Journal of Neuroimmune Pharmacology

, Volume 8, Issue 4, pp 840–856 | Cite as

Drainage of Cells and Soluble Antigen from the CNS to Regional Lymph Nodes



Despite the absence of conventional lymphatics, there is efficient drainage of both cerebrospinal fluid (CSF) and interstitial fluid (ISF) from the CNS to regional lymph nodes. CSF drains from the subarachnoid space by channels that pass through the cribriform plate of the ethmoid bone to the nasal mucosa and cervical lymph nodes in animals and in humans; antigen presenting cells (APC) migrate along this pathway to lymph nodes. ISF and solutes drain from the brain parenchyma to cervical lymph nodes by a separate route along 100–150 nm wide basement membranes in the walls of cerebral capillaries and arteries. This pathway is too narrow for the migration of APC so it is unlikely that APC traffic directly from brain parenchyma to lymph nodes by this route. We present a model for the pivotal involvement of regional lymph nodes in immunological reactions of the CNS. The role of regional lymph nodes in immune reactions of the CNS in virus infections, the remote influence of the gut microbiota, multiple sclerosis and stroke are discussed. Evidence is presented for the role of cervical lymph nodes in the induction of tolerance and its influence on neuroimmunological reactions. We look to the future by examining how nanoparticle technology will enhance our understanding of CNS-lymph node connections and by reviewing the implications of lymphatic drainage of the brain for diagnosis and therapy of diseases of the CNS ranging from neuroimmunological disorders to dementias. Finally, we review the challenges and opportunities for progress in CNS-lymph node interactions and their involvement in disease processes.


Antigen presenting cells CSF Interstitial fluid Nasal lymphatics Cervical lymph nodes Dendritic cells Perivascular drainage Immune privilege Multiple sclerosis Regulatory T and B cells Tolerance Stroke 



