen peroxide-induced apoptotic cell death of oligodendrocytes. J. Neurochem., 1999, 73, 2501-09.
91. Bonetti, B.; Stegagno, C.; Cannella, B.; Rizzuto, N.; Moretto, G.; Raine, C.S. Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. Implications for oligodendrocyte pathology. Am. J. Pathol., 1999, 155, 1433-38.
92. Achiron, A.; Gurevich, M. Peripheral blood gene expression signature mirrors central nervous system disease: the model of multiple sclerosis. Autoimmun. Rev., 2006, 5, 517-22.
93. Chabas, D.; Baranzini, S.E.; Mitchell, D.; Bernard, C.C.; Rittling, S.R.; Denhardt, D.T.; Sobel, R.A.; Lock, C.; Karpuj, M.; Pedotti, R.; Heller, R.; Oksenberg, J.R.; Steinman, L. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science, 2001, 294, 1731-35.
94. Lindberg, R.L.; De Groot, C.J.; Certa, U.; Ravid, R.; Hoffmann, F.; Kappos, L.; Leppert, D. Multiple sclerosis as a generalized CNS disease - comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS. J. Neuro-immunol., 2004, 152, 154-67.
95. Mycko, M.P.; Papoian, R.; Boschert, U.; Raine, C.S.; Selmaj, K.W. cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Brain, 2003, 126, 1048-57.
96. Mycko, M.P.; Papoian, R.; Boschert, U.; Raine, C.S.; Selmaj, K.W. Microarray gene expression profiling of chronic active and inactive lesions in multiple sclerosis. Clin. Neurol. Neurosurg., 2004, 106, 223-29.
97. Satoh, J.I.; Obayashi, S.; Misawa, T.; Tabunoki, H.; Yamamura, T.; Arima, K.; Konno, H. Neuromyelitis optica/Devic's disease: Gene expression profiling of brain lesions. Neuropathology, 2008, 28, 561-xxx.
98. Lock, C.; Hermans, G.; Pedotti, R.; Brendolan, A.; Schadt, E.; Garren, H.; Langer-Gould, A.; Strober, S.; Cannella, B.; Allard, J.; Klonowski, P.; Austin, A.; Lad, N.; Kaminski, N.; Galli, S.J.; Oksenberg, J.R.; Raine, C.S.; Heller, R.; Steinman, L. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med., 2002, 8, 500-08.
99. Tajouri, L.; Mellick, A.S.; Ashton, K.J.; Tannenberg, A.E.; Nagra, R.M.; Tourtellotte, W.W.; Griffiths, L.R. Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis. Brain Res. Mol. Brain Res., 2003, 119, 170-83.
100. Flores, N.; Duran, C.; Blasco, M.R.; Puerta, C.; Dorado, B.; Garcia-Merino, A.; Ballester, S. NFkappaB and AP-1 DNA binding activity in patients with multiple sclerosis. J. Neuroimmunol., 2003, 135, 141-47.
101. Eggert, M.; Goertsches, R.; Seeck, U.; Dilk, S.; Neeck, G.; Zettl, U.K. Changes in the activation level of NF-kappa B in lymphocytes of MS patients during glucocorticoid pulse therapy. J. Neurol. Sci., 2008, 264, 145-50.
102. Achiron, A.; Feldman, A.; Mandel, M.; Gurevich, M. Impaired expression of peripheral blood apoptotic-related gene transcripts in acute multiple sclerosis relapse. Ann. NY Acad. Sci., 2007, 1107, 155-67.
103. Bomprezzi, R.; Ringner, M.; Kim, S.; Bittner, M.L.; Khan, J.; Chen, Y.; Elkahloun, A.; Yu, A.; Bielekova, B.; Meltzer, P.S.; Martin, R.; McFarland, H.F.; Trent, J.M. Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Mol. Genet., 2003, 12, 2191-99.
104. Aktas, O.; Prozorovski, T.; Smorodchenko, A.; Savaskan, N.E.; Lauster, R.; Kloetzel, P.M.; Infante-Duarte, C.; Brocke, S.; Zipp, F. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol., 2004, 173, 5794-800.
105. Bettelli, E.; Dastrange, M.; Oukka, M. Foxp3 interacts with nuclear factor of activated T cells and NFkappa B to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl. Acad. Sci. USA, 2005, 102, 5138-43.
