The Role of T Cells in Brain Pathology

  • M. Bradl
  • A. Flügel
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 265)


The protective role of T cells in the adaptive immune response is well-established: T cells become activated in the course of infections and migrate to infected organs and tissues including the central nervous system (CNS; Fleischer and Kreth 1983; Müller et al. 1989; Hunter et al. 1992; Quagliarello and Scheld 1992; Kürger et al. 1994). And yet, T cells may also be found in the CNS even when it is seemingly not infected, as seen in human patients with neurodegenerative diseases.


Multiple Sclerosis Major Histocompatibility Complex Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Experimental Allergic Encephalomyelitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbas AK (1996) Die and let live: eliminating dangerous lymphocytes. Cell 84:655–657PubMedCrossRefGoogle Scholar
  2. Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 162:2964–2973PubMedGoogle Scholar
  3. Adelmann M, Wood J, Benzel I, Fiori P, Lassmann H, Matthieu J-M, Gardinier MV, Dornmair K, Linington C (1995) The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat. J Neu-roimmunol 63:17–27CrossRefGoogle Scholar
  4. Allen IV (1991) Pathology of multiple sclerosis. In: Matthews WB, Compston A, Allen IV, Martyn CN (eds) McAlpine’s multiple sclerosis. Churchill Livingstone, Edinburgh, pp 341–378Google Scholar
  5. Aloisi F, Ria F, Penna G, Adorini L (1998) Microglia are more efficient than astrocytes in antigen processing and in Th1, but not Th2 activation. J Immunol 160:4671–4680PubMedGoogle Scholar
  6. Antel JP, Williams K, Blain M, McRea E, McLaurin J (1994) Oligodendrocyte lysis by CD4+ T cells independent of tumor necrosis factor. Ann Neurol 35:341–348PubMedCrossRefGoogle Scholar
  7. Arenas E, Persson H (1994) Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo. Nature 367:368–371PubMedCrossRefGoogle Scholar
  8. Asensio VC, Campbell IL (1999) Chemokines in the CNS: plurifunctional mediators in diverse states. TINS 22:504–512PubMedGoogle Scholar
  9. Barde Y-A (1989) Trophic factors and neuronal survival. Neuron 2:1525–1534PubMedCrossRefGoogle Scholar
  10. Barker CF, Billingham RE (1977) Immunologically privileged sites. Adv Immunol 25:1–54PubMedCrossRefGoogle Scholar
  11. Barnaba V, Sinigaglia F (1997) Molecular mimicry and T cell-stimulated autoimmune disease. J Exp Med 185:1529–1531PubMedCrossRefGoogle Scholar
  12. Barnes D, Munro PMG, Youl BD, Prineas JW, McDonald WI (1991) The longstanding MS lesion. A quantitative MRI and electron microscopic study. Brain 114:1271–1280PubMedCrossRefGoogle Scholar
  13. Barres BA, Hart IK, Coles HSR, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31–46PubMedCrossRefGoogle Scholar
  14. Barres BA, Raff MC, Gaese F, Bartke I, Dechant G, Barde YA (1994) A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 367:371–375PubMedCrossRefGoogle Scholar
  15. Bauer J, Bradl M, Hickey WF, Forss-Petter SJ, Breitschopf H, Linington C, Wekerle H, Lassmann H (1998) T cell apoptosis in inflammatory brain lesions. Destruction of T cells does not depend on antigen recognition. Am J Pathol 153:715–724PubMedCrossRefGoogle Scholar
  16. Ben-Nun A, Wekerle H, Cohen IR (1981) The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 11:195–199PubMedCrossRefGoogle Scholar
  17. Benveniste EN, Benos DJ (1995) TNF-α and interferon-γ-mediated signal transduction pathways: Effects on glial cell gene expression and function. FASEB J. 9:1577–1584PubMedGoogle Scholar
  18. Berger T, Weerth S, Kojima K, Linington C, Wekerle H, Lassmann H (1997) Experimental autoimmune encephalomyelitis: the antigen specificity of T-lymphocytes determines the topography of lesions in the central and peripheral nervous system. Lab Invest 76:355–364PubMedGoogle Scholar
  19. Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL, Butcher EC (1995) α4 integrins mediate lymphocyte attachment and rolling under physiological flow. Cell 80:413–420PubMedCrossRefGoogle Scholar