Antigen presenting cell


Cervical lymph nodes


Central nervous system


Cerebrospinal fluid


Dendritic cells


Experimental autoimmune/allergic encephalomyelitis


Green fluorescent protein


Interstitial fluid


Myelin basic protein


Myelin oligodendrocyte glycoprotein


Magnetic resonance imaging


Multiple sclerosis




Proteolipid protein


Regulatory T cells


  1. Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552PubMedCrossRefGoogle Scholar
  2. Andersson PB, Perry VH, Gordon S (1992) Intracerebral injection of proinflammatory cytokines or leukocyte chemotaxins induces minimal myelomonocytic cell recruitment to the parenchyma of the central nervous system. J Exp Med 176:255–259PubMedCrossRefGoogle Scholar
  3. Bailey SL, Schreiner B, McMahon EJ, Miller SD (2007) CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol 8(2):172–180. doi:10.1038/ni1430 PubMedCrossRefGoogle Scholar
  4. Barua NU, Bienemann AS, Hesketh S, Wyatt MJ, Castrique E, Love S, Gill SS (2012) Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model. Fluids Barriers CNS 9:2. doi:10.1186/2045-8118-9-2 PubMedCrossRefGoogle Scholar
  5. Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28:5–11PubMedCrossRefGoogle Scholar
  6. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479(7374):538–541. doi:10.1038/nature10554 PubMedCrossRefGoogle Scholar
  7. Bergsneider M (2001) Evolving concepts of cerebrospinal fluid. Neurosurg Clin N Am 36:631–638Google Scholar
  8. Brancato D, Citarrella R, Richiusa P, Amato MC, Vetro C, Galluzzo CG (2013) Neck lymph nodes in chronic autoimmune thyroiditis: the sonographic pattern. Thyroid Off J Am Thyroid Assoc 23(2):173–177. doi:10.1089/thy.2012.0375 CrossRefGoogle Scholar
  9. Bulloch K, Miller MM, Gal-Toth J, Milner TA, Gottfried-Blackmore A, Waters EM, Kaunzner UW, Liu K, Lindquist R, Nussenzweig MC, Steinman RM, McEwen BS (2008) CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J Comp Neurol 508:687–710. doi:10.1002/cne.21668 PubMedCrossRefGoogle Scholar
  10. Burkhart C, Liu GY, Anderton SM, Metzler B, Wraith DC (1999) Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int Immunol 11(10):1625–1634PubMedCrossRefGoogle Scholar
  11. Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JAR, Perry VH, Weller RO (2008) 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. doi:10.1111/j.1365-2990.2007.00926 Google Scholar
  12. Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO (2013) 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. doi:10.1111/nan.12042 PubMedGoogle Scholar
  13. Cervantes-Barragan L, Firner S, Bechmann I, Waisman A, Lahl K, Sparwasser T, Thiel V, Ludewig B (2012) Regulatory T cells selectively preserve immune privilege of self-antigens during viral central nervous system infection. J Immunol 188(8):3678–3685. doi:10.4049/jimmunol.1102422 PubMedCrossRefGoogle Scholar
  14. Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R (2012) The immunology of acute stroke. Nat Rev Neurol 8(7):401–410. doi:10.1038/nrneurol.2012.98 PubMedCrossRefGoogle Scholar
  15. Chinnery HR, Ruitenberg MJ, McMenamin PG (2010) Novel characterization of monocyte-derived cell populations in the meninges and choroid plexus and their rates of replenishment in bone marrow chimeric mice. J Neuropathol Exp Neurol 69:896–909. doi:10.1097/NEN.0b013e3181edbc1a PubMedCrossRefGoogle Scholar
  16. Clarkson BD, Heninger E, Harris MG, Lee J, Sandor M, Fabry Z (2012) Innate-adaptive crosstalk: how dendritic cells shape immune responses in the CNS. Adv Exp Med Biol 946:309–333. doi:10.1007/978-1-4614-0106-3_18 PubMedCrossRefGoogle Scholar
  17. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506. doi:10.1126/science.1217697 PubMedCrossRefGoogle Scholar
