Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction


The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood–CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood–CNS barriers with focus on CNS autoimmune inflammation.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Ehrlich P (1904) Über die Beziehung chemischer Constitution, Vertheilung, und pharmakologischer Wirkung. Berlin

  2. 2.

    Goldmann EE (1913) Vitalfärbung am Zentralnervensystem. Abh Preuss Wissensch Phys-Math 1:1–60

  3. 3.

    Lewandowsky M (1890) Zur Lehre der Zerebrospinalflüssigkeit. Z Klin Med 40:480–494

  4. 4.

    Biedl A, Kraus R (1898) Über eine bisher unbekannte toxische Wirkung der Gallensäure auf das Zentralnervensystem. Zentralbl Inn Med 19:1185–1200

  5. 5.

    Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217

  6. 6.

    Leonhardt H (1980) Ependym und circumventriculäre Organe. In: Oksche A, Vollrath L (eds) Handbuch der mikroskopischen Anatomie des Menschen. Springer, Berlin, pp 177–666

  7. 7.

    Engelhardt B, Wolburg-Buchholz K, Wolburg H (2001) Involvement of the choroid plexus in central nervous system inflammation. Microsc Res Tech 52(1):112–129

  8. 8.

    Bouchaud C, Bosler O (1986) The circumventricular organs of the mammalian brain with special reference to monoaminergic innervation. IntRevCytol 105:283–327

  9. 9.

    Alcolado R, Weller RO, Parrish EP, Garrod D (1988) The cranial arachnoid and piamater in man: anatomical and ultrastructural observations. Neuropathol Appl Neurobiol 14:1–17

  10. 10.

    Wolburg H (1995) Orthogonal arrays of intramembranous particles: a review with special reference to astrocytes. J Hirnforsch 36(2):239–258

  11. 11.

    Zhang ET, Inman CBE, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 170:111–123

  12. 12.

    Sixt M, Engelhardt B, Pausch F et al (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153(5):933–946

  13. 13.

    Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185

  14. 14.

    Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barrier. Development, composition and regulation. Vasc Pharmacol 28:323–337

  15. 15.

    Furuse M, Hirase T, Itoh M et al (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123(6 Pt 2):1777–1788

  16. 16.

    Saitou M, Furuse M, Sasaki H et al (2000) Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 22:4131–4142

  17. 17.

    Furuse M, Tsukita S (2006) Claudins in occluding junctions of humans and flies. Trends Cell Biol 16(4):181–188

  18. 18.

    Wolburg H, Wolburg-Buchholz K, Kraus J et al (2003) Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol (Berl) 105(6):586–592

  19. 19.

    Martin-Padura I, Lostaglio S, Schneemann M et al (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142(1):117–127

  20. 20.

    Nasdala I, Wolburg-Buchholz K, Wolburg H et al (2002) A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J Biol Chem 277(18):16294–16303

  21. 21.

    Tsukita S, Furuse M, Itoh M (1999) Structural and signalling molecules come together at tight junctions. Curr Opin Cell Biol 11(5):628–633

  22. 22.

    Dejana E, Orsenigo F, Lampugnani MG (2008) The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121(Pt 13):2115–2122

  23. 23.

    Dejana E, Tournier-Lasserve E, Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16(2):209–221

  24. 24.

    Breier G, Breviaro F, Caveda L et al (1996) Molecular cloning and expression of murine VE-cadherin in early developing cardiovascular system. Blood 87(2):630–641

  25. 25.

    Taddei A, Giampietro C, Conti A et al (2008) Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nature cell biology 10(8):923–934

  26. 26.

    Liebner S, Corada M, Bangsow T et al (2008) Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol 183(3):409–417

  27. 27.

    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):325–332

  28. 28.

    Graesser D, Solowiej A, Bruckner M et al (2002) Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice. J Clin Invest 109(3):383–392

  29. 29.