  20. Besser M, Wank R (1999) Clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Thl/Th2-polarized expression of their receptors. J Immunol 162:6303–6306PubMedGoogle Scholar
  21. Bradl M, Bauer J, Inomata T, Zielasek J, Nave K-A, Toyka KV, Lassmann H, Wekerle H (1999) Transgenic Lewis rats overexpressing the proteolipid protein (PLP) gene: myelin degradation and its effect on T cell mediated experimental autoimmune encephalomyelitis (EAE) Acta Neuropathol 97:595–606PubMedCrossRefGoogle Scholar
  22. Brocke S, Piercy C, Steinman L, Weissman IL, Veromaa T (1999) Antibodies to CD44 and integrin alpha(4), but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment. Proc Natl Acad Sci USA 96:6896–6901PubMedCrossRefGoogle Scholar
  23. Brocke S, Veromaa T, Weissman IL, Gijbels K, Steinman L (1995) Infection and multiple sclerosis: a possible role for superantigens. Trends Microbiol 2:250–254CrossRefGoogle Scholar
  24. Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272:60–66PubMedCrossRefGoogle Scholar
  25. Chiang C-S, Powell HC, Gold LH, Samimi A, Campbell IL (1996) Macrophage/microglial-mediated primary demyelination and motor disease induced by the central nervous system production of interleukin-3 in transgenic mice. J Clin Invest 97:1512–1524PubMedCrossRefGoogle Scholar
  26. Compston A (1998) Genetic epidemiology of multiple sclerosis. J Neurol Neurosurg Psych 62:553–561CrossRefGoogle Scholar
  27. Cserr HF, Harling-Berg CJ, Knopf PM (1992) Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:269–276PubMedCrossRefGoogle Scholar
  28. Cuzner ML, Norton WT (1996) Biochemistry of demyelination. Brain Pathol 6:231–242PubMedCrossRefGoogle Scholar
  29. Davodeau F, Peyrat MA, Romagné F, Necker A, Hallet MM, Vié H, et al. (1995) Dual T cell receptor β chain expression on human lymphocytes. J Exp Med 181:1391–1398PubMedCrossRefGoogle Scholar
  30. Diacovo TG, Catalina MD, Siegelman MH, von Andrian UH (1998) Circulating activated platelets reconstitute lymphocyte homing and immunity in L-selectin deficient mice. J Exp Med 187:197–204PubMedCrossRefGoogle Scholar
  31. Dittel BN, Stefanova I, Germain RN, Janeway CA (1999a) Cross-antagonism of a T cell clone expressing two distinct T cell receptors. Immunity 11:289–298PubMedCrossRefGoogle Scholar
  32. Dittel BN, Visintin I, Merchant RM, Janeway CA (1999b) Presentation of the self antigen myelin basic protein by dendritic cells leads to experimental autoimmune encephalomyelitis. J Immunol 163:32–39PubMedGoogle Scholar
  33. Ehrhard PB, Erb P, Graumann U, Otten U (1993) Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T-cell clones. Proc Natl Acad Sci USA 90:10984–10988PubMedCrossRefGoogle Scholar
  34. Eikelenboom P, Rozemuller JM, Van Muiswinkel FL (1999) Inflammation and Alzheimer’s disease: Relationship between pathogenic mechanisms and clinical expression. Exp Neurol 154:89–98CrossRefGoogle Scholar
  35. Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16:2508–2521PubMedGoogle Scholar
  36. Fischer HG, Bielinsky AK (1999) Antigen presentation function of brain-derived dendriform cells depends on astrocyte help. Int Immunol 11:1265–1273PubMedCrossRefGoogle Scholar
  37. Fleischer B, Kreth HW (1983) Clonal analysis of HLA-restricted virus-specific cytotoxic T lymphocytes from cerebrospinal fluid in mumps meningitis. J Immunol 130:2187–2190PubMedGoogle Scholar
  38. Flügel A, Willem M, Berkowicz T, Wekerle H (1999) Gene transfer into CD4+ T lymphocytes: green fluorescent protein engineered, encephalitogenic T cells used to illuminate immune responses in the brain. Nat Med 5:843–847PubMedCrossRefGoogle Scholar
  39. Flügel A, Schwaiger FW, Neumann H, Medana I, Willem M, Wekerle H, Kreutzberg GW, Graeber MB (2000) Neuronal FasL induces cell death of encephalitogenic T lymphocytes. Brain Pathol 10:353–364PubMedCrossRefGoogle Scholar
  40. Fossati G, Cooke A, Papafio RQ, Haskins K, Stockinger B (1999) Triggering a second T cell receptor on diabetogenic T cells can prevent induction of diabetes. J Exp Med 190:577–583PubMedCrossRefGoogle Scholar