  18. Cserr HF, Knopf PM (1992) Cervical lymphatics, the blood–brain barrier and the immunoreactivity of the brain: a new view. Immunol Today 13(12):507–512PubMedCrossRefGoogle Scholar
  19. Cserr HF, Harling-Berg CJ, Knopf PM (1992) Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:269–276PubMedCrossRefGoogle Scholar
  20. Davson H, Welch K, Segal MB (1987) Physiology and pathophysiology of the cerebrospinal fluid. Churchill Livingstone, EdinburghGoogle Scholar
  21. de Vos AF, van Meurs M, Brok HP, Boven LA, Hintzen RQ, van der Valk P, Ravid R, Rensing S, Boon L, t Hart BA, Laman JD (2002) Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol 169(10):5415–5423PubMedGoogle Scholar
  22. Deleidi M, Isacson O (2012) Viral and inflammatory triggers of neurodegenerative diseases. Sci Transl Med 4(121):121ps123. doi:10.1126/scitranslmed.3003492 CrossRefGoogle Scholar
  23. Dunne PJ, Moran B, Cummins RC, Mills KH (2009) CD11c+CD8alpha+ dendritic cells promote protective immunity to respiratory infection with Bordetella pertussis. J Immunol 183(1):400–410. doi:10.4049/jimmunol.0900169 PubMedCrossRefGoogle Scholar
  24. Engelhardt B (2008) Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J Neurol Sci 274:23–26PubMedCrossRefGoogle Scholar
  25. Engelhardt B, Coisne C (2011) Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS 8:4–9PubMedCrossRefGoogle Scholar
  26. Fabriek BO, Zwemmer JN, Teunissen CE, Dijkstra CD, Polman CH, Laman JD, Castelijns JA (2005) In vivo detection of myelin proteins in cervical lymph nodes of MS patients using ultrasound-guided fine-needle aspiration cytology. J Neuroimmunol 161:190–194PubMedCrossRefGoogle Scholar
  27. Frenkel D, Puckett L, Petrovic S, Xia W, Chen G, Vega J, Dembinsky-Vaknin A, Shen J, Plante M, Burt DS, Weiner HL (2008) A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol 63(5):591–601. doi:10.1002/ana.21340 PubMedCrossRefGoogle Scholar
  28. Furtado GC, Marcondes MC, Latkowski JA, Tsai J, Wensky A, Lafaille JJ (2008) Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis. J Immunol 181:4648–4655PubMedGoogle Scholar
  29. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18PubMedCrossRefGoogle Scholar
  30. Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129(Pt 8):1953–1971. doi:10.1093/brain/awl075 PubMedCrossRefGoogle Scholar
  31. Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I (2006) T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80:797–801. doi:10.1189/jlb.0306176 PubMedCrossRefGoogle Scholar
  32. Goverman J, Woods A, Larson L, Weiner LP, Hood L, Zaller DM (1993) Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72(4):551–560PubMedCrossRefGoogle Scholar
  33. Grant JL, Ghosn EE, Axtell RC, Herges K, Kuipers HF, Woodling NS, Andreasson K, Herzenberg LA, Steinman L (2012) Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med 4(145):145ra105. doi:10.1126/scitranslmed.3004145 PubMedCrossRefGoogle Scholar
  34. Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328–334PubMedCrossRefGoogle Scholar
  35. Hamrah P, Dana MR (2007) Corneal antigen-presenting cells. Chem Immunol Allergy 92:58–70. doi:10.1159/000099254 PubMedCrossRefGoogle Scholar
  36. Hartman KB, Wilson LJ, Rosenblum MG (2008) Detecting and treating cancer with nanotechnology. Mol Diagn Ther 12(1):1–14PubMedCrossRefGoogle Scholar
  37. Hatterer E, Davoust N, Didier-Bazes M, Vuaillat C, Malcus C, Belin MF, Nataf S (2006) How to drain without lymphatics? dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 107:806–812PubMedCrossRefGoogle Scholar
  38. Hatterer E, Touret M, Belin MF, Honnorat J, Nataf S (2008) Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions. PLoS One 3:e3321. doi:10.1371/journal.pone.0003321 PubMedCrossRefGoogle Scholar
