Mechanisms in the development of multiple sclerosis lesions: Reconciling autoimmune and neurodegenerative factors

CNS and Neurological Disorders - Drug Targets

Volumn 11, Issue 5, 2012, Pages 556-569

  van Noort, Johannes M ^a   Baker, David ^b   Amor, Sandra ^b,c  

^a Delta Crystallon BV   (Netherlands)

^b QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^c VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Autoimmunity; HSPB5; Microglia; Multiple sclerosis; Neurodegeneration

Indexed keywords

AUTOANTIGEN; CCL1 CHEMOKINE; GAMMA INTERFERON; HEAT SHOCK PROTEIN; HEAT SHOCK PROTEIN ALPHA B CRYSTALLIN; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 17; MYELIN; RANTES; TOLL LIKE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; ARTICLE; AUTOIMMUNITY; CD4+ T LYMPHOCYTE; CYTOKINE PRODUCTION; DEGENERATIVE DISEASE; DEMYELINATING DISEASE; GENETIC LINKAGE; HUMAN; IMMUNE SYSTEM; IMMUNOLOGICAL TOLERANCE; INNATE IMMUNITY; MEMORY T LYMPHOCYTE; MICROGLIA; MULTIPLE SCLEROSIS; NERVE CELL DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROIMAGING; NEUROPROTECTION; PATHOPHYSIOLOGY; PHENOTYPE; POSITRON EMISSION TOMOGRAPHY; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION;

EID: 84863890704     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/187152712801661293     Document Type: Article

References (100)

1. Frohman, E.M.; Racke, M.K.; Raine, C.S. Multiple sclerosis-the plaque and its pathogenesis. New Engl. J. Med., 2006, 354, 942-955.
2. McFarland, H.F.; Martin, R. Multiple sclerosis: a complicated picture of autoimmunity. Nat. Immunol., 2007, 8, 913-919.
3. Miller, D.H.; Thompson, A.J.; Filippi, M. Magnetic resonance studies of abnormalities in the normal-appearing white matter and grey matter in multiple sclerosis. J. Neurol., 2003, 250, 1407-1419.
4. Van der Valk, P.; Amor, S. Preactive lesions in multiple sclerosis. Curr. Opin. Neurol., 2009, 22, 207-213.
5. International Multiple Sclerosis Genetics Consortium. Genetic risks and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 2011, 476, 214-219.
6. Compston, A.; Coles, A. Multiple sclerosis. Lancet, 2008, 372, 1502-1517.
7. Van Noort, J.M.; van den Elsen, P.J.; van Horssen, J.; Geurts, J.J.G.; van der Valk, P.; Amor, S. Preactive multiple sclerosis lesions offer novel clues for neuroprotective therapeutic strategies. CNS Neurol. Disord. Drug Targets, 2011, 10, 68-81.
8. Burnett, F.M. The Clonal Selection Theory. Cambridge Press, UK, 1959.
9. Chappert, P.; Schwartz, R.H. Induction of T-cell anergy: integration of environmental cues and infectious tolerance. Curr. Opin. Immunol., 2010, 22, 552-559.
10. Hori, S.; Nomura, T.; Sakaguchi, S. Control of regulatory T cell development by the transcription factor FoxP3. Science, 2003, 299, 1057-1061.
11. + T cells are not mirror images of each other. Trends Immunol., 2008, 29, 429-435.
12. Rudensky, A.Y. Regulatory T cells and FoxP3. Immunol. Rev., 2011, 241, 260-268.
13. Daniel, C.; von Boehmer, H. Extra-thymically induced regulatory T cells: do they have potential in disease prevention? Sem. Immunol., 2011, in press.
14. Murphy, K.M.; Stockinger, B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat. Immunol., 2010, 11, 674-680.
15. Nureiva, R.I.; Liu, X.; Dong, C. Molecular mechanisms of T-cell tolerance. Immunol. Rev., 2011, 241, 133-144.
16. Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol., 2008, 8, 958-969.
17. Gordon, S.; Martinez, F.O. Alternative activation of macrophages: mechanisms and functions. Immunity, 2010, 32, 593-604.
