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The movers and shapers in immune privilege of the CNS

Abstract

Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent rediscoveries of lymphatic vessels within the dura mater surrounding the brain, made possible by modern live-cell imaging technologies, have revived this discussion. This review emphasizes the fact that understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Endothelial, epithelial and glial brain barriers establish compartments in the CNS that differ strikingly with regard to their accessibility to immune-cell subsets. There is a unique system of lymphatic drainage from the CNS to the peripheral lymph nodes. We summarize current knowledge on the cellular and molecular mechanisms involved in immune-cell trafficking and lymphatic drainage from the CNS, and we take into account differences in rodent and human CNS anatomy.

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Figure 1: The acellular and cellular brain barriers.

Debbie Maizels/Springer Nature

Figure 2: Lymphatic drainage of the CNS in humans and in rodents.

Debbie Maizels/Springer Nature

Figure 3: Efferent immune pathways to the CNS.

Debbie Maizels/Springer Nature

Figure 4: Intravital fluorescence videomicroscopy of mouse and human CNS vasculature.

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References

  1. Billingham, R.E. & Boswell, T. Studies on the problem of corneal homografts. Proc. R. Soc. Lond. B Biol. Sci. 141, 392–406 (1953).

    Article  CAS  PubMed  Google Scholar 

  2. Shirai, Y. On the transplantation of the rat sarcoma in adult heterogeneous animals. Japan Med. World 1, 14–15 (1921).

    Google Scholar 

  3. Medawar, P.B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29, 58–69 (1948).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Knopf, P.M. et al. Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells. J. Immunol. 161, 692–701 (1998).

    CAS  PubMed  Google Scholar 

  5. Galea, I., Bechmann, I. & Perry, V.H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Andersson, P.B., Perry, V.H. & Gordon, S. The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues. Neuroscience 48, 169–186 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Locatelli, G. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat. Neurosci. 15, 543–550 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Traka, M., Podojil, J.R., McCarthy, D.P., Miller, S.D. & Popko, B. Oligodendrocyte death results in immune-mediated CNS demyelination. Nat. Neurosci. 19, 65–74 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Zamvil, S.S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579–621 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Mason, D.W. et al. The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents. Neuroscience 19, 685–694 (1986).

    Article  CAS  PubMed  Google Scholar 

  11. Nicholas, M.K., Antel, J.P., Stefansson, K. & Arnason, B.G. Rejection of fetal neocortical neural transplants by H-2 incompatible mice. J. Immunol. 139, 2275–2283 (1987).

    CAS  PubMed  Google Scholar 

  12. Cserr, H.F. & Knopf, P.M. Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol. Today 13, 507–512 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Raper, D., Louveau, A. & Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 39, 581–586 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Iliff, J.J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Asgari, M., de Zélicourt, D. & Kurtcuoglu, V. Glymphatic solute transport does not require bulk flow. Sci. Rep. 6, 38635 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mezey, É. & Palkovits, M. Neuroanatomy: forgotten findings of brain lymphatics. Nature 524, 415 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alcolado, R., Weller, R.O., Parrish, E.P. & Garrod, D. The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations. Neuropathol. Appl. Neurobiol. 14, 1–17 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Vandenabeele, F., Creemers, J. & Lambrichts, I. Ultrastructure of the human spinal arachnoid mater and dura mater. J. Anat. 189, 417–430 (1996).

    PubMed  PubMed Central  Google Scholar 

  21. Yasuda, K. et al. Drug transporters on arachnoid barrier cells contribute to the blood-cerebrospinal fluid barrier. Drug Metab. Dispos. 41, 923–931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hutchings, M. & Weller, R.O. Anatomical relationships of the pia mater to cerebral blood vessels in man. J. Neurosurg. 65, 316–325 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Weller, R.O. Microscopic morphology and histology of the human meninges. Morphologie 89, 22–34 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Howell, O.W. et al. Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space. Neuropathol. Appl. Neurobiol. 41, 798–813 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Zhang, E.T., Inman, C.B. & Weller, R.O. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J. Anat. 170, 111–123 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Morris, A.W. et al. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 131, 725–736 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sapsford, I., Buontempo, J. & Weller, R.O. Basement membrane surfaces and perivascular compartments in normal human brain and glial tumours. A scanning electron microscope study. Neuropathol. Appl. Neurobiol. 9, 181–194 (1983).

    Article  CAS  PubMed  Google Scholar 

  28. Salzman, K.L. et al. Giant tumefactive perivascular spaces. AJNR Am. J. Neuroradiol. 26, 298–305 (2005).

    PubMed  PubMed Central  Google Scholar 

  29. Pollock, H., Hutchings, M., Weller, R.O. & Zhang, E.T. Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes. J. Anat. 191, 337–346 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tietz, S. & Engelhardt, B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493–506 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Owens, T., Bechmann, I. & Engelhardt, B. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol. 67, 1113–1121 (2008).

