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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Billingham, R.E. & Boswell, T. Studies on the problem of corneal homografts. Proc. R. Soc. Lond. B Biol. Sci. 141, 392–406 (1953).
Shirai, Y. On the transplantation of the rat sarcoma in adult heterogeneous animals. Japan Med. World 1, 14–15 (1921).
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).
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).
Galea, I., Bechmann, I. & Perry, V.H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).
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).
Locatelli, G. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat. Neurosci. 15, 543–550 (2012).
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).
Zamvil, S.S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579–621 (1990).
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).
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).
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).
Raper, D., Louveau, A. & Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 39, 581–586 (2016).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
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).
Asgari, M., de Zélicourt, D. & Kurtcuoglu, V. Glymphatic solute transport does not require bulk flow. Sci. Rep. 6, 38635 (2016).
Mezey, É. & Palkovits, M. Neuroanatomy: forgotten findings of brain lymphatics. Nature 524, 415 (2015).
Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).
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).
Vandenabeele, F., Creemers, J. & Lambrichts, I. Ultrastructure of the human spinal arachnoid mater and dura mater. J. Anat. 189, 417–430 (1996).
Yasuda, K. et al. Drug transporters on arachnoid barrier cells contribute to the blood-cerebrospinal fluid barrier. Drug Metab. Dispos. 41, 923–931 (2013).
Hutchings, M. & Weller, R.O. Anatomical relationships of the pia mater to cerebral blood vessels in man. J. Neurosurg. 65, 316–325 (1986).
Weller, R.O. Microscopic morphology and histology of the human meninges. Morphologie 89, 22–34 (2005).
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).
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).
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).
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).
Salzman, K.L. et al. Giant tumefactive perivascular spaces. AJNR Am. J. Neuroradiol. 26, 298–305 (2005).
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).
Tietz, S. & Engelhardt, B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493–506 (2015).
Owens, T., Bechmann, I. & Engelhardt, B. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol. 67, 1113–1121 (2008).
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).
Engelhardt, B. et al. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132, 317–338 (2016).
Engelhardt, B. & Ransohoff, R.M. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579–589 (2012).
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).
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).
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).
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).
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).
Kaminski, M. et al. Migration of monocytes after intracerebral injection at entorhinal cortex lesion site. J. Leukoc. Biol. 92, 31–39 (2012).
Upton, M.L. & Weller, R.O. The morphology of cerebrospinal fluid drainage pathways in human arachnoid granulations. J. Neurosurg. 63, 867–875 (1985).
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).
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).
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).
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).
Pappolla, M. et al. Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice. Neurobiol. Dis. 71, 215–219 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
Beach, T.G. et al. Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci. Lett. 283, 9–12 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).
Sigmundsdottir, H. & Butcher, E.C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat. Immunol. 9, 981–987 (2008).
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).
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).
Odoardi, F. et al. T cells become licensed in the lung to enter the central nervous system. Nature 488, 675–679 (2012).
Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Bartholomäus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).
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).
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).
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).
Engelhardt, B. The Choroid Plexus in Health and Disease Vol. 52 (Wiley-Liss, New York, 2001).
Baruch, K. & Schwartz, M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34, 11–16 (2013).
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).
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).
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).
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).
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).
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).
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).
Blinder, P. et al. The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. Nat. Neurosci. 16, 889–897 (2013).
Czabanka, M. et al. Clinical implications of cortical microvasculature in adult Moyamoya disease. J. Cereb. Blood Flow Metab. 29, 1383–1387 (2009).
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).
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).
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).
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).
Klein, R.S., Garber, C. & Howard, N. Infectious immunity in the central nervous system and brain function. Nat. Immunol. 18, 132–141 (2017).
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).
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).
The authors declare no competing financial interests.
About this article
Cite this article
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
An evaluation of the recognised systemic inflammatory biomarkers of chronic sub-optimal inflammation provides evidence for inflammageing (IFA) during multiple sclerosis (MS)
Immunity & Ageing (2021)
Journal of Neuroinflammation (2021)
Fluids and Barriers of the CNS (2021)
Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies
Journal of Experimental & Clinical Cancer Research (2021)
Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges
Nature Neuroscience (2021)