  41. French LE, Hahne M, Viard I, Radlgruber G, Zanone R, Becker K, Müller C, Tschopp J (1996) Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. J Cell Biol 133:335–343PubMedCrossRefGoogle Scholar
  42. Fuentes ME, Durham SK, Swerdel MR, Lewin AC, Barton DS, Megill JR, Bravo R, Lira SA (1995) Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol 155:5769–5776PubMedGoogle Scholar
  43. Fujimura H, Nakatsuji Y, Sakoda S, Toyooka K, Okuda Y, Yoshikawa H, Kaido M, Saeki Y, Mima T, Kishimoto T, Yanagihara T (1997) Demyelination in severe combined immunodeficient mice by intracisternal injection of cerebrospinal fluid cells from patients with multiple sclerosis: neuro-pathological investigation. Acta Neuropathol 93:567–578PubMedCrossRefGoogle Scholar
  44. Genain CP, Hauser SL (1997) Creation of a model for multiple sclerosis in Callithrix jacchus marmosets. J Mol Med 75:187–197PubMedCrossRefGoogle Scholar
  45. Gilat D, Cahalon L, Hershkoviz R, Lider O (1996) Interplay of T cells and cytokines in the context of enzymatically modified extracellular matrix. Immunol Today 17:16–20PubMedCrossRefGoogle Scholar
  46. Godiska R, Chantry D, Dietsch GN, Gray PW (1995) Chemokine expression in murine experimental allergic encephalomyelitis. J Neuroimmunol 58:167–176PubMedCrossRefGoogle Scholar
  47. Goetzl EJ, Banda MJ, Leppert D (1996) Matrix metalloproteinases in immunity. J Immunol 156:1–4PubMedGoogle Scholar
  48. Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72:551–560PubMedCrossRefGoogle Scholar
  49. Greenwood J, Wang Y, Calder VL (1995) Lymphocyte adhesion and transendothelial migration in the central nervous system: The role of LFA-1, ICAM-1, VLA-4 and VCAM-1. Immunology 86:408–415PubMedGoogle Scholar
  50. Gutierrez-Ramos JC, Moreno de Alboran I, Martinez AC (1992) In vivo administration of interleukin-2 turns on anergic self-reative T cells and leads to autoimmune disease. Eur J Immunol 22:2867–2872PubMedCrossRefGoogle Scholar
  51. Hafler DA (1999) The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis. J Clin Invest 105:527–528CrossRefGoogle Scholar
  52. Harling-Berg CJ, Knopf PM, Merriam J, Cserr HF (1989) Role of the cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid. J Neuroimmunol 25:185–193PubMedCrossRefGoogle Scholar
  53. Head JR, Griffin WST (1985) Functional capacity of solid tissue implants in the brain: evidence for immunological privilege. Proc Roy Soc 224:375–387CrossRefGoogle Scholar
  54. Hickey WF (1991) Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol 1:97–106PubMedCrossRefGoogle Scholar
  55. Hickey WF, Gonatas NK, Kimura H, Wilson DB (1983) Identification and quantitation of T lymphocyte subsets found in the spinal cord of the Lewis rat during acute experimental allergic encephalomyelitis. J Immunol 131:2805–2809PubMedGoogle Scholar
  56. Hickey WF, Hsu BL, Kimura H (1991) T lymphocyte entry into the central nervous system. J Neurosci Res 28:254–260PubMedCrossRefGoogle Scholar
  57. Hohlfeld R (1997) Biotechnological agents for the immunotherapy of multiple sclerosis. Priciples, problems and perspectives. Brain 120:865–916PubMedCrossRefGoogle Scholar
  58. Hunter CA, Jennings FW, Kennedy PGE, Murray M (1992) Astrocyte activation correlates with cytokine production in central nervous system of Trypanosoma brurcei-infected mice. Lab Invest 67:635–642PubMedGoogle Scholar
  59. Jewtoukoff V, Lebar R, Bach MA (1989) Oligodendrocyte specific autoreactive T cells using an α/β T- cell receptor kill their target without self restriction. Proc Natl Acad Sci USA 86:2824–2828PubMedCrossRefGoogle Scholar
  60. Johns TG, Kerlero de Rosbo N, Menon KK, Abo S, Gonzales MF, Bernard CCA (1995) Myelin oligodendrocyte glycoprotein induces a demyelinating encephalomyelitis resembling multiple sclero sis. J Immunol 154:5536–5541PubMedGoogle Scholar
  61. Jones RE, Chou Y, Young A, Mass M, Vandenbark A, Offner H, Bourdette D (1995) T cells with encephalitogenic potential from multiple sclerosis patients and Lewis rats fail to induce disease in SCID mice following intracisternal injection. J Neuroimmunol 56:119–126PubMedCrossRefGoogle Scholar