    Article  PubMed  Google Scholar 

  32. Spector, R., Snodgrass, S.R. & Johanson, C.E. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp. Neurol. 273, 57–68 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Engelhardt, B. et al. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132, 317–338 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Engelhardt, B. & Ransohoff, R.M. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579–589 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Weller, R.O., Hawkes, C.A., Carare, R.O. & Hardy, J. Does the difference between PART and Alzheimer's disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau? Acta Neuropathol. 129, 763–766 (2015).

    Article  PubMed  Google Scholar 

  36. Hladky, S.B. & Barrand, M.A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11, 26 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kida, S., Pantazis, A. & Weller, R.O. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol. Appl. Neurobiol. 19, 480–488 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Szentistványi, I., Patlak, C.S., Ellis, R.A. & Cserr, H.F. Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. 246, F835–F844 (1984).

    PubMed  Google Scholar 

  39. Carare, R.O. et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol. Appl. Neurobiol. 34, 131–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Kaminski, M. et al. Migration of monocytes after intracerebral injection at entorhinal cortex lesion site. J. Leukoc. Biol. 92, 31–39 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Upton, M.L. & Weller, R.O. The morphology of cerebrospinal fluid drainage pathways in human arachnoid granulations. J. Neurosurg. 63, 867–875 (1985).

    Article  CAS  PubMed  Google Scholar 

  42. Cserr, H.F., Harling-Berg, C.J. & Knopf, P.M. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 2, 269–276 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Goldmann, J. et al. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J. Leukoc. Biol. 80, 797–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Hatterer, E. et al. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 107, 806–812 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Arbel-Ornath, M. et al. Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models. Acta Neuropathol. 126, 353–364 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Pappolla, M. et al. Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice. Neurobiol. Dis. 71, 215–219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Herzig, M.C., Van Nostrand, W.E. & Jucker, M. Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol. 16, 40–54 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Carare, R.O., Hawkes, C.A., Jeffrey, M., Kalaria, R.N. & Weller, R.O. Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol. Appl. Neurobiol. 39, 593–611 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Weller, R.O., Subash, M., Preston, S.D., Mazanti, I. & Carare, R.O. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 18, 253–266 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Carare, R.O., Hawkes, C.A. & Weller, R.O. Afferent and efferent immunological pathways of the brain. Anatomy, function and failure. Brain Behav. Immun. 36, 9–14 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Barua, N.U. et al. Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model. Fluids Barriers CNS 9, 2 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, E.T., Richards, H.K., Kida, S. & Weller, R.O. Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathol. 83, 233–239 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. Carare, R.O. et al. Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer's disease. Acta Neuropathol. Commun. 1, 48 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hawkes, C.A. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431–443 (2011).

    Article  PubMed  Google Scholar 

  55. Beach, T.G. et al. Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci. Lett. 283, 9–12 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Schley, D., Carare-Nnadi, R., Please, C.P., Perry, V.H. & Weller, R.O. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J. Theor. Biol. 238, 962–974 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Sharp, M.K., Diem, A.K., Weller, R.O. & Carare, R.O. Peristalsis with oscillating flow resistance: a mechanism for periarterial clearance of amyloid beta from the brain. Ann. Biomed. Eng. 44, 1553–1565 (2016).

    Article  PubMed  Google Scholar 

  58. Preston, S.D., Steart, P.V., Wilkinson, A., Nicoll, J.A. & Weller, R.O. Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol. Appl. Neurobiol. 29, 106–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Zekonyte, J., Sakai, K., Nicoll, J.A., Weller, R.O. & Carare, R.O. Quantification of molecular interactions between ApoE, amyloid-beta (Aβ) and laminin: relevance to accumulation of Aβ in Alzheimer's disease. Biochim. Biophys. Acta 1862, 1047–1053 (2015).

    Article  PubMed  CAS  Google Scholar 

  60. Shinkai, Y. et al. Amyloid beta-proteins 1-40 and 1-42(43) in the soluble fraction of extra- and intracranial blood vessels. Ann. Neurol. 38, 421–428 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Clapham, R., O'Sullivan, E., Weller, R.O. & Carare, R.O. Cervical lymph nodes are found in direct relationship with the internal carotid artery: significance for the lymphatic drainage of the brain. Clin. Anat. 23, 43–47 (2010).

    CAS  PubMed  Google Scholar 

  62. Rennels, M.L., Gregory, T.F., Blaumanis, O.R., Fujimoto, K. & Grady, P.A. Evidence for a 'paravascular' fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res. 326, 47–63 (1985).

    Article  CAS  PubMed  Google Scholar 

  63. Prinz, M., Priller, J., Sisodia, S.S. & Ransohoff, R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sigmundsdottir, H. & Butcher, E.C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat. Immunol. 9, 981–987 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. van Zwam, M. et al. Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J. Pathol. 217, 543–551 (2009).