    Davson H, Oldendorf WH (1967) Symposium on membrane transport. Transport in the central nervous system. Proc R Soc Med 60(4):326–329

  30. 30.

    Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325(6101):253–257

  31. 31.

    Bauer HC, Bauer H (2000) Neural induction of the blood-brain barrier: still an enigma. Cell Mol Neurobiol 20:13–28

  32. 32.

    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53

  33. 33.

    Nicholas DS, Weller RO (1988) The fine anatomy of the human spinal meninges. A light and scanning electron microscopy study. J Neurosurg 69(2):276–282

  34. 34.

    Hutchings M, Weller RO (1986) Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg 65(3):316–325

  35. 35.

    Garberg P, Ball M, Borg N et al (2005) In vitro models for the blood-brain barrier. Toxicol In Vitro 19(3):299–334

  36. 36.

    Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314(1):15–23

  37. 37.

    Bondjers C, He L, Takemoto M et al (2006) Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. Faseb J 20(10):1703–1705

  38. 38.

    Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245

  39. 39.

    Lindblom P, Gerhardt H, Liebner S et al (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17(15):1835–1840

  40. 40.

    Timpl R (1989) Structure and biological activity of basement membrane proteins. Eur J Biochem 180:487–502

  41. 41.

    Hallmann R, Horn N, Selg M et al (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85(3):979–1000

  42. 42.

    del Zoppo GJ, Milner R (2006) Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 26(9):1966–1975

  43. 43.

    Del Zoppo GJ, Milner R, Mabuchi T et al (2006) Vascular matrix adhesion and the blood-brain barrier. Biochem Soc Trans 34(Pt 6):1261–1266

  44. 44.

    Agrawal S, Anderson P, Durbeej M et al (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203(4):1007–1019

  45. 45.

    Wu C, Ivars F, Anderson P et al (2009) Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain. Nat Med 15(5):519–527

  46. 46.

    Jucker M, Tian M, Norton DD, Sherman C, Kusiak JW (1996) Laminin alpha 2 is a component of brain capillary basement membrane: reduced expression in dystrophic dy mice. Neuroscience 71:1153–1161

  47. 47.

    Zhou FC (1990) Four patterns of laminin-immunoreactive structure in developing rat brain. Brain Res Dev Brain Res 55(2):191–201

  48. 48.

    Vahedi K, Kubis N, Boukobza M et al (2007) COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage. Stroke 38(5):1461–1464

  49. 49.

    Gould DB, Phalan FC, Breedveld GJ et al (2005) Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308(5725):1167–1171

  50. 50.

    Poschl E, Schlotzer-Schrehardt U, Brachvogel B et al (2004) Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131(7):1619–1628

  51. 51.

    Wolburg-Buchholz K, Mack AF, Steiner E et al (2009) Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis. Acta Neuropathol 118(2):219–233

  52. 52.

    Brachvogel B, Pausch F, Farlie P et al (2007) Isolated Anxa5+/Sca-1+ perivascular cells from mouse meningeal vasculature retain their perivascular phenotype in vitro and in vivo. Exp Cell Res 313(12):2730–2743

  53. 53.

    Betsholtz C, Lindblom P, Bjarnegard M et al (2004) Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice. Curr Opin Nephrol Hypertens 13(1):45–52

  54. 54.

    Durbeej M, Henry MD, Ferletta M, Campbell KP, Ekblom P (1998) Distribution of dystroglycan in normal adult mouse tissues. J Histochem Cytochem 46:449–458

  55. 55.

    Milner R (2009) Microglial expression of alphavbeta3 and alphavbeta5 integrins is regulated by cytokines and the extracellular matrix: beta5 integrin null microglia show no defects in adhesion or MMP-9 expression on vitronectin. Glia 57(7):714–723

  56. 56.

    Proctor JM, Zang K, Wang D, Wang R, Reichardt LF (2005) Vascular development of the brain requires beta8 integrin expression in the neuroepithelium. J Neurosci 25(43):9940–9948

  57. 57.