106. Cvetkovic, I.; Miljkovic, D.; Vuckovic, O.; Harhaji, L.; Nikolic, Z.; Trajkovic, V.; Mostarica Stojkovic, M. Axol activates inducible nitric oxide synthase in rat astrocytes: the role of MAP kinases and NFkappaB. Cell Mol. Life Sci., 2004, 61, 1167-75.
107. Dasgupta, S.; Jana, M.; Zhou, Y.; Fung, Y.K.; Ghosh, S.; Pahan, K. Antineuroinflammatory effect of NFkappaB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis. J. Immunol. 2004, 173, 1344-54.
108. Dasgupta, S.; Zhou, Y.; Jana, M.; Banik, N.L.; Pahan, K. Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps. J. Immunol., 2003, 170, 3874-82.
109. Du, C.; Bright, J.J.; Sriram, S. Inhibition of CD40 signaling pathway by tyrphostin A1 reduces secretion of IL-12 in macrophage, Th1 cell development and experimental allergic encephalomyelitis in SJL/J mice. J. Neuroimmunol., 2001, 114, 69-79.
110. Du, C.; Khalil, M.W.; Sriram, S. Administration of dehydroepiandrosterone suppresses experimental allergic encephalomyelitis in SJL/J mice. J. Immunol., 2001, 167, 7094-101.
111. Dunn, S.E.; Ousman, S.S.; Sobel, R.A.; Zuniga, L.; Baranzini, S.E.; Youssef, S.; Crowell, A.; Loh, J.; Oksenberg, J.; Steinman, L. Peroxisome proliferator-activated receptor (PPAR) alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med., 2007, 204, 321-30.
112. Heneka, M.T.; Sharp, A.; Murphy, P.; Lyons, J.A.; Dumitrescu, L.; Feinstein, D.L. The heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice. J. Neurochem., 2001, 77, 568-79.
113. Hilliard, B.; Samoilova, E.B.; Liu, T.S.; Rostami, A.; Chen, Y. Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells. J. Immunol., 1999, 163, 2937-43.
114. Hilliard, B.A.; Mason, N.; Xu, L.; Sun, J.; Lamhamedi-Cherradi, S.E.; Liou, H.C.; Hunter, C.; Chen, Y.H. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J. Clin. Invest., 2002, 110, 843-50.
115. Ho, P.P.; Fontoura, P.; Ruiz, P.J.; Steinman, L.; Garren, H. An immunomodulatory GpG oligonucleotide for the treatment of autoimmunity via the innate and adaptive immune systems. J. Immunol., 2003, 171, 4920-26.
116. Hur, E.M.; Youssef, S.; Haws, M.E.; Zhang, S.Y.; Sobel, R.A.; Steinman, L. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat. Immunol., 2007, 8, 74-83.
117. Iruretagoyena, M.I.; Sepulveda, S.E.; Lezana, J.P.; Hermoso, M.; Bronfman, M.; Gutierrez, M.A.; Jacobelli, S.H.; Kalergis, A.M. Inhibition of nuclear factor-kappa B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis. J. Pharmacol. Exp. Ther., 2006, 318, 59-67.
118. Kaltschmidt, B.; Sparna, T.; Kaltschmidt, C. Activation of NF-kappa B by reactive oxygen intermediates in the nervous system. Antioxid. Redox Signal, 1999, 1, 129-44.
119. Kaltschmidt, C.; Kaltschmidt, B.; Lannes-Vieira, J.; Kreutzberg, G.W.; Wekerle, H.; Baeuerle, P.A.; Gehrmann, J. Transcription factor NF-kappa B is activated in microglia during experimental autoimmune encephalomyelitis. J. Neuroimmunol., 1994, 55, 99-106.
120. Martin-Saavedra, F.M.; Flores, N.; Dorado, B.; Eguiluz, C.; Bravo, B.; Garcia-Merino, A.; Ballester, S. Beta-interferon unbalances the peripheral T cell proinflammatory response in experimental autoimmune encephalomyelitis. Mol. Immunol., 2007, 44, 3597-607.
121. Mohamed, A.; Afridi, D.M.; Garani, O.; Tucci, M. Hymoquinone inhibits the activation of NF-kappaB in the brain and spinal cord of experimental autoimmune encephalomyelitis. Biomed. Sci. Instrum., 2005, 41, 388-93.
122. Moreno, B.; Hevia, H.; Santamaria, M.; Sepulcre, J.; Munoz, J.; Garcia-Trevijano, E.R.; Berasain, C.; Corrales, F.J.; Avila, M.A.; Villoslada, P. Methylthioadenosine reverses brain autoimmune disease. Ann. Neurol., 2006, 60, 323-34.