    Article  PubMed  Google Scholar 

  67. Phillips, M.J., Needham, M. & Weller, R.O. Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat. J. Pathol. 182, 457–464 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Odoardi, F. et al. T cells become licensed in the lung to enter the central nervous system. Nature 488, 675–679 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Kivisäkk, P. et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl. Acad. Sci. USA 100, 8389–8394 (2003).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Kerfoot, S.M. & Kubes, P. 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 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Vajkoczy, P., Laschinger, M. & Engelhardt, B. Alpha4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels. J. Clin. Invest. 108, 557–565 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Reboldi, A. et al. 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, 514–523 (2009).

    CAS  PubMed  Google Scholar 

  74. McCandless, E.E., Wang, Q., Woerner, B.M., Harper, J.M. & Klein, R.S. CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J. Immunol. 177, 8053–8064 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Kawakami, N. et al. The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis. J. Exp. Med. 199, 185–197 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kawakami, N. et al. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J. Exp. Med. 201, 1805–1814 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Lodygin, D. et al. A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nat. Med. 19, 784–790 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Bartholomäus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

    Article  PubMed  CAS  Google Scholar 

  80. Lopes Pinheiro, M.A. et al. Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim. Biophys. Acta 1862, 461–471 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Song, J. et al. Focal MMP-2 and MMP-9 activity at the blood-brain barrier promotes chemokine-induced leukocyte migration. Cell Reports 10, 1040–1054 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Engelhardt, B. The Choroid Plexus in Health and Disease Vol. 52 (Wiley-Liss, New York, 2001).

    Google Scholar 

  84. Baruch, K. & Schwartz, M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34, 11–16 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Steffen, B.J., Breier, G., Butcher, E.C., Schulz, M. & Engelhardt, B. ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. Am. J. Pathol. 148, 1819–1838 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Shechter, R. et al. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38, 555–569 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  88. Zhang, X., Wu, C., Song, J., Götte, M. & Sorokin, L. Syndecan-1, a cell surface proteoglycan, negatively regulates initial leukocyte recruitment to the brain across the choroid plexus in murine experimental autoimmune encephalomyelitis. J. Immunol. 191, 4551–4561 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Engelhardt, B., Vajkoczy, P. & Laschinger, M. Detection of endothelial/lymphocyte interaction in spinal cord microvasculature by intravital videomicroscopy. Methods Mol. Med. 89, 83–93 (2003).

    PubMed  Google Scholar 

  90. Bayerl, S.H. et al. Time lapse in vivo microscopy reveals distinct dynamics of microglia-tumor environment interactions-a new role for the tumor perivascular space as highway for trafficking microglia. Glia 64, 1210–1226 (2016).

    Article  PubMed  Google Scholar 

  91. Atangana, E. et al. Intravascular inflammation triggers intracerebral activated microglia and contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Transl. Stroke Res. http://dx.doi.org/10.1007/s12975-016-0485-3 (2016).

  92. Blinder, P. et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat. Neurosci. 16, 889–897 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Czabanka, M. et al. Clinical implications of cortical microvasculature in adult Moyamoya disease. J. Cereb. Blood Flow Metab. 29, 1383–1387 (2009).

    Article  PubMed  Google Scholar 

  94. Woitzik, J., Peña-Tapia, P.G., Schneider, U.C., Vajkoczy, P. & Thomé, C. Cortical perfusion measurement by indocyanine-green videoangiography in patients undergoing hemicraniectomy for malignant stroke. Stroke 37, 1549–1551 (2006).

    Article  PubMed  Google Scholar 

  95. Lane, B., Bohnstedt, B.N. & Cohen-Gadol, A.A. A prospective comparative study of microscope-integrated intraoperative fluorescein and indocyanine videoangiography for clip ligation of complex cerebral aneurysms. J. Neurosurg. 122, 618–626 (2015).

    Article  PubMed  Google Scholar 

  96. Nicholas, D.S. & Weller, R.O. The fine anatomy of the human spinal meninges. A light and scanning electron microscopy study. J. Neurosurg. 69, 276–282 (1988).

    Article  CAS  PubMed  Google Scholar 

  97. Schebesch, K.M. et al. Sodium fluorescein-guided resection under the YELLOW 560 nm surgical microscope filter in malignant brain tumor surgery—a feasibility study. Acta Neurochir. (Wien) 155, 693–699 (2013).

    Article  Google Scholar 

  98. Klein, R.S., Garber, C. & Howard, N. Infectious immunity in the central nervous system and brain function. Nat. Immunol. 18, 132–141 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Carson, M.J., Doose, J.M., Melchior, B., Schmid, C.D. & Ploix, C.C. CNS immune privilege: hiding in plain sight. Immunol. Rev. 213, 48–65 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

B.E. is supported by the Swiss National Science Foundation (grants 154483, 154483 and 170131), the Swiss Multiple Sclerosis Society, the Novartis Foundation for Medical-Biological Research, EU FP7 ITN nEUROinflammation (607962), EU Horizon 2020 ITN BtRAIN (675619) and the EU/Eureka-funded Eurostars Siagen-MS (9059).

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Engelhardt, B., Vajkoczy, P. & Weller, R. The movers and shapers in immune privilege of the CNS. Nat Immunol 18, 123–131 (2017). https://doi.org/10.1038/ni.3666

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