18. Biswas, S.K.; Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol., 2010, 11, 889-896.
19. Goverman, J. Immune tolerance in multiple sclerosis. Immunol. Rev., 2011, 241, 228-240.
20. Baker, D.; Gerritsen, W.; Rundle, J.; Amor, S. Critical appraisal of animal models of multiple sclerosis. Mult. Scler., 2011, 17, 647-657.
21. Friese, M.; Fugger, L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain, 2005, 128, 1747-1763.
22. + regulatory T cells in human autoimmune diseases. Nat. Rev. Immunol., 2010, 10, 849-859.
23. Battistini, L.; Piccio, L; Rossi, B.; Bach, S.; Galgani, S.; Gasperini, C.; Ottoboni, L.; Ciabini, D.; Caramia, M.D.; Bernardi, G.; Laudanna, C.; Scarpini, C.; McEver, R.P.; Butcher, E.C. CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for Pselectin glycoprotein ligand-1. Blood, 2003, 101, 4775-4782.
24. Weber, M.S.; Hemmer, B.; Cepok, S. The role of antibodies in multiple sclerosis. Biochim. Biophys. Acta, 2011, 1812, 239-245.
25. Link, H.; Huang, Y.-M. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J. Neuroimmunol., 2006, 180, 17-28.
26. Hauser, S.L.; Waubant, E.; Arnold, D.L.; Vollmer, T.; Antel, J.; Fox, R.J.; Bar-Or, A.; Panzara, M.; Sarkar, N.; Agarwal, S.; Langer-Gould, A.; Smith, C.H.; the HERMES trial group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. New Engl. J. Med., 2008, 358, 676-688.
27. Weber, M.S.; Prod'homme, T.; Patarroyo, J.C.; Molnarfi, N.; Karzenjis, T.; Lehmann-Horn, K.; Danilenko, D.M.; Eastham-Anderson, J.; Slavin, A.J.; Linington, C.; Bernard, C.C.; Martin, F.; Zamvil,. S.S. B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann. Neurol., 2010, 68, 369-383
28. Von Büdingen, H.-C.; Bar-Or, A.; Zamvil, S.S. B cells in multiple sclerosis: connecting the dots. Curr. Opin. Immunol., 2011, 23, 1-8.
29. Van Noort, J.M.; Van Sechel, A.C.; Bajramovic, J.J.; El Ouagmiri, M.; Polman, C.H.; Lassmann, H.; Ravid, R. The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature, 1995, 375, 798-801.
30. van Noort, J.M.; Bsibsi, M.; Gerritsen, W.H.; van der Valk, P.; Bajramovic, J.J.; Steinman, L.; Amor, S. Alpha B-crystallin is a target for adaptive immune responses and a trigger of innate responses in preactive multiple sclerosis lesions. J. Neuropathol. Exp. Neurol., 2010, 69, 694-703.
31. Lehman, P.V.; Sercarz, E.E.; Forsthuber, T.; Dayan, C.M.; Gammon, G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol. Today, 1993, 14, 203-208.
32. Vanderlugt, C.L.; Miller, S.D. Epitope spreading in autoimmune diseases: implications for immunotherapy. Nat. Rev. Immunol., 2002, 2, 85-95.
33. Medawar, P.B. Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol., 1948, 29, 58-69.
34. Locatelli, G.; Wörtge, S.; Buch, T.; Ingold, B,; Frommer, F.; Sobottka, B.; Krüger, M.; Karram, K.; Bühlmann, C.; Bechmann, I.; Heppner, F.L.; Waisman, A.; Becher, B. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat. Neurosci., 2012, 15, 543-551.
35. Vogelsang, A.; Dressel, A. Immunological consequences of ischemic stroke: immunosuppression and autoimmunity. J. Neuroimmunol., 2011, 132, 105-110.
36. Smith, P.A.; Morris-Downes, M.; Heijmans, N.; Pryce, G.; Arter, E.; O'Neill, J.K.; 't Hart, B.; Baker, D.; Amor, S. Epitope spread is not critical for the relapse and progression of MOG 8-21 induced EAE in Biozzi ABH mice. J. Neuroimmunol., 2005, 164, 76-84.