123. Ousman, S.S.; Tomooka, B.H.; van Noort, J.M.; Wawrousek, E.F.; O'Connor, K.C.; Hafler, D.A.; Sobel, R.A.; Robinson, W.H.; Steinman, L. Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature, 2007, 448, 474-79.
124. Pahan, K.; Schmid, M. Activation of nuclear factork-B in the spinal cord of experimental allergic encephalomyelitis. Neurosci. Lett., 2000, 287, 17-20.
125. Prasad, R.; Giri, S.; Nath, N.; Singh, I.; Singh, A.K. Inhibition of phosphoinositide 3 kinase-Akt (protein kinase B)-nuclear factor-kappa B pathway by lovastatin limits endothelial-monocyte cell interaction. J. Neurochem., 2005, 94, 204-14.
126. Prasad, R.; Giri, S.; Nath, N.; Singh, I.; Singh, A.K. 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates experimental autoimmune encephalomyelitis via modulation of endothelialmonocyte interaction. J. Neurosci. Res., 2006, 84, 614-25.
127. Quinones, M.P.; Kalkonde, Y.; Estrada, C.A.; Jimenez, F.; Ramirez, R.; Mahimainathan, L.; Mummidi, S.; Choudhury, G.G.; Martinez, H.; Adams, L.; Mack, M.; Reddick, R.L.; Maffi, S.; Haralambous, S.; Probert, L.; Ahuja, S.K.; Ahuja, S.S. Role of astrocytes and chemokine systems in acute TNFalpha induced demyelinating syndrome: CCR2-dependent signals promote astrocyte activation and survival via NFkappaB and Akt. Mol. Cell Neurosci., 2008, 37, 96-109.
128. Rolls, A.; Cahalon, L.; Bakalash, S.; Avidan, H.; Lider, O.; Schwartz, M. A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation-associated neurodegeneration. FASEB J., 2006, 20, 547-49.
129. Sanchez, A.J.; Puerta, C.; Ballester, S.; Gonzalez, P.; Arriaga, A.; Garcia-Merino, A. Rolipram impairs NFkappaB activity and MMP-9 expression in experimental autoimmune encephalomyelitis. J. Neuroimmunol., 2005, 168, 13-20.
130. Wang, Z.; Qiu, J.; Guo, T.B.; Liu, A.; Wang, Y.; Li, Y.; Zhang, J.Z. Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental autoimmune encephalomyelitis. J. Immunol., 2007, 179, 5958-65.
131. Yin, P.; Luby, T.M.; Chen, H.; Etemad-Moghadam, B.; Lee, D.; Aziz, N.; Ramstedt, U.; Hedley, M.L. Generation of expression constructs that secrete bioactive alphaMSH and their use in the treatment of experimental autoimmune encephalomyelitis. Gene Ther., 2003, 10, 348-55.
132. van Loo, G.; De Lorenzi, R.; Schmidt, H.; Huth, M.; Mildner, A.; Schmidt-Supprian, M.; Lassmann, H.; Prinz, M.R.; Pasparakis, M. Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat. Immunol., 2006, 7, 954-61.
133. Elliott, P.J.; Zollner, T.M.; Boehncke, W.H. Proteasome inhibition: a new anti-inflammatory strategy. J. Mol. Med., 2003, 81, 235-45.
134. Paintlia, A.S.; Paintlia, M.K.; Singh, I.; Singh, A.K. IL-4-induced peroxisome proliferator-activated receptor gamma activation inhibits NF-kappaB trans activation in central nervous system (CNS) glial cells and protects oligodendrocyte progenitors under neuroinflammatory disease conditions: implication for CNS-demyelinating diseases. J. Immunol., 2006, 176, 4385-98.
135. Lovett-Racke, A.E.; Hussain, R.Z.; Northrop, S.; Choy, J.; Rocchini, A.; Matthes, L.; Chavis, J.A.; Diab, A.; Drew, P.D.; Racke, M.K. Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease. J. Immunol., 2004, 172, 5790-98.
136. Olerup, O.; Hillert, J. HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Tissue antigens, 1991, 38 1-15.
137. Svejgaard, A. The immunogenetics of multiple sclerosis. Immunogenetics, 2008, 60, 275-86.
138. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature, 1999, 401, 921-23.