    Zhu J, Motejlek K, Wang D et al (2002) beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 129(12):2891–2903

  58. 58.

    Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis and organogenesis precede lethality in mice lacking all av integrins. Cell 95:507–519

  59. 59.

    McCarty JH, Monahan-Earley RA, Brown LF et al (2002) Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol 22:7667–7777

  60. 60.

    Moore SA, Saito F, Chen J et al (2002) Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418(6896):422–425

  61. 61.

    Ohtsuki S, Terasaki T (2007) Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24(9):1745–1758

  62. 62.

    Boado RJ, Pardridge WM (1993) Glucose deprivation causes posttranscriptional enhancement of brain capillary endothelial glucose transporter gene expression via GLUT1 mRNA stabilization. J Neurochem 60(6):2290–2296

  63. 63.

    Lyck R, Ruderisch N, Moll AG, et al. (2009) Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo. J Cereb Blood Flow Metab 29:1491–1502

  64. 64.

    Lee HJ, Engelhardt B, Lesley J, Bickel U, Pardridge WM (2000) Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J Pharmacol Exp Ther 292(3):1048–1052

  65. 65.

    Banks WA (2005) Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11(8):973–984

  66. 66.

    Begley DJ (2004) ABC transporters and the blood-brain barrier. Curr Pharm Des 10(12):1295–1312

  67. 67.

    Hickey WF, Hsu BL, Kimura H (1991) T-lymphocyte entry into the central nervous system. J Neurosci Res 28(2):254–260

  68. 68.

    Wekerle H, Linington C, Lassmann H, Meyermann R (1986) Cellular immune reactivity within the CNS. TINS 9:271–277

  69. 69.

    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):557–565

  70. 70.

    Laschinger M, Vajkoczy P, Engelhardt B (2002) Encephalitogenic T cells use LFA-1 during transendothelial migration but not during capture and adhesion in spinal cord microvessels in vivo. Eur J Immunol 32:3598–3606

  71. 71.

    Kerfoot SM, Norman MU, Lapointe BM et al (2006) Reevaluation of P-selectin and alpha 4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis. J Immunol 176:6225–6234

  72. 72.

    Bauer M, Brakebusch C, Coisne C et al (2009) {beta}1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proc Natl Acad Sci U S A 106:1920–1925

  73. 73.

    Engelhardt B, Laschinger M, Schulz M et al (1998) The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin. J Clin Invest 102(12):2096–2105

  74. 74.

    Piccio L, Rossi B, Scarpini E et al (2002) Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors. J Immunol 168:1940–1949

  75. 75.

    Engelhardt B, Ransohoff RM (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26(9):485–495

  76. 76.

    Kerfoot S, Kubes P (2002) Overlapping roles of P-selectin and alpha 4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis. J Immunol 169:1000–1006

  77. 77.

    Osmers I, Bullard DC, Barnum SR (2005) PSGL-1 is not required for development of experimental autoimmune encephalomyelitis. J Neuroimmunol 166:193–196

  78. 78.

    Engelhardt B, Vestweber D, Hallmann R, Schulz M (1997) E- and P-selectin are not involved in the recruitment of inflammatory cells across the blood-brain barrier in experimental autoimmune encephalomyelitis. Blood 90(11):4459–4472

  79. 79.

    Engelhardt B, Kempe B, Merfeld-Clauss S et al (2005) P-selectin glycoprotein ligand 1 is not required for the development of experimental autoimmune encephalomyelitis in SJL and C57BL/6 mice. J Immunol 175(2):1267–1275

  80. 80.

    Doring A, Wild M, Vestweber D, Deutsch U, Engelhardt B (2007) E- and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice. J Immunol 179(12):8470–8479

  81. 81.