37. Trapp, B. Pathogenesis of multiple sclerosis: the eyes only see what the mind is prepared to comprehend. Ann. Neurol., 2004, 555, 455-457.
38. Stadelman, C. Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr. Opin. Neurol., 2011, 24, 224-229.
39. Wheeler, D.; Bandaru, V.V.; Calabresi, P.A.; Nath, A.; Hauhgey, N.J. A defect in sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain, 2008, 131, 3092-3102.
40. Laule, C.; Vavasour, I.M.; Leung, E.; Li, D.K.; Kozlowski, P.; Traboulsee, A.L.; Oger, J.; Mackay, A.L.; Moore, G.R. Pathological basis of diffusely abnormal white matter: insights from magnetic resonance imaging and histology. Mult. Scler., 2011, 17, 144-150.
41. Fu, L.; Matthews, P.M.; De Stefano, N.; Worsley, K.J.; Narayanan, S.; Francis, G.S.; Antel, J.P.; Wolfson, C.; Arnold, D.L. Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain, 1998, 121, 103-113.
42. Zeis, T.; Graumann, U.; Reynolds, R.; Schaeren-Wiemers, N. Normal appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain, 2008, 131, 288-303.
43. Petzold, A.; Tozer, D.J.; Schmierer, K. Axonal damage in the making: neurofilament phosphorylation, proton mobility and magnetization transfer in multiple sclerosis normal appearing white matter. Exp. Neurol., 2011, 232, 234-239.
44. Frisher, J.M.; Bramow, S.; Dal-Bianco, A.; Lucchinetti, C.F.; Rauschka, H.; Schmidbauer, M.; Laursen, H.; Sorensen, P.S.; Lassmann, H. The relation between inflammation and neurodegeneration in multiple sclerosis. Brain, 2009, 132, 1175-1189.
45. Gallo, A.; Rovaris, M.; Riva, R.; Ghezzi, A.; Benedetti, B.; Martinelli, V.; Falini, A.; Comi, G.; Filippi, M. Diffusion-tensor magnetic resonance imaging detects normal-appearing white matter damage unrelated to short-term disease activity in patients at the earliest clinical stage of multiple sclerosis. Arch. Neurol., 2005, 62, 803-808.
46. Saidha, S.; Syc, S.B.; Ibrahim, M.A.; Eckstein, C.; Warner, C.V.; Farrell, S.K.; Oakley, J.D.; Durbin, M.K.; Meyer, S.A.; Balcer, L.J.; Frohman, E.M.; Rosenzweig, J.M.; Newsome, S.D.; Ratchford, J.N.; Nguyen, Q.D.; Calabresi, P.A. Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography. Brain, 2011, 134, 518-533.
47. Traugott, U.; Lebon, P. Multiple sclerosis: involvement of interferons in lesion pathogenesis. Ann. Neurol., 1988, 24, 243-251.
48. Woodroofe, M.N.; Cuzner, M.L. Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by nonradioactive in situ hybridization. Cytokine, 1993, 5, 583-588.
49. Windhagen, A.; Newcombe, J.; Dangond, F.; Strand, C.; Woodroofe, M.N.; Cuzner, M.L.; Hafler, D.A. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86) and interleukin 12 cytokine in multiple sclerosis lesions. J. Exp. Med., 1995, 182, 1985-1996.
50. Man, S.; Uboqu, E.E.; Ransohoff, R.M. Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol., 2007, 17, 243-250.
51. Graeber, M.B. Changing face of microglia. Science, 2010, 330, 783-788
52. Sanders, V.; Conrad, A.J.; Touretellotte, W.W. On classification of post-mortem multiple sclerosis plaques for neuroscientists. J. Neuroimmunol., 1993, 45, 207-216.
53. Gay, F.W.; Drye, T.J.; Dick, G.W.; Esiri, M.M. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain, 1997, 120, 1461-1483.
54. De Groot, C.J.; Bergers, E.; Kamphorst, W.; Ravid, R.; Polman, C.H.; Barkhof, F.; van der Valk, P. Post-mortem MRI guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions. Brain, 2001, 124, 1635-1645.