139. Huang, C.J.; Nazarian, R.; Lee, J.; Zhao, P.M.; Espinosa-Jeffrey, A.; de Vellis, J. Tumor necrosis factor modulates transcription of myelin basic protein gene through nuclear factor kappa B in a human oligodendroglioma cell line. Int. J. Dev. Neurosci., 2002, 20, 289-96.
140. Allcock, R.J.; de la Concha, E.G.; Fernandez-Arquero, M.; Vigil, P.; Conejero, L.; Arroyo, R.; Price, P. Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster. Hum. Immunol., 1999, 60, 1266-73.
141. Garcia-Merino, A.; Alper, C.A.; Usuku, K.; Marcus-Bagley, D.; Lincoln, R.; Awdeh, Z.; Yunis, E.J.; Eisenbarth, G.S.; Brink, S.J.; Hauser, S.L. Tumor necrosis factor (TNF) microsatellite haplotypes in relation to extended haplotypes, susceptibility to diseases associated with the major histocompatibility complex and TNF secretion. Hum. Immunol., 1996, 50, 11-21.
142. Albertella, M.R.; Campbell, R.D. Characterization of a novel gene in the human major histocompatibility complex that encodes a potential new member of the I kappa B family of proteins. Hum. Mol. Genet., 1994, 3, 793-99.
143. Shiina, T.; Tamiya, G.; Oka, A.; Yamagata, T.; Yamagata, N.; Kikkawa, E.; Goto, K.; Mizuki, N.; Watanabe, K.; Fukuzumi, Y.; Taguchi, S.; Sugawara, C.; Ono, A.; Chen, L.; Yamazaki, M.; Tashiro, H.; Ando, A.; Ikemura, T.; Kimura, M.; Inoko, H. Nucleotide sequencing analysis of the 146-kilobase segment around the IkBL and MICA genes at the centromeric end of the HLA class I region. Genomics, 1998, 47, 372-82.
144. Allcock, R.J.; Christiansen, F.T.; Price, P. The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3, B7, DR15. Immunogenetics, 1999, 49, 660-65.
145. Miterski, B.; Bohringer, S.; Klein, W.; Sindern, E.; Haupts, M.; Schimrigk, S.; Epplen, J.T. Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations. Genes Immun., 2002, 3, 211-19.
146. Castiblanco, J.; Anaya, J.-M. The IkappaBL gene polymorphism influences risk of acquiring systemic lupus erythematosus and Sjögren's syndrome. Human Immunol., 2008, 69, 45-61.
147. Hamamcioglu, K.; Reder, A.T. Interferon-beta regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis. Mult. Scler., 2007, 13, 459-70.
148. Wandinger, K.P.; Sturzebecher, C.S.; Bielekova, B.; Detore, G.; Rosenwald, A.; Staudt, L.M.; McFarland, H.F.; Martin, R. Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes. Ann. Neurol., 2001, 50, 349-57.
149. Kim, M.O.; Si, Q.; Zhou, J.N.; Pestell, R.G.; Brosnan, C.F.; Locker, J.; Lee, S.C. Interferon-beta activates multiple signaling cascades in primary human microglia. J. Neurochem. 2002, 81, 1361-71.
150. Ma, X.Y.; Wang, H.; Ding, B.; Zhong, H.; Ghosh, S.; Lengyel, P. The interferon-inducible p202a protein modulates NF-kappaB activity by inhibiting the binding to DNA of p50/p65 heterodimers and p65 homodimers while enhancing the binding of p50 homodimers. J. Biol. Chem., 2003, 278, 23008-19.
151. Dale, E.; Davis, M.; Faustman, D.L. A role for transcription factor NF-kappaB in autoimmunity: possible interactions of genes, sex, and the immune response. Adv. Physiol. Educ., 2006, 30, 152-58.
152. Payne, D.N.; Adcock, I.M. Molecular mechanisms of crticosteroid actions. Paediatr. Respir. Rev., 2001, 2, 145-50.
153. Tiede, I.; Fritz, G.; Strand, S.; Poppe, D.; Dvorsky, R.; Strand, D.; Lehr, H.A.; Wirtz, S.; Becker, C.; Atreya, R.; Mudter, J.; Hildner, K.; Bartsch, B.; Holtmann, M.; Blumberg, R.; Walczak, H.; Iven, H.; Galle, P.R.; Ahmadian, M.R.; Neurath, M.F. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J. Clin. Invest., 2003, 111, 1133-45.
154. Li, Q.Q.; Bever, C.T. Glatiramer acetate blocks interleukin-1-dependent nuclear factor-kappaB activation and RANTES expression in human U-251 MG astroglial cells. Brain Res. Mol. Brain Res., 2001, 87, 48-60.