  39. Hawkes CA, McLaurin J (2009) Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci U S A 106:1261–1266PubMedCrossRefGoogle Scholar
  40. Hawkes CA, Hartig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO (2011) Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121:431–443. doi:10.1007/s00401-011-0801-7 PubMedCrossRefGoogle Scholar
  41. Hawkes CA, Sullivan PM, Hands S, Weller RO, Nicoll JA, Carare RO (2012) Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PLoS One 7:e41636. doi:10.1371/journal.pone.0041636 PubMedCrossRefGoogle Scholar
  42. Hochmeister S, Zeitelhofer M, Bauer J, Nicolussi EM, Fischer MT, Heinke B, Selzer E, Lassmann H, Bradl M (2008) After injection into the striatum, in vitro-differentiated microglia- and bone marrow-derived dendritic cells can leave the central nervous system via the blood stream. Am J Pathol 173:1669–1681PubMedCrossRefGoogle Scholar
  43. Hutchings M, Weller RO (1986) Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg 65:316–325PubMedCrossRefGoogle Scholar
  44. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 15:147ra111CrossRefGoogle Scholar
  45. Ishibashi S, Maric D, Mou Y, Ohtani R, Ruetzler C, Hallenbeck JM (2009) Mucosal tolerance to E-selectin promotes the survival of newly generated neuroblasts via regulatory T-cell induction after stroke in spontaneously hypertensive rats. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 29(3):606–620. doi:10.1038/jcbfm.2008.153 CrossRefGoogle Scholar
  46. Ji Q, Perchellet A, Goverman JM (2010) Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs. Nat Immunol 11(7):628–634. doi:10.1038/ni.1888 PubMedCrossRefGoogle Scholar
  47. Ji Q, Castelli L, Goverman JM (2013) MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8(+) T cells. Nat Immunol 14(3):254–261. doi:10.1038/ni.2513 PubMedCrossRefGoogle Scholar
  48. Johanson CE, Duncan JA, Klinge PM, Brinker T, Stopa EG, Silverberg GD (2008) Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res 5:10PubMedCrossRefGoogle Scholar
  49. Kaminski M, Bechmann I, Pohland M, Kiwit J, Nitsch R, Glumm J (2012) Migration of monocytes after intracerebral injection at entorhinal cortex lesion site. J Leukoc Biol 92:31–39PubMedCrossRefGoogle Scholar
  50. Karman J, Ling C, Sandor M, Fabry Z (2004) Initiation of immune responses in brain is promoted by local dendritic cells. J Immunol 173:2353–2361PubMedGoogle Scholar
  51. Keijzer C, Slutter B, van der Zee R, Jiskoot W, van Eden W, Broere F (2011) PLGA, PLGA-TMC and TMC-TPP nanoparticles differentially modulate the outcome of nasal vaccination by inducing tolerance or enhancing humoral immunity. PLoS One 6(11):e26684. doi:10.1371/journal.pone.0026684 PubMedCrossRefGoogle Scholar
  52. Kida S, Pantazis A, Weller RO (1993a) CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19:480–488PubMedCrossRefGoogle Scholar
  53. Kida S, Steart PV, Zhang ET, Weller RO (1993b) Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes, microglia and macrophages. Acta Neuropathol 85:646–652PubMedCrossRefGoogle Scholar
  54. Kooi EJ, van Horssen J, Witte ME, Amor S, Bo L, Dijkstra CD, van der Valk P, Geurts JJ (2009) Abundant extracellular myelin in the meninges of patients with multiple sclerosis. Neuropathol Appl Neurobiol 35(3):283–295. doi:10.1111/j.1365-2990.2008.00986.x PubMedCrossRefGoogle Scholar
  55. Lake J, Weller RO, Phillips MJ, Needham M (1999) Lymphocyte targeting of the brain in adoptive transfer cryolesion-EAE. J Pathol 187(2):259–265PubMedCrossRefGoogle Scholar
  56. Laman JD, Weller RO (2012) Editorial: route by which monocytes leave the brain is revealed. J Leukoc Biol 92:6–9PubMedCrossRefGoogle Scholar