55. Barnett, M.H.; Prineas, J.W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol., 2004, 55, 458-468.
56. Marik, C.; Felts, P.A.; Bauer, J.; Lassmann, H.; Smith, K.J. Lesion genesis in a subset of multiple sclerosis patients: a role for innate immunity? Brain, 2007, 130, 2800-2815.
57. Banati, R.B.; Newcombe, J.; Gunn, R.N.; Cagnin, A.; Turkheimer, F.; Heppner, F.; Price, G.; Wegner, F.; Giovannoni, G.; Miller, D.H.; Perkin, G.D.; Smith, T.; Hewson, A.K.; Bydder, G.; Kreutzberg, G.W.; Jones, T.; Cuzner, M. KL.; Myers, R. The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Quantitative in vivo imaging of microglia as a measure of disease activity. Brain, 2000, 123, 2321-2337.
58. Bajramovic, J.J.; Van der Goes, A.; Koevoets, C.; van Sechel, A.C.; Newcombe, J.; Cuzner, M.L.; van Noort, J.M. Presentation to T cells of alpha B-crystallin in MS lesions, an early event following inflammatory demyelination. J. Immunol., 2000, 164, 4359-4366.
59. Van Noort, J.M.; Verbeek, R.; Polman, C.H.; Meilof, J.; Amor, S. Autoantibodies against alpha B-crystallin, a candidate autoantigen in multiple sclerosis, are part of a normal human immune repertoire. Mult. Scler., 2006, 12, 287-293.
60. Van Noort, J.M.; Bajramovic, J.J.; van Sechel, A.C.; van Stipdonk, M.J. Mistaken self: a novel model which links microbial infection with myelin-directed autoimmunity in MS. J. Neuroimmunol., 2000, 105, 46-57.
61. Van Sechel, A.C.; Bajramovic, J.J.; van Stipdonk, M.J.B.; Persoon-Deen, C.; Geutskens, S.; van Noort, J.M. Epstein-Barr virusinduced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J. Immunol., 1999, 162, 129-135.
62. Van Stipdonk, M.J.; Willems, A.A.; Plomp, A.C.; van Noort, J.M.; Boog, C.J.P. Tolerance controls encephalitogenicity of alpha Bcrystallin in Lewis rats. J. Neuroimmunol., 2000, 103, 103-111.
63. Van Stipdonk, M.J.; Willems, A.A.; Verbeek, R.; Boog, C.J.; van Noort, J.M. T-and B-cell nonresponsiveness to self alpha Bcrystallin in SJL mice prevents induction of experimental allergic encephalomyelitis. Cell. Immunol., 2000, 204, 128-134.
64. Thoua, N.M.; van Noort, J.M.; Baker, D.; Bose, A.; van Sechel, A.C.; van Stipdonk, M.J.; Travers, P.J.; Amor, S. Encephalitogenicity and immunogenic potential of the stress protein alpha B-crystallin in Biozzi ABH (H-2Ag(g7) mice. J. Neuroimmunol., 2000, 104, 47-57.
65. Chabas, D.; Baranzini, S.E.; Mitchell, D.; Bernard, C.C.; Ritling, 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, 1731-1735.
66. Tajouri, L.; Mellick, A.S.; Ashton, K.J.; Tannenberg, A.E.G.; Nagra, R.M.; Tourtelotte, W.W.; Griffiths, L.R. Quantitative and qualitative changes in gene expression patterns characterise the activity of plaques in multiple sclerosis. Mol. Brain Res., 2003, 119, 170-183.
67. Sinclair, C.; Mirakhur, M.; Kirk, J.; Farrell, M.; McQuaid, S. Upregulation of osteopontin and alpha B-crystallin in the normalappearing white matter of multiple sclerosis: an immunohistochemical study utilising tissue microarrays. Neuropathol. Appl. Neurobiol., 2005, 31, 292-303.
68. Duvanel, C.B.; Monnet-Tschudi, F.; Braissant, O.; Matthieu, J.M.; Honegger, P. Tumor necrosis factor-alpha and alpha B-crystallin up-regulation during antibody-mediated demyelination in vitro: a putative protective mechanism in oligodendrocytes. J. Neurosci. Res., 2004, 78, 711-722.