155. Glabinski, A.R.; Bielecki, B.; Kawczak, J.A.; Tuohy, V.K.; Selmaj, K.; Ransohoff, R.M. Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression. Autoimmunity, 2004, 37, 465-71.
156. Selmaj, K.; Raine, C.S.; Cross, A.H. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann. Neurol., 1991, 30, 694-700.
157. van Oosten, B.W.; Barkhof, F.; Truyen, L.; Boringa, J.B.; Bertelsmann, F.W.; von Blomberg, B.M.E.; Woody, J.N.; Hartung, H.P.; Polman, C.H. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal antitumor necrosis factor antibody cA2. Neurology, 1996, 47, 1531-34.
158. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology, 1999, 53, 457-65.
159. Plummer, S.M.; Holloway, K.A.; Manson, M.M.; Munks, R.J.; Kaptein, A.; Farrow, S.; Howells, L. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene, 1999, 18, 6013-20.
160. Chearwae, W.; Bright, J. 15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of toll-like receptors 4 and 9 in autoimmune T lymphocyte. J. Clin. Immunol., 2008, 28, 558-70.
161. Greve, B.; Weissert, R.; Hamdi, N.; Bettelli, E.; Sobel, R.A.; Coyle, A.; Kuchroo, V.K.; Rajewsky, K.; Schmidt-Supprian, M. I kappa B kinase 2/ beta deficiency controls expansion of autoreactive T cells and suppresses experimental autoimmune encephalomyelitis. J. Immunol., 2007, 179, 179-85.
162. Vanderlugt, C.L.; Rahbe, S.M.; Elliott, P.J.; Dal Canto, M.C.; Miller, S.D. Treatment of established relapsing experimental autoimmune encephalomyelitis with the proteasome inhibitor PS-519. J. Autoimmun., 2000, 14, 205-11.
163. Sethi, G.; Ahn, K.S.; Aggarwal, B.B. Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol. Cancer Res., 2008, 6, 1059-70.
164. Confavreux, C.; Hutchinson, M.; Hours, M.M.; Cortinovis-Tourniaire, P.; Moreau, T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N. Eng l. J. Med., 1998, 339, 285-91.
165. Salemi, G.; Callari, G.; Gammino, M.; Battaglieri, F.; Cammarata, E.; Cuccia, G.; D'Amelio, M.; Lupo, I.; Ragonese, P.; Savettieri, G. The relapse rate of multiple sclerosis changes during pregnancy: a cohort study. Acta Neurol. Scand., 2004, 110, 23-26.
166. Whitaker, J.N. Effects of pregnancy and delivery on disease activity in multiple sclerosis. N. Engl. J. Med., 1998, 339, 339-40.
167. Vukusic, S.; Confavreux, C. Pregnancy and multiple sclerosis: the children of PRIMS. Clin. Neurol. Neurosurg., 2006, 108, 266-70.
168. Zang, Y.C.; Halder, J.B.; Hong, J.; Rivera, V.M.; Zhang, J.Z. Regulatory effects of estriol on T cell migration and cytokine profile: inhibition of transcription factor NF-kappa B. J. Neuroimmunol., 2002, 124, 106-14.
169. Zhu, W.H.; Lu, C.Z.; Huang, Y.M.; Link, H.; Xiao, B.G. A putative mechanism on remission of multiple sclerosis during pregnancy: estrogen-induced indoleamine 2,3-dioxygenase by dendritic cells. Mult. Scler., 2007, 13, 33-40.
170. Mattson, M.P.; Culmsee, C.; Yu, Z.F. Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res., 2000, 301, 173-87.
171. DeLuca, G.C.; Williams, K.; Evangelou, N.; Ebers, G.C.; Esiri, M.M. The contribution of demyelination to axonal loss in multiple sclerosis. Brain, 2006, 129, 1507-16.
172. Breij, E.C.W.; Brink, B.P.; Veerhuis, R.; van den Berg, C.; Vloet, R.; Yan, R.; Dijkstra, C.D.; van der Valk, P.; Bo, L. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann. Neurol., 2008, 63, 16-25.
173. Lucchinetti, C.; Brück, W.; Parisi, J.; Scheithauer, B.; Rodriguez, M.; Lassmann, H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol., 2000, 47, 707-17.
174. Sadatipour, B.T.; Greer, J.M.; Pender, M.P. Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann. Neurol., 1998, 44, 980-83.