  57. Lieberman SM, Kim JS, Corbo-Rodgers E, Kambayashi T, Maltzman JS, Behrens EM, Turka LA (2012) Site-specific accumulation of recently activated CD4+ Foxp3+ regulatory T cells following adoptive transfer. Eur J Immunol 42(6):1429–1435. doi:10.1002/eji.201142286 PubMedCrossRefGoogle Scholar
  58. Ling C, Sandor M, Fabry Z (2003) In situ processing and distribution of intracerebrally injected OVA in the CNS. J Neuroimmunol 141:90–98PubMedCrossRefGoogle Scholar
  59. Locatelli G, Wortge S, Buch T, Ingold B, Frommer F, Sobottka B, Kruger M, Karram K, Buhlmann C, Bechmann I, Heppner FL, Waisman A, Becher B (2012) Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat Neurosci 15:543–550. doi:10.1038/nn.3062 PubMedCrossRefGoogle Scholar
  60. Marten NW, Stohlman SA, Zhou J, Bergmann CC (2003) Kinetics of virus-specific CD8+ -T-cell expansion and trafficking following central nervous system infection. J Virol 77(4):2775–2778PubMedCrossRefGoogle Scholar
  61. Mascarell L, Saint-Lu N, Moussu H, Zimmer A, Louise A, Lone Y, Ladant D, Leclerc C, Tourdot S, Van Overtvelt L, Moingeon P (2011) Oral macrophage-like cells play a key role in tolerance induction following sublingual immunotherapy of asthmatic mice. Mucosal Immunol 4(6):638–647. doi:10.1038/mi.2011.28 PubMedCrossRefGoogle Scholar
  62. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774PubMedCrossRefGoogle Scholar
  63. McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD (2005) Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11(3):335–339. doi:10.1038/nm1202 PubMedCrossRefGoogle Scholar
  64. Meredith MM, Liu K, Kamphorst AO, Idoyaga J, Yamane A, Guermonprez P, Rihn S, Yao KH, Silva IT, Oliveira TY, Skokos D, Casellas R, Nussenzweig MC (2012) Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state. J Exp Med 209(9):1583–1593. doi:10.1084/jem.20121003 PubMedCrossRefGoogle Scholar
  65. Mohammad MG, Hassanpour M, Tsai VW, Li H, Ruitenberg MJ, Booth DW, Serrats J, Hart PH, Symonds GP, Sawchenko PE, Breit SN, Brown DA (2012) Dendritic cells and multiple sclerosis: disease, tolerance and therapy. Int J Mol Sci 14(1):547–562. doi:10.3390/ijms14010547 PubMedCrossRefGoogle Scholar
  66. Moingeon P, Mascarell L (2012) Induction of tolerance via the sublingual route: mechanisms and applications. Clin Dev Immunol 2012:623474. doi:10.1155/2012/623474 PubMedCrossRefGoogle Scholar
  67. Monteiro M, Almeida CF, Caridade M, Ribot JC, Duarte J, Agua-Doce A, Wollenberg I, Silva-Santos B, Graca L (2010) Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-beta. J Immunol 185(4):2157–2163. doi:10.4049/jimmunol.1000359 PubMedCrossRefGoogle Scholar
  68. Muldoon LL, Varallyay P, Kraemer DF, Kiwic G, Pinkston K, Walker-Rosenfeld SL, Neuwelt EA (2004) Trafficking of superparamagnetic iron oxide particles (Combidex) from brain to lymph nodes in the rat. Neuropathol Appl Neurobiol 30(1):70–79PubMedCrossRefGoogle Scholar
  69. Mutlu L, Brandt C, Kwidzinski E, Sawitzki B, Gimsa U, Mahlo J, Aktas O, Nitsch R, van Zwam M, Laman JD, Bechmann I (2007) Tolerogenic effect of fiber tract injury: reduced EAE severity following entorhinal cortex lesion. Exp Brain Res 178:542–553PubMedCrossRefGoogle Scholar
  70. Nance EA, Woodworth GF, Sailor KA, Shih TY, Xu Q, Swaminathan G, Xiang D, Eberhart C, Hanes J (2012) A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med 4(149):149ra119. doi:10.1126/scitranslmed.3003594 PubMedCrossRefGoogle Scholar
  71. Navarrete-Talloni MJ, Kalkuhl A, Deschl U, Ulrich R, Kummerfeld M, Rohn K, Baumgartner W, Beineke A (2010) Transient peripheral immune response and central nervous system leaky compartmentalization in a viral model for multiple sclerosis. Brain Pathol 20(5):890–901. doi:10.1111/j.1750-3639.2010.00383.x PubMedGoogle Scholar