69. Morris-Downes, M.M.; Smith, P.A.; Rundle, J.L.; Piddlesden, S.J.; Baker, D.; Pham-Dinh, D.; Heijmans, N.; Amor, S. Pathological and regulatory effects of anti-myelin antibodies in experimental allergic encephalomyelitis in mice. J. Neuroimmunol., 2002, 125, 114-124.
70. Ousman, S.S.; Tomooka, B.H.; van Noort, J.M.; Wawrousek, E.F.; O'Conner, K.; Hafler, D.A.; Sobel, R.A.; Robinson, W.H.; Steinman, L. Protective and therapeutic role for SSB-crystallin in autoimmune demyelination. Nature, 2007, 448, 474-479.
71. Arac, A.; Brownell, S.E.; Rothbard, J.B.; Chen, C.; Ko, R.M.; Pereira, M.P.; Albers, G.W.; Steinman, L.; Steinberg, G.K. Systemic augmentation of SSB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation. Proc. Natl. Acad. Sci. USA, 2011, 108, 13287-13292.
72. Masilamoni, J.G.; Jesudason, E.P.; Baben, B.; Jabaraj, C.E.; Dhandayuthapani, S.; Jayakumar, R. Molecular chaperone alphacrystallin prevents detrimental effects of neuroinflammation. Biochim. Biophys. Acta, 2006, 1762, 284-293.
73. Masilamoni, J.G.; Vignesh, S.; Kirubagaran, R.; Jesudason, E.P.; Jayakumar, R. The neuroprotective efficacy of alpha-crystallin against acute inflammation in mice. Brain Res. Bull., 2005, 67, 235-241.
74. Masilamoni, J.G.; Jesudason, E.P.; Barathi, S.N.; Jayakumar, R. The protective effect of alpha-crystallin against acute inflammation in mice. Biochim. Biophys. Acta, 2005, 1740, 411-420.
75. Pangratz-Fuehrer, S.; Kaur, K.; Ousman, S.S.; Steinman, L.; Liao, Y.J. Functional rescue of experimental ischemic optic neuropathy with wwB-crystallin. Eye, 2011, 25, 809-817.
76. Velotta, J.B.; Kimura, N.; Chang, S.H.; Chung, J.; Itoh, S.; Rothbard, J.; Yang, P.C.; Steinman, L.; Robbins, R.C.; Fischbein, M.P. MMB-Crystallin improves murine cardiac function and attenuates apoptosis in human endothelial cells exposed to ischemia-reperfusion. Ann. Thorac. Surg., 2011, 91, 1907-1913.
77. Soler, D.; Chapman, T.R.; Poisson, L.R.; Wang, L.; Cote-Sierra, J.; Ryan, M.; McDonald, E.; Badola, S.; Fedyk, E.; Coyle, A.J.; Hodge, M.R.; Kolbeck, R. CCR8 expression identifies CD4memory T cells enriched for FoxP3 regulatory and Th2 effector lymphocytes. J. Immunol., 2006, 177, 6940-6951.
78. Dhaunchak, A.S.; Becker, C.; Schulman, H.; De Faria Junior, O.; Rajasekharan, S.; Banwell, B.; Colman, D.R.; Bar-Or, A.; on behalf of the Canadian Pediatric Demyelinating Disease Group. Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann. Neurol., 2012, 71(5), 601-613.
79. Tischner, D.; Weishaupt, A.; van den Brandt, J.; Müller, N.; Beyersdorf, N.; Ip, C.W.; Toyka, K.V.;Hünig, T.; Gold, R.; Kerkau, T.; Reichardt, H.M. Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis. Brain, 2006, 129, 2635-2647.
80. Fasler-Kan, E.; Suenderhauf, C.; Barteneva, N.; Poller, B.; Gygax, D.; Huwyler, J. Cytokine signaling in the human brain capillary endothelial cell line hCMEC/D3. Brain Res., 2010, 1354, 15-22.