    Uboldi C, Doring A, Alt C et al (2008) L-Selectin-deficient SJL and C57BL/6 mice are not resistant to experimental autoimmune encephalomyelitis. Eur J Immunol 38(8):2156–2167

  82. 82.

    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(5):2964–2973

  83. 83.

    Lyck R, Reiss Y, Gerwin N et al (2003) T cell interaction with ICAM-1/ICAM-2-double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells. Blood 102:3675–3683 Epub 2003 Jul 3631

  84. 84.

    Vestweber D (2007) Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol Rev 218:178–196

  85. 85.

    Carman CV, Springer TA (2008) Trans-cellular migration: cell-cell contacts get intimate. Curr Opin Cell Biol 20(5):533–540

  86. 86.

    Barreiro O, Yanez-Mo M, Serrador JM et al (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157:1233–1245

  87. 87.

    Carman CV, Springer TA (2004) A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167:377–388

  88. 88.

    Cross AH, Raine CS (1991) Central nervous system endothelial cell-polymorphonuclear cell interactions during autoimmune demyelination. American 139(6):1401–1409

  89. 89.

    Engelhardt B, Wolburg H (2004) Mini-review: transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Immunol 34(11):2955–2963

  90. 90.

    Wolburg H, Wolburg-Buchholz K, Engelhardt B (2005) Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol (Berl) 109(2):181–190

  91. 91.

    Geberhiwot T, Assefa D, Kortesmaa J et al (2001) Laminin-8 (alpha4beta1gamma1) is synthesized by lymphoid cells, promotes lymphocyte migration and costimulates T cell proliferation. J Cell Sci 114(Pt 2):423–433

  92. 92.

    Thyboll J, Kortesmaa J, Cao R et al (2002) Deletion of the laminin alpha4 chain leads to impaired microvessel maturation. Mol Cell Biol 22(4):1194–1202

  93. 93.

    Colognato H, Yurchenco PD (2000) Form and function: the laminin family of heterotrimers. Dev Dyn 218(2):213–234

  94. 94.

    Yurchenco PD, Smirnov S, Mathus T (2002) Analysis of basement membrane self-assembly and cellular interactions with native and recombinant glycoproteins. Methods Cell Biol 69:111–144

  95. 95.

    Graesser D, Mahooti S, Madri JA (2000) Distinct roles for matrix metalloproteinase-2 and alpha4 integrin in autoimmune T cell extravasation and residency in brain parenchyma during experimental autoimmune encephalomyelitis. J Neuroimmunol 109(2):121–131

  96. 96.

    Dubois B, Masure S, Hurtenbach U et al (1999) Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J Clin Invest 104:1507–1515

  97. 97.

    Kieseier BC, Clements JM, Pischel HB et al (1998) Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barre syndrome. Annals 43(4):427–434

  98. 98.

    Toft-Hansen H, Nuttall RK, Edwards DR, Owens T (2004) Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis. J Immunol 173(8):5209–5218

  99. 99.

    Toft-Hansen H, Babcock AA, Millward JM, Owens T (2007) Downregulation of membrane type-matrix metalloproteinases in the inflamed or injured central nervous system. J Neuroinflammation 4:24

  100. 100.

    Nygardas P, Hinkkanen A (2002) Up-regulation of MMP-8 and MMP-9 activity in the BALB/c mouse spinal cord correlates with the severity of experimental autoimmune encephalomyelitis. Clin Exp Immunol 128:245–254

  101. 101.

    Gijbels K, Galardy RE, Steinman L (1994) Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J Clin Invest 94(6):2177–2182

  102. 102.

    Morini M, Roccatagliata L, Dell’Eva R et al (2004) Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol 148(1–2):146–153

  103. 103.

    Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature reviews 4(8):617–629

  104. 104.

    McCawley LJ, Matrisian LM (2001) Matrix metalloproteinases: they’re not just for matrix anymore!. Curr Opin Cell Biol 13:534–540

  105. 105.