175. Kutzelnigg, A.; Lassmann, H. Cortical demyelination in multiple sclerosis: a substrate for cognitive deficits? J. Neurol. Sci., 2006, 245, 123-26.
176. Pender, M.P.; Csurhes, P.A.; Wolfe, N.P.; Hooper, K.D.; Good, M.F.; McCombe, P.A.; Greer, J.M. Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis. J. Clin. Neurosci., 2003, 10, 63-66.
177. Greer, J.M.; Csurhes, P.A.; Cameron, K.D.; McCombe, P.A.; Good, M.F.; Pender, M.P. Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis. Brain, 1997, 120 1447-60.
178. Goodin, D.S.; Frohman, E.M.; Garmany, G.P., Jr.; Halper, J.; Likosky, W.H.; Lublin, F.D.; Silberberg, D.H.; Stuart, W.H.; van den Noort, S. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology, 2002, 58, 169-78.
179. Penton-Rol, G.; Cervantes-Llanos, M.; Cabrera-Gomez, J.A.; Alonso-Ramirez, R.; Valenzuela-Silva, C.; Rodriguez-Lara, R.; Montero-Casimiro, E.; Bello-Rivero, I.; Lopez-Saura, P. Treatment with type I interferons induces a regulatory T cell subset in peripheral blood mononuclear cells from multiple sclerosis patients. Int. Immunopharmacol., 2008, 8, 881-86.
180. Wingerchuk, D.M. Current evidence and therapeutic strategies for multiple sclerosis. Semin. Neurol., 2008, 28, 56-66.
181. Ford, C.C.; Johnson, K.P.; Lisak, R.P.; Panitch, H.S.; Shifronis, G.; Wolinsky, J.S. A prospective openlabel study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients. Mult. Scler., 2006, 12, 309-20.
182. Martinelli Boneschi, F.; Rovaris, M.; Johnson, K.P.; Miller, A.; Wolinsky, J.S.; Ladkani, D.; Shifroni, G.; Comi, G.; Filippi, M. Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials. Mult. Scler., 2003, 9, 349-55.
183. Munari, L.; Lovati, R.; Boiko, A. Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst. Rev., 2004, CD004678.
184. Wolinsky, J.S.; Narayana, P.A.; O'Connor, P.; Coyle, P.K.; Ford, C.; Johnson, K.; Miller, A.; Pardo, L.; Kadosh, S.; Ladkani, D. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann. Neurol., 2007, 61, 14-24.
185. Ghalie, R.G.; Edan, G.; Laurent, M.; Mauch, E.; Eisenman, S.; Hartung, H.P.; Gonsette, R.E.; Butine, M.D.; Goodkin, D.E. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS. Neurology, 2002, 59, 909-13.
186. Ghalie, R.G.; Mauch, E.; Edan, G.; Hartung, H.P.; Gonsette, R.E.; Eisenmann, S.; Le Page, E.; Butine, M.D.; De Goodkin, D.E. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult. Scler., 2002, 8, 441-45.
187. Hartung, H.P.; Gonsette, R.; Konig, N.; Kwiecinski, H.; Guseo, A.; Morrissey, S.P.; Krapf, H.; Zwingers, T. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet, 2002, 360, 2018-25.
188. Kleinschmidt-DeMasters, B.K.; Tyler, K.L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N. Engl. J. Med., 2005, 353, 369-74.
189. Polman, C.H.; O'Connor, P.W.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D.H.; Phillips, J.T.; Lublin, F.D.; Giovannoni, G.; Wajgt, A.; Toal, M.; Lynn, F.; Panzara, M.A.; Sandrock, A.W. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med., 2006, 354, 899-910.
190. Rice, G.P.; Hartung, H.P.; Calabresi, P.A. Antialpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology, 2005, 64, 1336-42.
191. Filippi, M.; Rocca, M.A.; Pagani, E.; Iannucci, G.; Sormani, M.P.; Fazekas, F.; Ropele, S.; Hommes, O.R.; Comi, G. European study on intravenous immunoglobulin in multiple sclerosis: results of magnetization transfer magnetic resonance imaging analysis. Arch. Neurol., 2004, 61, 1409-12.
192. Hommes, O.R.; Sorensen, P.S.; Fazekas, F.; Enriquez, M.M.; Koelmel, H.W.; Fernandez, O.; Pozzilli, C.; O'Connor, P. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet, 2004, 364, 1149-56.