  72. Nicholas DS, Weller RO (1988) The fine anatomy of the human spinal meninges. A light and scanning electron microscopy study. J Neurosurg 69:276–282PubMedCrossRefGoogle Scholar
  73. Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, Kasper LH (2009) Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 183(10):6041–6050. doi:10.4049/jimmunol.0900747 PubMedCrossRefGoogle Scholar
  74. Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, Kasper DL, Kasper LH (2010a) Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol 185(7):4101–4108. doi:10.4049/jimmunol.1001443 PubMedCrossRefGoogle Scholar
  75. Ochoa-Reparaz J, Mielcarz DW, Wang Y, Begum-Haque S, Dasgupta S, Kasper DL, Kasper LH (2010b) A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol 3(5):487–495. doi:10.1038/mi.2010.29 PubMedCrossRefGoogle Scholar
  76. Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schlager C, Lodygin D, Heckelsmiller K, Nietfeld W, Ellwart J, Klinkert WE, Lottaz C, Nosov M, Brinkmann V, Spang R, Lehrach H, Vingron M, Wekerle H, Flugel-Koch C, Flugel A (2012) T cells become licensed in the lung to enter the central nervous system. Nature 488(7413):675–679. doi:10.1038/nature11337 PubMedCrossRefGoogle Scholar
  77. Oude Engberink RD, Blezer EL, Dijkstra CD, van der Pol SM, van der Toorn A, de Vries HE (2010) Dynamics and fate of USPIO in the central nervous system in experimental autoimmune encephalomyelitis. NMR Biomed 23(9):1087–1096. doi:10.1002/nbm.1536 PubMedCrossRefGoogle Scholar
  78. Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15(8):1096–1101. doi:10.1038/nn.3161 PubMedCrossRefGoogle Scholar
  79. Pachter JS, de Vries HE, Fabry Z (2003) The blood–brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 62:593–604PubMedGoogle Scholar
  80. Phillips MJ, Needham M, Weller RO (1997) Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat. J Pathol 182:457–464PubMedCrossRefGoogle Scholar
  81. Planas AM, Gomez-Choco M, Urra X, Gorina R, Caballero M, Chamorro A (2012) Brain-derived antigens in lymphoid tissue of patients with acute stroke. J Immunol 188(5):2156–2163. doi:10.4049/jimmunol.1102289 PubMedCrossRefGoogle Scholar
  82. Ploix CC, Noor S, Crane J, Masek K, Carter W, Lo DD, Wilson EH, Carson MJ (2011) CNS-derived CCL21 is both sufficient to drive homeostatic CD4+ T cell proliferation and necessary for efficient CD4+ T cell migration into the CNS parenchyma following Toxoplasma gondii infection. Brain Behav Immun 25(5):883–896. doi:10.1016/j.bbi.2010.09.014 PubMedCrossRefGoogle Scholar
  83. Preston SD, Steart PV, Wilkinson A, Nicoll JAR, Weller RO (2003) Capillary and arterial amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117PubMedCrossRefGoogle Scholar
  84. Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14(10):1227–1235. doi:10.1038/nn.2923 PubMedCrossRefGoogle Scholar
  85. Ransohoff RM (2010) Turning over the chance card on MS susceptibility. Nat Immunol 11(7):570–572. doi:10.1038/ni0710-570 PubMedCrossRefGoogle Scholar
  86. Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15(8):1074–1077. doi:10.1038/nn.3168 PubMedCrossRefGoogle Scholar
  87. Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635. doi:10.1038/nri3265 PubMedCrossRefGoogle Scholar
  88. Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (1985) 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 326:47–63PubMedCrossRefGoogle Scholar
  89. Rynda A, Maddaloni M, Mierzejewska D, Ochoa-Reparaz J, Maslanka T, Crist K, Riccardi C, Barszczewska B, Fujihashi K, McGhee JR, Pascual DW (2008) Low-dose tolerance is mediated by the microfold cell ligand, reovirus protein sigma1. J Immunol 180(8):5187–5200PubMedGoogle Scholar
  90. Samsom JN, Hauet-Broere F, Unger WW, Vanb LA, Kraal G (2004) Early events in antigen-specific regulatory T cell induction via nasal and oral mucosa. Ann N Y Acad Sci 1029:385–389. doi:10.1196/annals.1309.045 PubMedCrossRefGoogle Scholar
  91. Samsom JN, van Berkel LA, van Helvoort JM, Unger WW, Jansen W, Thepen T, Mebius RE, Verbeek SS, Kraal G (2005) Fc gamma RIIB regulates nasal and oral tolerance: a role for dendritic cells. J Immunol 174(9):5279–5287PubMedGoogle Scholar
  92. Samsom JN, van der Marel AP, van Berkel LA, van Helvoort JM, Simons-Oosterhuis Y, Jansen W, Greuter M, Nelissen RL, Meeuwisse CM, Nieuwenhuis EE, Mebius RE, Kraal G (2007) Secretory leukoprotease inhibitor in mucosal lymph node dendritic cells regulates the threshold for mucosal tolerance. J Immunol 179(10):6588–6595PubMedGoogle Scholar
  93. Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO (2006) Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 238:962–974PubMedCrossRefGoogle Scholar
  94. Schwalbe G (1869) Der Arachnoidalraum, ein Lymphraum und sein Zusammenhang mit dem Perichoroidalraum. Zentralb Med Wiss 7:465–467Google Scholar
  95. Serot JM, Foliguet B, Bene MC, Faure GC (1997) Ultrastructural and immunohistological evidence for dendritic-like cells within human choroid plexus epithelium. Neuroreport 8:1995–1998PubMedCrossRefGoogle Scholar
  96. Sun D, Tani M, Newman TA, Krivacic K, Phillips M, Chernosky A, Gill P, Wei T, Griswold KJ, Ransohoff RM, Weller RO (2000) Role of chemokines, neuronal projections, and the blood–brain barrier in the enhancement of cerebral EAE following focal brain damage. J Neuropathol Exp Neurol 59:1031–1043PubMedGoogle Scholar
  97. Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF (1984) Drainage of interstitial fluid from different regions of rat brain. Am J Physiol 246:F835–F844PubMedGoogle Scholar
  98. Trandem K, Anghelina D, Zhao J, Perlman S (2010) Regulatory T cells inhibit T cell proliferation and decrease demyelination in mice chronically infected with a coronavirus. J Immunol 184(8):4391–4400. doi:10.4049/jimmunol.0903918 PubMedCrossRefGoogle Scholar
  99. Tripathi BJ, Tripathi RC (1974) Vacuolar transcellular channels as a drainage pathway for cerebrospinal fluid. J Physiol 239:195–206PubMedGoogle Scholar
  100. Tschen SI, Stohlman SA, Ramakrishna C, Hinton DR, Atkinson RD, Bergmann CC (2006) CNS viral infection diverts homing of antibody-secreting cells from lymphoid organs to the CNS. Eur J Immunol 36(3):603–612. doi:10.1002/eji.200535123 PubMedCrossRefGoogle Scholar
  101. van Helvoort JM, Samsom JN, Chantry D, Jansen W, Schadee-Eestermans I, Thepen T, Mebius RE, Kraal G (2004) Preferential expression of IgG2b in nose draining cervical lymph nodes and its putative role in mucosal tolerance induction. Allergy 59(11):1211–1218. doi:10.1111/j.1398-9995.2004.00510.x PubMedCrossRefGoogle Scholar
  102. van Zwam M, Huizinga R, Heijmans N, van Meurs M, Wierenga-Wolf AF, Melief M-J, Hintzen RQ, ’t Hart BA, Amor S, Boven LA, Laman JD (2009a) Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing EAE. J Pathol 217:543–551CrossRefGoogle Scholar
  103. van Zwam M, Huizinga R, Melief MJ, Wierenga-Wolf AF, van Meurs M, Voerman JS, Biber KP, Boddeke HW, Höpken UE, Meisel C, Meisel A, Bechmann I, Hintzen RQ, ’t Hart BA, Amor S, Laman JD, Boven LA (2009b) Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE. J Mol Med 87:273–286CrossRefGoogle Scholar
  104. von Budingen HC, Kuo TC, Sirota M, van Belle CJ, Apeltsin L, Glanville J, Cree BA, Gourraud PA, Schwartzburg A, Huerta G, Telman D, Sundar PD, Casey T, Cox DR, Hauser SL (2012) B cell exchange across the blood–brain barrier in multiple sclerosis. J Clin Investig 122(12):4533–4543. doi:10.1172/JCI63842 CrossRefGoogle Scholar