81. Lin, W.; Kemper, A.; Dupree, J.L.; Harding, H.P.; Ron, D.; Popko, B. Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain, 2006, 129, 1306-1318.
82. Zaadstra, B.M.; Chorus, A.M.J.; van Buuren, S.; Kalsbeek, H.; van Noort, J.M. Selective association of multiple sclerosis with infectious mononucleosis. Mult. Scler., 2008, 14, 307-313.
83. Salvetti, M.; Giovannoni, G.;Aloisi, F. Epstein-Barr virus and multiple sclerosis. Curr. Opin. Neurol., 2009, 22, 201-206.
84. Waubant, E.; Mowry, E.M.; Krupp, L. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology, 2011, 76, 1989-1995.
85. Alonso, A.; Hernan, M.A.; Ascherio, A. Allergy, family history of autoimmune diseases, and the risk of multiple sclerosis. Acta Neurol. Scand., 2008, 117, 15-20.
86. Van Oosten, B.W.; Barkhof, F.; Truyen, L.; Boringa, J.B.; Bertelsmann, F.W.; von Blomberg, B.M.; 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, 1531-1514.
87. Panitch, H.S.; Hirsch, R.L.; Haley, A.S.; Johnson, K.P. Exacerbations of multiple sclerosis in patients treated with interferon-gamma. Lancet, 1987, 1, 893-895.
88. Miller, D.H.; Khan, O.A.; Sheremata, W.A.; Blumhardt, L.D.; Rice, G.P.; Libonati, M.A.; Millmer-Hulme, A.J.; Dalton, C.M.; Miszkiel, K.A.; O'Connor, P.W.; International Natalizumab Multiple Sclerosis Trial group. A controlled trial of natalizumab for relapsing multiple sclerosis. New Engl. J. Med., 2003, 348, 15-23.
89. Kappos, L.; Radue, E.W.; O'Connor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L.; Burtin, P; FREEDOMS study group. A placebocontrolled trial of oral fingolimod in relapsing multiple sclerosis. New Engl. J. Med. 2010, 362, 387-401.
90. Quintana, F.J.; Farez, M.F.; Izquierdio, G.; Lucas, M.; Cogen, I.R.; Weiner, H.L. Antigen microarrays iden5tify CNS-produced autoantibodies in RRMS. Neurology, 2012, 78, 532-539.
91. Sabat, R.; Grütz, G.; Warszawka, K.; Kirsch, S.; Witte, E.;Wolk, K.; Geginat, J. Biology of IL-10. Cytokines Growth Factor Rev., 2010, 21, 331-344.
92. Carrieri, P.B.; Provitera, V.; de Rosa, T.; Tartaglia, G.; Gorga, F.; Perella, O. Profile of cerebrospinal fluid and serum cytokines in patients with relapsing-remitting multiple sclerosis: a correlation with clinical activity. Immunopharmacol. Immunotoxicol., 1998, 20, 373-382.
93. Nakashima, I.; Fujihara, K.; Misu, T.; Okita, N.; Takase, S.; Itoyama, Y. Significant correlation between IL-10 levels and IgG indices in the cerebrospinal fluid of patients with multiple sclerosis. J. Neuroimmunol., 2000, 111, 64-67.
94. Lassmann, H.; Brück, W.; Lucchinetti, C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol. Med., 2001, 7, 115-121.
95. Kurschus, F.C.; Wörtge, S.; Waisman, A. Modeling a complex disease: multiple sclerosis. Adv. Immunol., 2011, 110, 111-137.
96. 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, 707-717.
97. Breij, E.C.; Brink, B.P.; Veerhuis, R.; van den Berg, C.; Vloet, R; Yan, R.; Dijkstra C.D.; van der Valk, P.; Bø, L. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann. Neurol., 2008, 63, 16-25.
98. Scott D.L.; Wolfe, F.; Huizinga, T.W. Rheumatoid arthritis. Lancet, 2010, 376, 1094-1108.
99. Atkinson, M.A.; Eisenbarth, G.S. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet, 2001, 358, 221-229.
100. Brown, K.A. Factors modifying the migration of lymphocytes across the blood-brain barrier. Int. Immunopharmacol., 2001, 1, 2043-2062.