  62. Jurewicz A, Biddison WE, Antel JP (1998) MHC class I restricted lysis of human oligodendrocytes by myelin basic protein peptide specific CD8 T lymphocytes. J Immunol 160:3056–3059PubMedGoogle Scholar
  63. Kagawa T, Ikenaka K, Inoue Y, Kuriyama S, Tsujii T, Nakao J, Nakajima K, Aruga J, Okano H, Mikoshiba K (1994) Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron 13:427–442PubMedCrossRefGoogle Scholar
  64. Kansas GS, Ley K, Munro JM, Tedder TF (1993) Regulation of leukocyte rolling and adhesion to high endothelial venules through the cytoplasmic domain of L-selectin. J Exp Med 177:833–838PubMedCrossRefGoogle Scholar
  65. Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD (1995) An important role for the chemokine macrophage inflammatory protein-1α in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 155:5003–5010PubMedGoogle Scholar
  66. Karpus WJ, Ransohoff RM (1998) Chemokine regulation of experimental autoimmune encephalomyelitis: Temporal and spatial expression patterns govern disease pathogenesis. J Immunol 161:2667–2671PubMedGoogle Scholar
  67. Kawamata T, Akiyama H, Yamada T, McGeer PL (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord. Am J Pathol 140:691–707PubMedGoogle Scholar
  68. Kääb G, Brandi G, Marx A, Wekerle H, Bradl M (1996) The myelin basic protein specific T cell repertoire in (transgenic) Lewis rat/SCID mouse chimeras: preferential Vß8.2 T cell receptor usage depends on an intact Lewis thymic microenvironment. Eur J Immunol 26:981–988PubMedCrossRefGoogle Scholar
  69. Kerschensteiner M, Gallmeier E, Behrens L, Klinkert WEF, Kolbeck R, Hoppe E, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells and monocytes produce brain-derived neurotrophic factor (BDNF) in vitro and in brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870PubMedCrossRefGoogle Scholar
  70. Kida S, Weiler RO, Zhang E-T, Phillips MJ, Lannotti F (1995) Anatomical pathways for lymphatic drainage of the brain and their pathological significance. Neuropathol Appl Neurobiol 21:181–184PubMedCrossRefGoogle Scholar
  71. Knopf PM, Cser HF, Nolan SC, Wu T-Y, Harling-Berg CJ (1995) Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 21:175–180PubMedCrossRefGoogle Scholar
  72. Kojima K, Berger T, Lassmann H, Hinze-Selch D, Zhang Y, Gehrmann J, Wekerle H, Linington C (1994) Experimental autoimmune panencephalitis and uveoretinitis in the Lewis rat transferred by T lymphocytes specific for the S100β molecule, a calcium binding protein of astroglia. J Exp Med 180:817–829PubMedCrossRefGoogle Scholar
  73. Kramer R, Zhang Y, Gehrmann J, Gold R, Thoenen H, Wekerle H (1995) Gene transfer through the blood-nerve barrier: Nerve growth factor engineered neuritogenic T lymphocytes attenuate experimental autoimmune neuritis. Nat Med 1:1162–1166PubMedCrossRefGoogle Scholar
  74. Krüger H, Reuss K, Rohrbach E, Pflughaupt K-W, Martin R, Mertens HG (1994) Meningoradiculitis and encephalomyelitis due to Borrelia burgdorferi: a follow-up study of 72 patients over 27 years. J Neurol 236:322–328CrossRefGoogle Scholar
  75. Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999) The inflammatory reaction following l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine intoxication in mouse. Exp Neurol 156:50–61PubMedCrossRefGoogle Scholar
  76. Laschinger M, Engelhardt B (2000) Interactions of alpha4-integrin with VCAM-1 is involved in adhesion of encephalitogenic T cell blasts to brain endothelium but not in their transendothelial migration in vitro. J Neuroimmunol 102:32–43PubMedCrossRefGoogle Scholar
  77. Lassmann H, Brunner C, Bradl M, Linington C (1988) Experimental allergic encephalomyelitis: the balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol 75:566–576PubMedCrossRefGoogle Scholar
  78. Lassmann H, Vass K (1995) Are current immunological concepts of multiple sclerosis reflected by the immunopathology of its lesions? Springer Semin Immunopathol 17:77–87PubMedCrossRefGoogle Scholar
  79. Laouar Y, Sarukhan A, Pasqualetto V, Garcia C, Ezine S (1998) Involvement of the Fas (CD95) system in peripheral cell death and lymphoid organ development. Eur J Immunol 28:1078–1088PubMedCrossRefGoogle Scholar
  80. Lavi E, Rostami A (1996) Demyelination following transfer of human lymphocytes into mice with severe combined immunodeficiency. Pathobiology 64:136–141PubMedCrossRefGoogle Scholar
  81. Lehmann PV, Forsthuber T, Miller A, Sercarz EE (1992) Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358:155–157PubMedCrossRefGoogle Scholar
  82. Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130:443–454PubMedGoogle Scholar
  83. Linington C, Engelhardt B, Kapocs G, Lassmann H (1992) Induction of persistently demyelinating lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibodies. J Neuroimmunol 40:219–224PubMedCrossRefGoogle Scholar
  84. Lucchinetti CF, Brück W, Rodriguez M, Lassmann H (1996) Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesis. Brain Pathol 6:259–274PubMedCrossRefGoogle Scholar
  85. Madsen LS, Andersson EC, Jansson L, Krogsgaard M, Andersen CB, Engberg J, Strominger JL, Svejgaard A, Hjorth JP, Holmdahl R, Wucherpfennig KW, Fugger L (1999) A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nature Genet 23:343–347PubMedCrossRefGoogle Scholar
  86. Maehlen J, Olsson T, Zachau A, Klareskog L, Kristenssen K (1989) Local enhancement of major histocompatibility complex (MHC) class I and class II expression and cell infiltration in experimental allergic encephalomyelitis around axotomized motor neurons. J Neuroimmunol 23:125–132PubMedCrossRefGoogle Scholar
  87. Martino G, Furlan R, Brambilla E, Castellano M, Terreni MR, Comi G, Grimaldi LM (1994) Absence of central nervous system pathology in severe combined immunodeficiency mice intraperitoneally injected with peripheral blood lymphocytes from multiple sclerosis patients. J Neuroimmunol 55:213–217PubMedCrossRefGoogle Scholar
  88. Matsuda M, Tsukada N, Koh C-S, Iwahishi T, Shimada K, Yanagisawa N (1994) Expression of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in the spinal cord of rats during acute experimental allergic encephalomyelitis. Autoimmunity 19:15–22PubMedCrossRefGoogle Scholar
  89. Matsuo A, Lee GC, Terai K, Takami K, Hickey WF, McGeer EG, McGeer PL (1997) Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans. A potential mechanism for the generation of autoantigens. Am J Pathol 150:1253–1266PubMedGoogle Scholar
  90. Matyszak MK, Perry VH (1996) The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 74:599–608PubMedCrossRefGoogle Scholar
  91. McCombe PA, Harness J, Pender MP (1999) Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein. J Neuroimmunol 97:60–69PubMedCrossRefGoogle Scholar
  92. McRae BL, Vanderlugt CL, Dal Canto MC, Miller SD (1995) Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J Exp Med 182:75–85PubMedCrossRefGoogle Scholar
  93. Meinl E, ’t Hart BA, Bontrop RE, Hoch RM, Iglesias A, De Waal Malefijt R, Fickenscher H, Müller-Fleckenstein I, Fleckenstein B, Wekerle H, Hohlfeld R, Jonker M (1995) Activation of a myelin basic protein-specific human T cell clone by antigen-presenting cells from rhesus monkeys. Int Immunol 7:1489–1495PubMedCrossRefGoogle Scholar
  94. Meinl E, Hoch RM, Dornmair K, De Waal Malefijt R, Bontrop RE, Jonker M, Lassmann H, Hohlfeld R, Wekerle H, ’tHart BA (1997) Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques. Am J Pathol 150:445–453PubMedGoogle Scholar
  95. Menon KK, Piddlesden SJ, Bernard CC (1997) Demyelinating antibodies to myelin oligodendrocyte glycoprotein and galactocerebroside induce degradation of myelin basic protein in isolated human myelin. J Neurochem 69:214–222PubMedCrossRefGoogle Scholar
  96. Mitsumoto H, Ikeda K, Klinkosz B, Cedarbaum JM, Wong V, Lindsay RM (1994) Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265:1107–1110PubMedCrossRefGoogle Scholar
  97. Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M (1999) Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med 5:49–55PubMedCrossRefGoogle Scholar
  98. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T (1994) Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain of parkinsonian patients. Neurosci Lett 180:147–150PubMedCrossRefGoogle Scholar
  99. Moneta ME, Gehrmann J, Topper R, Banati RB, Kreutzberg GW (1993) Cell adhesion molecule expression in the regenerating rat facial nucleus. J Neuroimmunol 45:203–206PubMedCrossRefGoogle Scholar
  100. Morrison-Bogorad M, Pardue S, Mclntire DD, Miller EK (1994) Cell size and the heat-shock response in rat brain. J Neurochem 63:857–867PubMedCrossRefGoogle Scholar
  101. Moser HW (1997) Adrenoleukodystrophy: Phenotype, genetics, pathogenesis and therapy. Brain 120. 1485–1508PubMedCrossRefGoogle Scholar
  102. Müller C, Kägi D, Aebischer T, Odermatt B, Held W, Podack ER, Zinkernagel RM, Hengartner H (1989) Detection of perforin and granzyme A mRNA in infiltrating cells during infection of mice with lymphocytic choriomeningitis virus. Eur J Immunol 19:1253–1259PubMedCrossRefGoogle Scholar
  103. Nagata S, Golstein P (1995) The Fas death factor. Science 267:1449–1456PubMedCrossRefGoogle Scholar
  104. Naparstek Y, Cohen IR, Fuks Z, Vlodavsky I (1984) Activated T lymphocytes produce a matrix-degrading heparan sulfate endoglycosidase. Nature 310:241–244PubMedCrossRefGoogle Scholar
  105. Neumann H, Boucraut J, Hahnel C, Misgeld T, Wekerle H (1996) Neuronal control of MHC class II inducibility in rat astrocytes and microglia. Eur J Neurosci 8:2582–2590PubMedCrossRefGoogle Scholar
  106. Neumann H, Misgeld T, Matsumuro K, Wekerle H (1998) Neurotrophins inhibit class II inducibility of microglia: Involvement of the p75 receptor. Proc Natl Acad Sci USA 95:5779–5784PubMedCrossRefGoogle Scholar
  107. Nguyen KB, Pender MP (1998) Phagocytosis of apoptotic lymphocytes by oligodendrocytes in experimental autoimmune encephalomyelitis. Acta Neuropathol 95:40–46PubMedCrossRefGoogle Scholar
  108. Oksenberg JR, Panzara MA, Begovich AB, Mitchell D, Erlich HA, Murray RS, Shimonkevitz R, Sherritt M, Rothbard J, Bernard CCA, Steinman L (1993) Selection for T-cell receptor Vβ-Dβ-Jβ gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 362:68–70PubMedCrossRefGoogle Scholar
  109. Olsson T, Diener P, Ljungdahl A, Höjeberg B, Van der Meide P, Kristensson K (1992) Facial nerve transection causes expansion of myelin autoreactive T cells in regional lymph nodes and T cell homing to the facial nucleus. Autoimmunity 13:117–126PubMedCrossRefGoogle Scholar
  110. Ozawa K, Suchanek G, Breitschopf H, Brück W, Budka H, Jellinger K, Lassmann H (1994) Patterns of Oligodendroglia pathology in multiple sclerosis. Brain 117:1311–1322PubMedCrossRefGoogle Scholar
  111. Padovan E, Casorati G, Dellabonna P, Meyer S, Brockhaus M, Lanzavecchia A (1993) Expression of two T cell receptor β chains: dual receptor T cells. Science 262:422–424PubMedCrossRefGoogle Scholar
  112. Padovan E, Giachino C, Cella M, Valitutti S, Acuto O, Lanzavecchia A (1995) Normal T lymphocytes can express two different T cell receptor β chains: implications for the mechanism of allelic exclusion. J Exp Med 181:1587–1591PubMedCrossRefGoogle Scholar
  113. Paterson PY (1966) Experimental allergic encephalomyelitis and autoimmune disease. Adv Immunol 5:131–208PubMedCrossRefGoogle Scholar
  114. Pender MP, Nguyen KB, McCombe PA, Kerr JFR (1991) Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci 104:81–87PubMedCrossRefGoogle Scholar
  115. Pette M, Fujita K, Wilkinson D, Altmann DM, Trowsdale J, Giegerich G, Hinkkanen A, Epplen JT, Kappos L, Wekerle H (1990) Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple sclerosis patients and healthy donors. Proc Natl Acad Sci USA 87:7968–7972PubMedCrossRefGoogle Scholar
  116. Powers JM, Liu Y, Moser AB, Moser HW (1992) The inflammatory myelinopathy of adreno-leuk-odystrophy: Cells, effector molecules, and pathogenic implications. J Neuropathol Exp Neurol 51:630–643PubMedCrossRefGoogle Scholar
  117. Probert L, Akassoglou K, Pasparakis M, Kontogeorgos G, Kollias G (1995) Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor a. Proc Natl Acad Sci USA 92:11294–11298PubMedCrossRefGoogle Scholar
  118. Quagliarello V, Scheid WM (1992) Bacterial meningitis: Pathogenesis, pathophysiology and progress. N Engl J Med 327:864–872PubMedCrossRefGoogle Scholar
  119. Raivich G, Jones LL, Kloss CUA, Werner A, Neumann H, Kreutzberg GW (1998) Immune surveillance in the injured nervous system: T lymphocytes invade the axotomized mouse facial motor nucleus and aggregate around sites of neuronal degeneration. J Neurosci 18:5804–5816PubMedGoogle Scholar
  120. Raivich G, Bohatschek M, Kloss CUA, Werner A, Jones LL, Kreutzberg GW (1999) The neuroglial activation repertoire in the injured brain: molecular mechanisms and cues to physiological function. Brain Res Rev 30:77–105PubMedCrossRefGoogle Scholar
  121. Readhead C, Schneider A, Griffiths I, Nave K-A (1994) Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12:583–595PubMedCrossRefGoogle Scholar
  122. Sabelko-Downes KA, Cross AH, Russell JH (1999) Dual role for Fas ligand in the initiation and recovery from experimental allergic encephalomyelitis. J Exp Med 189:1195–1206PubMedCrossRefGoogle Scholar
  123. Saeki Y, Mima T, Sakoda S, Fujimura H, Arita N, Nomura T, Kishimoto T (1992) Transfer of multiple sclerosis into severe combined immunodeficiency mice by mononuclear cells from cerebrospinal fluid of the patients. Proc Natl Acad Sci USA 89:6157–6161PubMedCrossRefGoogle Scholar
  124. Santambrogio L, Benedetti M, Chao MV, Muzaffar R, Kulig K, Gabelli N, Hochwald G (1994) Nerve growth factor production by lymphocytes. J Immunol 153:4488–495PubMedGoogle Scholar
  125. Satoh JI, Lee SB, Kim SU (1995) T cell costimulatory molecules B7–1 (CD80) and B7–2 (CD86) are expressed in human microglia but not in astrocytes. Brain Res 704:92–96PubMedCrossRefGoogle Scholar
  126. Saugier-Veber P, Munnich A, Bonneau D, Rozet J-M, Le Merrer M, Gil R, Boespflug-Tanguy O (1994) X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 6:257–262PubMedCrossRefGoogle Scholar
  127. Schiffenbauer J, Soos J, Johnson H (1998) The possible role of bacterial superantigen in the pathogenesis of autoimmune disorders. Immunol Today 19:117–120PubMedGoogle Scholar
  128. Schmied M, Breitschopf H, Gold R, Zischler H, Rothe G, Wekerle H, Lassmann H (1993) Apoptosis of T lymphocytes — a mechanism to control inflammation in the brain. Am J Pathol 143:446–452PubMedGoogle Scholar
  129. Selmaj K, Cross AH, Farooq M, Brosnan CF, Raine CS (1991) Non-specific oligodendrocyte cytotoxicity mediated by soluble products of activated T cells. J Neuroimmunol 35:261–271PubMedCrossRefGoogle Scholar
  130. Sendtner M, Holtmann B, Kolbeck R, Thoenen H, Barde Y-A (1992) Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 360:757–759PubMedCrossRefGoogle Scholar
  131. Snider ED (1994) Functions of the neurotrophins during nervous system development: What the knockouts are teaching us. Cell 77:627–638PubMedCrossRefGoogle Scholar
  132. Soos JM, Morrow J, Ashley TA, Szente BE, Bikoff EK, Zamvil SS (1998) Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation to encephalitogenic T cells. J Immunol 161:5959–5966PubMedGoogle Scholar
  133. Soos JM, Ashley TA, Morrow J, Patarroyo JC, Szente BE, Zamvil SS (1999) Differential expression of B7 co-stimulatory molecules by astrocytes correlates with T cell activation and cytokine production. Int Immunol 11:1169–1179PubMedCrossRefGoogle Scholar
  134. Sun D, Coleclough C, Whitaker JN (1997) Nonactivated astrocytes downregulate T cell receptor expression and reduce antigen-specific proliferation and cytokine production of myelin basic protein (MBP) reactive T cells. J Neuroimmunol 78:69–78PubMedCrossRefGoogle Scholar
  135. Swanborg RH (1995) Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease. Clin Immunol Immunopathol 77:4–13PubMedCrossRefGoogle Scholar
  136. Tabira T, Sakai K (1987) Demyelination induced by T cell lines and clones specific for myelin basic protein. Lab Invest 56:518–525PubMedGoogle Scholar
  137. Tanaka Y, Adams DH, Hubscher S, Hirano H, Siebenlist U, Shaw S (1993) T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-lß. Nature 361:79–82PubMedCrossRefGoogle Scholar
  138. Tani M., Fuentes ME, Peterson JW, Trapp BD, Durham SK, Loy JK, Bravo R, Ransohoff RM, Lira SA (1996) Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes. J Clin Invest 98:529–539PubMedCrossRefGoogle Scholar
  139. Thoenen H, Barde Y-A, Davies AM, Johnson JE (1987) Neurotrophic factors and neuronal death. CIBA Found Symp 126:82–95PubMedGoogle Scholar
  140. Thorpe JW, Kidd D, Moseley IF, Kendall BE, Thompson AJ, MacManus DG, McDonald WI, Miller DH (1996) Serial gadolinium-enhanced MRI of the brain and spinal cord in early relapsing-remitting multiple sclerosis. Neurology 46:373–378PubMedCrossRefGoogle Scholar
  141. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal transection in the lesion of multiple sclerosis. N Engl J Med 338:278–285PubMedCrossRefGoogle Scholar
  142. Tuohy VK, Yu M, Yin L, Kawczak JA, Kinkel RP (1999) Spontaneous regression of primary autore-activity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis. J Exp Med 189:1033–1042PubMedCrossRefGoogle Scholar
  143. Van Waesberghe JHTM, Kamphorst W, De Groot CJA, Van Walderveen MAA, Castelijns JA, Ravid R, Lycklama à Nijeholt GJ, Van der Valk P, Polman CH, Thompson AJ, Barkhof F (1999) Axonal loss in multiple sclerosis lesions: Magnetic resonance imaging insights into substrates of disability. Ann Neurol 46:747–754PubMedCrossRefGoogle Scholar
  144. Vass K, Lassmann H (1990) Intrathecal application of interferon gamma. Progressive appearance of MHC antigens within the rat nervous system. Am J Pathol 137:789–800PubMedGoogle Scholar
  145. Weissert R, Wallström E, Storch MK, Stefferl A, Lorentzen J, Lassmann H, Linington C, Olsson T (1998) MHC haplotype dependent regulation of MOG induced EAE in rats. J Clin Invest 102:1265–1273PubMedCrossRefGoogle Scholar
  146. Wekerle H (1994) Antigen presentation by CNS glia. In: Kettenmann H, Ransom B (eds) Neuroglial cells. Oxford University Press, Oxford, UKGoogle Scholar
  147. Wekerle H, Kojima K, Lannes-Vieira J, Lassmann H, Linington C (1994) Animal models. Ann Neurol 36:S47–S53CrossRefGoogle Scholar
  148. Wekerle H, Linington C, Lassmann H, Meyermann R (1986) Cellular immune reactivity within the CNS. Trends Neurosci 9:271–277CrossRefGoogle Scholar
  149. Wekerle H, Sun D, Oropeza-Wekerle RL, Meyermann R (1987) Immune reactivity in the nervous system: Modulation of T-lymphocyte activation by glial cells. J Exp Biol 132:43–57PubMedGoogle Scholar
  150. Weiler RO, Kida S, Zhang E-T (1992) Pathways of fluid drainage from the brain: morphological aspects and immunological significance. Brain Pathol 2:227–284Google Scholar
  151. Werner H, Jung M, Klugmann M, Sereda M, Griffiths IR, Nave K-A (1998) Mouse models of myelin diseases. Brain Pathol 8:771–793PubMedCrossRefGoogle Scholar
  152. Williams K, Bar-Or A, Ulvestad E, Olivier A, Antel JP, Yong VW (1992) Biology of adult human microglia in culture: comparisons with peripheral blood monocytes and astrocytes. J Neuropathol Exp Neurol 51:538–549PubMedCrossRefGoogle Scholar
  153. Williams K, Ulvestad E, Antel JP (1994) B7/BB-1 antigen expression on adult human microglia studied in vitro and in situ. Eur J Immunol 24:3031–3037PubMedCrossRefGoogle Scholar
  154. Wong D, Prameya R, Dorovini-Zis K (1999) In vitro adhesion and migration of T lymphocytes across monolayers of human brain microvessels endothelial cells: regulation by ICAM-1, VCAM-1, E-selectin and PECAM-1. J Neuropathol Exp Neurol 58:138–152PubMedCrossRefGoogle Scholar
  155. Wucherpfennig KW, Strominger JL (1995) Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 80:695–705PubMedCrossRefGoogle Scholar
  156. Yan Q, Elliott J, Snider WD (1992) Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360:753–755PubMedCrossRefGoogle Scholar
  157. Zhang J, Vandevyver C, Stinissen P, Raus J (1995) In vivo clonotypic regulation in human myelin basic protein-reactive T cells by T cell vaccination. J Immunol 155:5868–5877PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • M. Bradl
    • 1
  • A. Flügel
    • 1
  1. 1.Department of NeuroimmunologyMax-Planck-Institute for NeurobiologyMartinsriedGermany

Personalised recommendations