  105. Wang SH, Fan Y, Makidon PE, Cao Z, Baker JR (2012) Induction of immune tolerance in mice with a novel mucosal nanoemulsion adjuvant and self-antigen. Nanomedicine (London) 7(6):867–876. doi:10.2217/nnm.11.187 CrossRefGoogle Scholar
  106. Weinstein JS, Varallyay CG, Dosa E, Gahramanov S, Hamilton B, Rooney WD, Muldoon LL, Neuwelt EA (2010) Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 30(1):15–35. doi:10.1038/jcbfm.2009.192 CrossRefGoogle Scholar
  107. Weller RO (1998) Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol 57:885–894PubMedCrossRefGoogle Scholar
  108. Weller RO (1999) Reaction of intrathecal and epidural spaces to infection and inflammation. In: Yaksh TL (ed) Spinal drug delivery. Elsevier, Amsterdam, pp 297–315Google Scholar
  109. Weller RO (2005) Microscopic morphology and histology of the human meninges. Morphologie 89:22–34PubMedCrossRefGoogle Scholar
  110. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266PubMedCrossRefGoogle Scholar
  111. Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14PubMedCrossRefGoogle Scholar
  112. Weller RO, Galea I, Carare RO, Minagar A (2010) Pathophysiology of the lymphatic drainage of the central nervous system: implications for pathogenesis and therapy of multiple sclerosis. Pathophysiol Off J Int Soc Pathophysiol/ISP 17:295–306Google Scholar
  113. Willart MA, Jan de Heer H, Hammad H, Soullie T, Deswarte K, Clausen BE, Boon L, Hoogsteden HC, Lambrecht BN (2009) The lung vascular filter as a site of immune induction for T cell responses to large embolic antigen. J Exp Med 206(12):2823–2835. doi:10.1084/jem.20082401 PubMedCrossRefGoogle Scholar
  114. Wolvers DA, Coenen-de Roo CJ, Mebius RE, van der Cammen MJ, Tirion F, Miltenburg AM, Kraal G (1999) Intranasally induced immunological tolerance is determined by characteristics of the draining lymph nodes: studies with OVA and human cartilage gp-39. J Immunol 162:1994–1998PubMedGoogle Scholar
  115. Yamazaki S, Maruyama A, Okada K, Matsumoto M, Morita A, Seya T (2012) Dendritic cells from oral cavity induce Foxp3(+) regulatory T cells upon antigen stimulation. PLoS One 7(12):e51665. doi:10.1371/journal.pone.0051665 PubMedCrossRefGoogle Scholar
  116. Yogev N, Frommer F, Lukas D, Kautz-Neu K, Karram K, Ielo D, von Stebut E, Probst HC, van den Broek M, Riethmacher D, Birnberg T, Blank T, Reizis B, Korn T, Wiendl H, Jung S, Prinz M, Kurschus FC, Waisman A (2012) Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 37(2):264–275. doi:10.1016/j.immuni.2012.05.025 PubMedCrossRefGoogle Scholar
  117. Zhang ET, Inman CB, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 170:111–123PubMedGoogle Scholar
  118. Zhang ET, Richards HK, Kida S, Weller RO (1992) Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathol 83:233–239PubMedCrossRefGoogle Scholar
  119. Zhang H, Podojil JR, Luo X, Miller SD (2008) Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis. J Immunol 181(7):4638–4647PubMedGoogle Scholar
  120. Zhong Y, Wang X, Ji Q, Mao X, Tang H, Yi G, Meng K, Yang X, Zeng Q (2012) CD4+LAP + and CD4 +CD25 +Foxp3 + regulatory T cells induced by nasal oxidized low-density lipoprotein suppress effector T cells response and attenuate atherosclerosis in ApoE-/- mice. J Clin Immunol 32(5):1104–1117. doi:10.1007/s10875-012-9699-7 PubMedCrossRefGoogle Scholar
  121. Zwillinger H (1912) Die Lymphbahnen des oberen Nasalschnittes und deren Beziehungen zu den perimeningealen Lymphraumen. Arch Laryngol und Rhinol 26:66–78Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Immunology, room NB-1148a Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  2. 2.Clinical Neurosciences, Faculty of MedicineSouthampton UniversitySouthamptonUK

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