    Dean RA, Overall CM (2007) Proteomics discovery of metalloproteinase substrates in the cellular context by iTRAQ labeling reveals a diverse MMP-2 substrate degradome. Mol Cell Proteomics 6(4):611–623

  106. 106.

    Overall CM, Blobel CP (2007) In search of partners: linking extracellular proteases to substrates. Nature reviews 8(3):245–257

  107. 107.

    Talts JF, Andac Z, Göhring W, Brancaccio A, Timpl R (1999) Binding of G domains of laminin alpha 1 and alpha 2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins. EMBO J 18:863–870

  108. 108.

    Toft-Hansen H, Buist R, Sun XJ et al (2006) Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system. J Immunol 177(10):7242–7249

  109. 109.

    Betz LA, Goldstein GW, Katzman R (1989) Blood-brain-cerebrospinal fluid barriers. In: Siegel GJ (ed) Basic neurochemistry: molecular, cellular, and medical aspects. Raven, New York, pp 591–606

  110. 110.

    Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B (2001) Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett 307(2):77–80

  111. 111.

    Bronstein JM, Tiwari-Woodruff S, Buznikov AG, Stevens DB (2000) Involvement of OSP/Claudin-11 in oligodendrocyte membrane interactions: role in biology and disease [review]. J Neurosci Res 59(6):706–711

  112. 112.

    de Lange EC (2004) Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Adv Drug Deliv Rev 56(12):1793–1809

  113. 113.

    Liao KK, Lu KS (1993) Cast-model and scanning electron microscopy of the rat brain ventricular system. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 9(6):328–337

  114. 114.

    Ling EA, Kaur C, Lu J (1998) Origin, nature and some functional considerations of intraventrucular macrophages, with special reference to the epiplexus cells. Microsc Res Tech 41:43–56

  115. 115.

    Lu J, Kaur C, Ling EA (1994) Up-regulation of surface antigens on epiplexus cells in postnatal rats following intraperitoneal injections of lipopolysaccaride. Neurosci 63:1169–1178

  116. 116.

    Wolburg K, Gerhardt H, Schulz M, Wolburg H, Engelhardt B (1999) Ultrastructural localization of adhesion molecules in the healthy and inflamed choroid plexus of the mouse. Cell Tissue Res 296(2):259–269

  117. 117.

    Steffen BJ, Breier G, Butcher EC, Schulz M, Engelhardt B (1996) ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. American 148(6):1819–1838

  118. 118.

    Kivisakk P, Mahad DJ, Callahan MK et al (2005) Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 100:8389–8394 Epub 2003 Jun 8326

  119. 119.

    Reboldi A, Coisne C, Baumjohann D et al (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):514–523

  120. 120.

    Dickeson SK, Mathis NL, Rahman M, Bergelson JM, Santoro SA (1999) Determinants of ligand binding specificity of the alpha(1)beta(1) and alpha(2)beta(1) integrins. J Biol Chem 274(45):32182–32191

  121. 121.

    Eble JA, Kassner A, Niland S, et al (2006) Collagen XVI harbors an integrin alpha1 beta1 recognition site in its C-terminal domains. J Biol Chem 28 (35):25745–25756

  122. 122.

    Eble JA (2005) Collagen-binding integrins as pharmaceutical targets. Curr Pharm Des 11(7):867–880

  123. 123.

    Wagner S, Gardner H (2000) Modes of regulation of laminin-5 production by rat astrocytes. Neurosci Lett 284(1–2):105–108

Download references

Author information

Correspondence to Britta Engelhardt or Lydia Sorokin.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Engelhardt, B., Sorokin, L. The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31, 497–511 (2009).

Download citation


  • Blood–brain barrier
  • Blood–cerebrospinal fluid barrier
  • Extracellular matrix
  • Basement membrane
  • Choroid plexus
  • Experimental autoimmune encephalomyelitis