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Brain dendritic cells: biology and pathology

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Abstract

Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. In their quiescent and mature form, the presentation of self‐antigens by DC leads to tolerance; whereas, antigen presentation by mature DC, after stimulation by pathogen‐associated molecular patterns, leads to the onset of antigen-specific immunity. DC have been found in many of the major organs in mammals (e.g. skin, heart, lungs, intestines and spleen); while the brain has long been considered devoid of DC in the absence of neuroinflammation. Consequently, microglia, the resident immune cell of the brain, have been charged with many functional attributes commonly ascribed to DC. Recent evidence has challenged the notion that DC are either absent or minimal players in brain immune surveillance. This review will discuss the recent literature examining DC involvement within both the young and aged steady-state brain. We will also examine DC contributions during various forms of neuroinflammation resulting from neurodegenerative autoimmune disease, injury, and CNS infections. This review also touches upon DC trafficking between the central nervous system and peripheral immune compartments during viral infections, the new molecular technologies that could be employed to enhance our current understanding of brain DC ontogeny, and some potential therapeutic uses of DC within the CNS.

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References

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

    PubMed  CAS  Google Scholar 

  2. Agger R, Crowley MT, Witmer-Pack MD (1990) The surface of dendritic cells in the mouse as studied with monoclonal antibodies. Int Rev Immunol 6(2–3):89–101

    PubMed  CAS  Google Scholar 

  3. Aleyas AG, George JA, Han YW, Rahman MM, Kim SJ, Han SB, