Inflammation at the Blood–Brain Barrier in Multiple Sclerosis

  • Mark R. MizeeEmail author
  • Ruben van Doorn
  • Alexandre Prat
  • Helga E. de Vries
Part of the Topics in Medicinal Chemistry book series (TMC, volume 10)


The blood–brain barrier is specialized to function as a barrier to protect the central nervous system (CNS) by restricting entry of unwanted molecules and immune cells into the brain and inversely, to prevent CNS-born agents from reaching the systemic circulation. The blood–brain barrier endothelium, together with the cells involved in its regulation, forms the neurovascular unit. Blood–brain barrier dysfunction is an important hallmark of early multiple sclerosis pathophysiology, leading to a consequent loss of the imperative brain homeostasis. The unrestrained access of immune cells and blood-borne compounds into the CNS play a central role in demyelination and axonal damage, two major hallmarks of multiple sclerosis pathology underlying the clinical symptoms of patients. The neuroinflammatory changes at the blood–brain barrier are numerous and include the loss of barrier function, altered communication with surrounding cells, and activation of both inflammation promoting and dampening mechanisms. A better understanding of the blood–brain barrier alterations in neuroinflammation might lead to new ways to promote blood–brain barrier function in neurological diseases like multiple sclerosis.


Astrocytes Blood–brain barrier Endothelial cells Multiple sclerosis Neuroinflammation 


  1. 1.
    Abbott N (2002) Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat 200(5):527Google Scholar
  2. 2.
    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53Google Scholar
  3. 3.
    Adams CW, Poston RN, Buk SJ (1989) Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J Neurol Sci 92(2–3):291–306Google Scholar
  4. 4.
    Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203(4):1007–1019Google Scholar
  5. 5.
    Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonniere L, Bernard M, van Horssen J, De Vries HE, Charron F, Prat A (2011) The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334(6063):1727–1731Google Scholar
  6. 6.
    Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood–brain barrier. Nature 468(7323):557–561Google Scholar
  7. 7.
    Arthur FE, Shivers RR, Bowman PD (1987) Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Brain Res 433(1):155–159Google Scholar
  8. 8.
    Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ (2001) Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286(24):3083–3088Google Scholar
  9. 9.
    Bajramovic JJ, Plomp AC, Goes A, Koevoets C, Newcombe J, Cuzner ML, van Noort JM (2000) Presentation of alpha B-crystallin to T cells in active multiple sclerosis lesions: an early event following inflammatory demyelination. J Immunol 164(8):4359–4366Google Scholar
  10. 10.
    Barreiro O, Yanez-Mo M, Sala-Valdes M, Gutierrez-Lopez MD, Ovalle S, Higginbottom A, Monk PN, Cabanas C, Sanchez-Madrid F (2005) Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation. Blood 105(7):2852–2861Google Scholar
  11. 11.
    Barreiro O, Zamai M, Yanez-Mo M, Tejera E, Lopez-Romero P, Monk PN, Gratton E, Caiolfa VR, Sanchez-Madrid F (2008) Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms. J Cell Biol 183(3):527–542Google Scholar
  12. 12.
    Bellamy WT (1996) P-glycoproteins and multidrug resistance. Annu Rev Pharmacol Toxicol 36:161–183Google Scholar
  13. 13.
    Berthelot L, Laplaud DA, Pettre S, Ballet C, Michel L, Hillion S, Braudeau C, Connan F, Lefrere F, Wiertlewski S, Guillet JG, Brouard S, Choppin J, Soulillou JP (2008) Blood CD8+ T cell responses against myelin determinants in multiple sclerosis and healthy individuals. Eur J Immunol 38(7):1889–1899Google Scholar
  14. 14.
    Berzin TM, Zipser BD, Rafii MS, Kuo-Leblanc V, Yancopoulos GD, Glass DJ, Fallon JR, Stopa EG (2000) Agrin and microvascular damage in Alzheimer's disease. Neurobiol Aging 21(2):349–355Google Scholar
  15. 15.
    Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28(8):1043–1054Google Scholar
  16. 16.
    Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, McFarland HF, Martin R (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6(10):1167–1175Google Scholar
  17. 17.
    Bielekova B, Sung MH, Kadom N, Simon R, McFarland H, Martin R (2004) Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J Immunol 172(6):3893–3904Google Scholar
  18. 18.
    Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48(6):893–901Google Scholar
  19. 19.
    Brand-Schieber E, Werner P, Iacobas DA, Iacobas S, Beelitz M, Lowery SL, Spray DC, Scemes E (2005) Connexin43, the major gap junction protein of astrocytes, is down-regulated in inflamed white matter in an animal model of multiple sclerosis. J Neurosci Res 80(6):798–808Google Scholar
  20. 20.
    Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40(3):648–677Google Scholar
  21. 21.
    Bruck W, Sommermeier N, Bergmann M, Zettl U, Goebel HH, Kretzschmar HA, Lassmann H (1996) Macrophages in multiple sclerosis. Immunobiology 195(4–5):588–600Google Scholar
  22. 22.
    Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, van Noort JM (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53(7):688–695Google Scholar
  23. 23.
    Carson-Walter EB, Hampton J, Shue E, Geynisman DM, Pillai PK, Sathanoori R, Madden SL, Hamilton RL, Walter KA (2005) Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis. Clin Cancer Res 11(21):7643–7650Google Scholar
  24. 24.
    Cayrol R, Wosik K, Berard JL, Dodelet-Devillers A, Ifergan I, Kebir H, Haqqani AS, Kreymborg K, Krug S, Moumdjian R, Bouthillier A, Becher B, Arbour N, David S, Stanimirovic D, Prat A (2008) Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol 9(2):137–145Google Scholar
  25. 25.
    Cohen Z, Bonvento G, Lacombe P, Hamel E (1996) Serotonin in the regulation of brain microcirculation. Prog Neurobiol 50(4):335–362Google Scholar
  26. 26.
    Cohen Z, Molinatti G, Hamel E (1997) Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex. J Cereb Blood Flow Metab 17(8):894–904Google Scholar
  27. 27.
    Cuzner ML, Hayes GM, Newcombe J, Woodroofe MN (1988) The nature of inflammatory components during demyelination in multiple sclerosis. J Neuroimmunol 20(2–3):203–209Google Scholar
  28. 28.
    Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA (2009) Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci USA 106(2):641–646Google Scholar
  29. 29.
    Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468(7323):562–566Google Scholar
  30. 30.
    Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390(6661):680–683Google Scholar
  31. 31.
    Dawkins JL, Hulme DJ, Brahmbhatt SB, uer-Grumbach M, Nicholson GA (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 27(3):309–312Google Scholar
  32. 32.
    de Rosbo NK, Kaye JF, Eisenstein M, Mendel I, Hoeftberger R, Lassmann H, Milo R, Ben-Nun A (2004) The myelin-associated oligodendrocytic basic protein region MOBP15–36 encompasses the immunodominant major encephalitogenic epitope(s) for SJL/J mice and predicted epitope(s) for multiple sclerosis-associated HLA-DRB1*1501. J Immunol 173(2):1426–1435Google Scholar
  33. 33.
    Dermietzel R (1974) Junctions in the central nervous system of the cat. 3. Gap junctions and membrane-associated orthogonal particle complexes (MOPC) in astrocytic membranes. Cell Tissue Res 149(1):121–135Google Scholar
  34. 34.
    Didier N, Romero IA, Creminon C, Wijkhuisen A, Grassi J, Mabondzo A (2003) Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J Neurochem 86(1):246–254Google Scholar
  35. 35.
    Dore-Duffy P, LaManna JC (2007) Physiologic angiodynamics in the brain. Antioxid Redox Signal 9(9):1363–1371Google Scholar
  36. 36.
    Dyment DA, Ebers GC, Sadovnick AD (2004) Genetics of multiple sclerosis. Lancet Neurol 3(2):104–110Google Scholar
  37. 37.
    Ebers GC, Bulman DE, Sadovnick AD, Paty DW, Warren S, Hader W, Murray TJ, Seland TP, Duquette P, Grey T et al (1986) A population-based study of multiple sclerosis in twins. N Engl J Med 315(26):1638–1642Google Scholar
  38. 38.
    el Hasny B, Bourre JM, Roux F (1996) Synergistic stimulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities by retinoic acid and astroglial factors in immortalized rat brain microvessel endothelial cells. J Cell Physiol 167(3):451–460Google Scholar
  39. 39.
    Elhofy A, Depaolo RW, Lira SA, Lukacs NW, Karpus WJ (2009) Mice deficient for CCR6 fail to control chronic experimental autoimmune encephalomyelitis. J Neuroimmunol 213(1–2):91–99Google Scholar
  40. 40.
    Enbom M (2001) Human herpesvirus 6 in the pathogenesis of multiple sclerosis. APMIS 109(6):401–411Google Scholar
  41. 41.
    Errede M, Girolamo F, Ferrara G, Strippoli M, Morando S, Boldrin V, Rizzi M, Uccelli A, Perris R, Bendotti C, Salmona M, Roncali L, Virgintino D (2012) Blood–brain barrier alterations in the cerebral cortex in experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol 71(10):840–854Google Scholar
  42. 42.
    Esen M, Schreiner B, Jendrossek V, Lang F, Fassbender K, Grassme H, Gulbins E (2001) Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis 6(6):431–439Google Scholar
  43. 43.
    Esiri MM, Reading MC (1987) Macrophage populations associated with multiple sclerosis plaques. Neuropathol Appl Neurobiol 13(6):451–465Google Scholar
  44. 44.
    Fabis MJ, Scott GS, Kean RB, Koprowski H, Hooper DC (2007) Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models. Proc Natl Acad Sci USA 104(13):5656–5661Google Scholar
  45. 45.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3):393–399Google Scholar
  46. 46.
    Fiebich BL, Lieb K, Berger M, Bauer J (1995) Stimulation of the sphingomyelin pathway induces interleukin-6 gene expression in human astrocytoma cells. J Neuroimmunol 63(2):207–211Google Scholar
  47. 47.
    Flanagan K, Fitzgerald K, Baker J, Regnstrom K, Gardai S, Bard F, Mocci S, Seto P, You M, Larochelle C, Prat A, Chow S, Li L, Vandevert C, Zago W, Lorenzana C, Nishioka C, Hoffman J, Botelho R, Willits C, Tanaka K, Johnston J, Yednock T (2012) Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS. PLoS One 7(7):e40443Google Scholar
  48. 48.
    Floris S, Blezer EL, Schreibelt G, Dopp E, van der Pol SM, Schadee-Eestermans IL, Nicolay K, Dijkstra CD, De Vries HE (2004) Blood–brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain 127(Pt 3):616–627Google Scholar
  49. 49.
    Friedman JE, Lyons MJ, Cu G, Ablashl DV, Whitman JE, Edgar M, Koskiniemi M, Vaheri A, Zabriskie JB (1999) The association of the human herpesvirus-6 and MS. Mult Scler 5(5):355–362Google Scholar
  50. 50.
    Froger N, Orellana JA, Calvo CF, Amigou E, Kozoriz MG, Naus CC, Saez JC, Giaume C (2010) Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective. Mol Cell Neurosci 45(1):37–46Google Scholar
  51. 51.
    Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis – the plaque and its pathogenesis. N Engl J Med 354(9):942–955Google Scholar
  52. 52.
    Fromm MF (2004) Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci 25(8):423–429Google Scholar
  53. 53.
    Gensure RH, Zeidel ML, Hill WG (2006) Lipid raft components cholesterol and sphingomyelin increase H+/OH− permeability of phosphatidylcholine membranes. Biochem J 398(3):485–495Google Scholar
  54. 54.
    Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100(1):328–335Google Scholar
  55. 55.
    Grassme H, Jendrossek V, Riehle A, Von Kürthy G, Berger J, Schwarz H, Weller M, Kolesnick R, Gulbins E (2003) Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med 9(3):322–330Google Scholar
  56. 56.
    Greer JM, Csurhes PA, Cameron KD, McCombe PA, Good MF, Pender MP (1997) Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis. Brain 120(Pt 8):1447–1460Google Scholar
  57. 57.
    Hallmann R, Mayer DN, Berg EL, Broermann R, Butcher EC (1995) Novel mouse endothelial cell surface marker is suppressed during differentiation of the blood brain barrier. Dev Dyn 202(4):325–332Google Scholar
  58. 58.
    Hamm S, Dehouck B, Kraus J, Wolburg-Buchholz K, Wolburg H, Risau W, Cecchelli R, Engelhardt B, Dehouck MP (2004) Astrocyte mediated modulation of blood–brain barrier permeability does not correlate with a loss of tight junction proteins from the cellular contacts. Cell Tissue Res 315(2):157–166Google Scholar
  59. 59.
    Harkness KA, Adamson P, Sussman JD, vies-Jones GA, Greenwood J, Woodroofe MN (2000) Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium. Brain 123(Pt 4):698–709Google Scholar
  60. 60.
    Haseloff RF, Blasig IE, Bauer HC, Bauer H (2005) In search of the astrocytic factor(s) modulating blood–brain barrier functions in brain capillary endothelial cells in vitro. Cell Mol Neurobiol 25(1):25–39Google Scholar
  61. 61.
    Hauck CR, Grassme H, Bock J, Jendrossek V, Ferlinz K, Meyer TF, Gulbins E (2000) Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of Neisseria gonorrhoeae. FEBS Lett 478(3):260–266Google Scholar
  62. 62.
    Hauser SL, Bhan AK, Gilles F, Kemp M, Kerr C, Weiner HL (1986) Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol 19(6):578–587Google Scholar
  63. 63.
    Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185Google Scholar
  64. 64.
    Hayashi M, Luo Y, Laning J, Strieter RM, Dorf ME (1995) Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol 60(1–2):143–150Google Scholar
  65. 65.
    Hemler ME (2001) Specific tetraspanin functions. J Cell Biol 155(7):1103–1107Google Scholar
  66. 66.
    Hemler ME (2003) Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 19:397–422Google Scholar
  67. 67.
    Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6(10):801–811Google Scholar
  68. 68.
    Hemler ME (2008) Targeting of tetraspanin proteins – potential benefits and strategies. Nat Rev Drug Discov 7(9):747–758Google Scholar
  69. 69.
    Hendriks JJ, Alblas J, van der Pol SM, van Tol EA, Dijkstra CD, De Vries HE (2004) Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med 200(12):1667–1672Google Scholar
  70. 70.
    Hofmeister R, Wiegmann K, Korherr C, Bernardo K, Kronke M, Falk W (1997) Activation of acid sphingomyelinase by interleukin-1 (IL-1) requires the IL-1 receptor accessory protein. J Biol Chem 272(44):27730–27736Google Scholar
  71. 71.
    Igarashi Y, Utsumi H, Chiba H, Yamada-Sasamori Y, Tobioka H, Kamimura Y, Furuuchi K, Kokai Y, Nakagawa T, Mori M, Sawada N (1999) Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood–brain barrier. Biochem Biophys Res Commun 261(1):108–112Google Scholar
  72. 72.
    Kakalacheva K, Lunemann JD (2011) Environmental triggers of multiple sclerosis. FEBS Lett 585(23):3724–3729Google Scholar
  73. 73.
    Katsuki H, Kurimoto E, Takemori S, Kurauchi Y, Hisatsune A, Isohama Y, Izumi Y, Kume T, Shudo K, Akaike A (2009) Retinoic acid receptor stimulation protects midbrain dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling. J Neurochem 110(2):707–718Google Scholar
  74. 74.
    Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med 13(10):1173–1175Google Scholar
  75. 75.
    Kinnunen E, Koskenvuo M, Kaprio J, Aho K (1987) Multiple sclerosis in a nationwide series of twins. Neurology 37(10):1627–1629Google Scholar
  76. 76.
    Kooij G, Mizee MR, van Horssen J, Reijerkerk A, Witte ME, Drexhage JA, van der Pol SM, van het Hof B, Scheffer G, Scheper R, Dijkstra CD, van der Valk P, De Vries HE (2011) Adenosine triphosphate-binding cassette transporters mediate chemokine (C–C motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis. Brain 134(Pt 2):555–570Google Scholar
  77. 77.
    Kooij G, van Horssen J, de Lange EC, Reijerkerk A, van der Pol SM, van het Hof B, Drexhage J, Vennegoor A, Killestein J, Scheffer G, Oerlemans R, Scheper R, van der Valk P, Dijkstra CD, De Vries HE (2010) T lymphocytes impair P-glycoprotein function during neuroinflammation. J Autoimmun 34(4):416–425Google Scholar
  78. 78.
    Kort JJ, Kawamura K, Fugger L, Weissert R, Forsthuber TG (2006) Efficient presentation of myelin oligodendrocyte glycoprotein peptides but not protein by astrocytes from HLA-DR2 and HLA-DR4 transgenic mice. J Neuroimmunol 173(1–2):23–34Google Scholar
  79. 79.
    Lai CH, Kuo KH (2005) The critical component to establish in vitro BBB model: pericyte. Brain Res Brain Res Rev 50(2):258–265Google Scholar
  80. 80.
    Lande MB, Donovan JM, Zeidel ML (1995) The relationship between membrane fluidity and permeabilities to water, solutes, ammonia, and protons. J Gen Physiol 106(1):67–84Google Scholar
  81. 81.
    Lang PA, Schenck M, Nicolay JP, Becker JU, Kempe DS, Lupescu A, Koka S, Eisele K, Klarl BA, Rubben H, Schmid KW, Mann K, Hildenbrand S, Hefter H, Huber SM, Wieder T, Erhardt A, Haussinger D, Gulbins E, Lang F (2007) Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med 13(2):164–170Google Scholar
  82. 82.
    Larochelle C, Cayrol R, Kebir H, Alvarez JI, Lecuyer MA, Ifergan I, Viel E, Bourbonniere L, Beauseigle D, Terouz S, Hachehouche L, Gendron S, Poirier J, Jobin C, Duquette P, Flanagan K, Yednock T, Arbour N, Prat A (2012) Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain 135(Pt 10):2906–2924Google Scholar
  83. 83.
    Lassmann H (2012) Targeting intracerebral inflammation in multiple sclerosis: is it feasible? Acta Neuropathol 124(3):395–396Google Scholar
  84. 84.
    Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM (2011) Epstein–Barr virus in the multiple sclerosis brain: a controversial issue – report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 134(Pt 9):2772–2786Google Scholar
  85. 85.
    Layh-Schmitt G, Bendl C, Hildt U, Dong-Si T, Juttler E, Schnitzler P, Grond-Ginsbach C, Grau AJ (2000) Evidence for infection with Chlamydia pneumoniae in a subgroup of patients with multiple sclerosis. Ann Neurol 47(5):652–655Google Scholar
  86. 86.
    Lee EJ, Hung YC, Lee MY (1999) Early alterations in cerebral hemodynamics, brain metabolism, and blood–brain barrier permeability in experimental intracerebral hemorrhage. J Neurosurg 91(6):1013–1019Google Scholar
  87. 87.
    Lee JY, Kim HS, Choi HY, Oh TH, Yune TY (2012) Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain 135(Pt 8):2375–2389Google Scholar
  88. 88.
    Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, Kim YJ, Kim KW (2003) SSeCKS regulates angiogenesis and tight junction formation in blood–brain barrier. Nat Med 9(7):900–906Google Scholar
  89. 89.
    Levy S, Shoham T (2005) The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5(2):136–148Google Scholar
  90. 90.
    Librizzi L, Mazzetti S, Pastori C, Frigerio S, Salmaggi A, Buccellati C, Di Gennaro A, Folco G, Vitellaro-Zuccarello L, de Curtis M (2006) Activation of cerebral endothelium is required for mononuclear cell recruitment in a novel in vitro model of brain inflammation. Neuroscience 137(4):1211–1219Google Scholar
  91. 91.
    Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, Taketo MM, von Melchner H, Plate KH, Gerhardt H, Dejana E (2008) Wnt/beta-catenin signaling controls development of the blood–brain barrier. J Cell Biol 183(3):409–417Google Scholar
  92. 92.
    Loscher W, Potschka H (2005) Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2(1):86–98Google Scholar
  93. 93.
    Lublin FD, Reingold SC (1996) 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 46(4):907–911Google Scholar
  94. 94.
    Lunemann JD (2012) Epstein–Barr virus in multiple sclerosis: a continuing conundrum. Neurology 78(1):11–12Google Scholar
  95. 95.
    Markoullis K, Sargiannidou I, Schiza N, Hadjisavvas A, Roncaroli F, Reynolds R, Kleopa KA (2012) Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 123(6):873–886Google Scholar
  96. 96.
    McFarland HF (1992) Twin studies and multiple sclerosis. Ann Neurol 32(6):722–723Google Scholar
  97. 97.
    Miller DH, Chard DT, Ciccarelli O (2012) Clinically isolated syndromes. Lancet Neurol 11(2):157–169Google Scholar
  98. 98.
    Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348(1):15–23Google Scholar
  99. 99.
    Minagar A, Alexander JS (2003) Blood–brain barrier disruption in multiple sclerosis. Mult Scler 9(6):540–549Google Scholar
  100. 100.
    Mizee MR, Wooldrik D, Lakeman KA, van het Hof B, Drexhage JA, Geerts D, Bugiani M, Aronica E, Mebius RE, Prat A, De Vries HE, Reijerkerk A (2013) Retinoic acid induces blood–brain barrier development. J Neurosci 33(4):1660–1671Google Scholar
  101. 101.
    Moore FG, Wolfson C (2002) Human herpes virus 6 and multiple sclerosis. Acta Neurol Scand 106(2):63–83Google Scholar
  102. 102.
    Morre SA, van Beek J, De Groot CJ, Killestein J, Meijer CJ, Polman CH, van der Valk P, Middeldorp JM, van Den Brule AJ (2001) Is Epstein–Barr virus present in the CNS of patients with MS? Neurology 56(5):692Google Scholar
  103. 103.
    Nagasawa K, Chiba H, Fujita H, Kojima T, Saito T, Endo T, Sawada N (2006) Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells. J Cell Physiol 208(1):123–132Google Scholar
  104. 104.
    Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 129(4):905–913Google Scholar
  105. 105.
    Nagy JI, Rash JE (2000) Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev 32(1):29–44Google Scholar
  106. 106.
    Nakagawa S, Deli MA, Nakao S, Honda M, Hayashi K, Nakaoke R, Kataoka Y, Niwa M (2007) Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol 27(6):687–694Google Scholar
  107. 107.
    Newcombe J, Uddin A, Dove R, Patel B, Turski L, Nishizawa Y, Smith T (2008) Glutamate receptor expression in multiple sclerosis lesions. Brain Pathol 18(1):52–61Google Scholar
  108. 108.
    Noell S, Fallier-Becker P, Beyer C, Kroger S, Mack AF, Wolburg H (2007) Effects of agrin on the expression and distribution of the water channel protein aquaporin-4 and volume regulation in cultured astrocytes. Eur J Neurosci 26(8):2109–2118Google Scholar
  109. 109.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343(13):938–952Google Scholar
  110. 110.
    Ohara Y (1999) Multiple sclerosis and measles virus. Jpn J Infect Dis 52(5):198–200Google Scholar
  111. 111.
    oki-Yoshino K, Uchihara T, Duyckaerts C, Nakamura A, Hauw JJ, Wakayama Y (2005) Enhanced expression of aquaporin 4 in human brain with inflammatory diseases. Acta Neuropathol 110(3):281–288Google Scholar
  112. 112.
    Pardridge WM, Golden PL, Kang YS, Bickel U (1997) Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem 68(3):1278–1285Google Scholar
  113. 113.
    Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1(3):223–236Google Scholar
  114. 114.
    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(20):7968–7972Google Scholar
  115. 115.
    Puranam KL, Guo WX, Qian WH, Nikbakht K, Boustany RM (1999) CLN3 defines a novel antiapoptotic pathway operative in neurodegeneration and mediated by ceramide. Mol Genet Metab 66(4):294–308Google Scholar
  116. 116.
    Puranam K, Qian WH, Nikbakht K, Venable M, Obeid L, Hannun Y, Boustany RM (1997) Upregulation of Bcl-2 and elevation of ceramide in Batten disease. Neuropediatrics 28(1):37–41Google Scholar
  117. 117.
    Quintana A, Muller M, Frausto RF, Ramos R, Getts DR, Sanz E, Hofer MJ, Krauthausen M, King NJ, Hidalgo J, Campbell IL (2009) Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. J Immunol 183(3):2079–2088Google Scholar
  118. 118.
    Ramagopalan SV, Dobson R, Meier UC, Giovannoni G (2010) Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol 9(7):727–739Google Scholar
  119. 119.
    Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10(5):514–523Google Scholar
  120. 120.
    Rohlena J, Volger OL, van Buul JD, Hekking LH, van Gils JM, Bonta PI, Fontijn RD, Post JA, Hordijk PL, Horrevoets AJ (2009) Endothelial CD81 is a marker of early human atherosclerotic plaques and facilitates monocyte adhesion. Cardiovasc Res 81(1):187–196Google Scholar
  121. 121.
    Sadovnick AD, Baird PA, Ward RH (1988) Multiple sclerosis: updated risks for relatives. Am J Med Genet 29(3):533–541Google Scholar
  122. 122.
    Sanvicens N, Cotter TG (2006) Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptor cells. J Neurochem 98(5):1432–1444Google Scholar
  123. 123.
    Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D’alfonso S, Blackburn H, Martinelli BF, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D’hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sorensen PS, Sondergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219Google Scholar
  124. 124.
    Scherrmann JM (2002) Exchanges through the blood–brain barrier. Ann Pharm Fr 60(6):372–379Google Scholar
  125. 125.
    Schreibelt G, Musters RJ, Reijerkerk A, de Groot LR, van der Pol SM, Hendrikx EM, Dopp ED, Dijkstra CD, Drukarch B, De Vries HE (2006) Lipoic acid affects cellular migration into the central nervous system and stabilizes blood–brain barrier integrity. J Immunol 177(4):2630–2637Google Scholar
  126. 126.
    Schutze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Kronke M (1992) TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 71(5):765–776Google Scholar
  127. 127.
    Seigneuret M, Delaguillaumie A, Lagaudriere-Gesbert C, Conjeaud H (2001) Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J Biol Chem 276(43):40055–40064Google Scholar
  128. 128.
    Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV (2012) Deficiency in mural vascular cells coincides with blood–brain barrier disruption in Alzheimer’s disease. Brain Pathol 23(3):303–10Google Scholar
  129. 129.
    Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Capello E, Mancardi GL, Aloisi F (2006) Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 65(2):124–141Google Scholar
  130. 130.
    Shimizu F, Sano Y, Maeda T, Abe MA, Nakayama H, Takahashi R, Ueda M, Ohtsuki S, Terasaki T, Obinata M, Kanda T (2008) Peripheral nerve pericytes originating from the blood-nerve barrier expresses tight junctional molecules and transporters as barrier-forming cells. J Cell Physiol 217(2):388–399Google Scholar
  131. 131.
    Shue EH, Carson-Walter EB, Liu Y, Winans BN, Ali ZS, Chen J, Walter KA (2008) Plasmalemmal vesicle associated protein-1 (PV-1) is a marker of blood–brain barrier disruption in rodent models. BMC Neurosci 9:29Google Scholar
  132. 132.
    Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129(4):877–896Google Scholar
  133. 133.
    Simons K, van Meer G (1988) Lipid sorting in epithelial cells. Biochemistry 27(17):6197–6202Google Scholar
  134. 134.
    Sinclair C, Kirk J, Herron B, Fitzgerald U, McQuaid S (2007) Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 113(2):187–194Google Scholar
  135. 135.
    Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, Mitchell WM (1999) Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol 46(1):6–14Google Scholar
  136. 136.
    Stalder AK, Pagenstecher A, Yu NC, Kincaid C, Chiang CS, Hobbs MV, Bloom FE, Campbell IL (1997) Lipopolysaccharide-induced IL-12 expression in the central nervous system and cultured astrocytes and microglia. J Immunol 159(3):1344–1351Google Scholar
  137. 137.
    Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281(13):8379–8388Google Scholar
  138. 138.
    Tong XK, Hamel E (1999) Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer’s disease. Neuroscience 92(1):163–175Google Scholar
  139. 139.
    Tran ND, Correale J, Schreiber SS, Fisher M (1999) Transforming growth factor-beta mediates astrocyte-specific regulation of brain endothelial anticoagulant factors. Stroke 30(8):1671–1678Google Scholar
  140. 140.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285Google Scholar
  141. 141.
    Vajkoczy P, Laschinger M, Engelhardt B (2001) Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels. J Clin Invest 108(4):557–565Google Scholar
  142. 142.
    van der Goes A, Wouters D, van der Pol SM, Huizinga R, Ronken E, Adamson P, Greenwood J, Dijkstra CD, De Vries HE (2001) Reactive oxygen species enhance the migration of monocytes across the blood–brain barrier in vitro. FASEB J 15(10):1852–1854Google Scholar
  143. 143.
    van der Valk P, De Groot CJ (2000) Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26(1):2–10Google Scholar
  144. 144.
    van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van het Hoff B, Kooij G, Reijerkerk A, Dijkstra C, van der Valk P, van Horssen J, De Vries HE (2012) Fingolimod attenuates ceramide-induced blood–brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathol 124(3):397–410Google Scholar
  145. 145.
    van Doorn R, van Horssen J, Verzijl D, Witte M, Ronken E, van het Hof B, Lakeman K, Dijkstra CD, van der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE (2010) Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia 58(12):1465–1476Google Scholar
  146. 146.
    van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, De Vries HE (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med 45(12):1729–1737Google Scholar
  147. 147.
    van Itallie CM, Anderson JM (2004) The molecular physiology of tight junction pores. Physiology (Bethesda) 19:331–338Google Scholar
  148. 148.
    Vaucher E, Tong XK, Cholet N, Lantin S, Hamel E (2000) GABA neurons provide a rich input to microvessels but not nitric oxide neurons in the rat cerebral cortex: a means for direct regulation of local cerebral blood flow. J Comp Neurol 421(2):161–171Google Scholar
  149. 149.
    Villares R, Cadenas V, Lozano M, Almonacid L, Zaballos A, Martinez A, Varona R (2009) CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues. Eur J Immunol 39(6):1671–1681Google Scholar
  150. 150.
    Vizuete ML, Venero JL, Vargas C, Ilundain AA, Echevarria M, Machado A, Cano J (1999) Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema. Neurobiol Dis 6(4):245–258Google Scholar
  151. 151.
    von Tell D, Armulik A, Betsholtz C (2006) Pericytes and vascular stability. Exp Cell Res 312(5):623–629Google Scholar
  152. 152.
    Wang Y, Imitola J, Rasmussen S, O’Connor KC, Khoury SJ (2008) Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol 64(4):417–427Google Scholar
  153. 153.
    Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeska-Solgot A, LeTourneau Y, Wang Y, Chopp M (2006) Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 26(22):5996–6003Google Scholar
  154. 154.
    Warth A, Kroger S, Wolburg H (2004) Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol 107(4):311–318Google Scholar
  155. 155.
    Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, Ebers GC (1989) The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 112(Pt 1):133–146Google Scholar
  156. 156.
    Williams A, Piaton G, Aigrot MS, Belhadi A, Theaudin M, Petermann F, Thomas JL, Zalc B, Lubetzki C (2007) Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain 130(Pt 10):2554–2565Google Scholar
  157. 157.
    Willis CL, Taylor GL, Ray DE (2007) Microvascular P-glycoprotein expression at the blood–brain barrier following focal astrocyte loss and at the fenestrated vasculature of the area postrema. Brain Res 1173:126–136Google Scholar
  158. 158.
    Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125(1):111–120Google Scholar
  159. 159.
    Wolburg H, Lippoldt A (2002) Tight junctions of the blood–brain barrier: development, composition and regulation. Vascul Pharmacol 38(6):323–337Google Scholar
  160. 160.
    World Health Organization (2008) Atlas multiple sclerosis resources in the world 2008. WHO Press, GenevaGoogle Scholar
  161. 161.
    Xu J, Drew PD (2006) 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. J Neuroimmunol 171(1–2):135–144Google Scholar
  162. 162.
    Yanez-Mo M, Alfranca A, Cabanas C, Marazuela M, Tejedor R, Ursa MA, Ashman LK, de Landazuri MO, Sanchez-Madrid F (1998) Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J Cell Biol 141(3):791–804Google Scholar
  163. 163.
    Yu D, Corbett B, Yan Y, Zhang GX, Reinhart P, Cho SJ, Chin J (2012) Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 33(12):2942–2947Google Scholar
  164. 164.
    Zador Z, Bloch O, Yao X, Manley GT (2007) Aquaporins: role in cerebral edema and brain water balance. Prog Brain Res 161:185–4Google Scholar
  165. 165.
    Zeinstra E, Wilczak N, De KJ (2003) Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2. J Neuroimmunol 135(1–2):166–171Google Scholar
  166. 166.
    Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA (1994) Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 179(3):973–984Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Mark R. Mizee
    • 1
    Email author
  • Ruben van Doorn
    • 1
  • Alexandre Prat
    • 2
  • Helga E. de Vries
    • 1
  1. 1.Department of Molecular Cell Biology and ImmunologyVU University Medical Center AmsterdamAmsterdamThe Netherlands
  2. 2.Neuroimmunology Research Laboratory, Faculty of MedicineUniversity of Montréal, Hospital Complex of the Université de Montréal, Notre Dame HospitalMontréalCanada

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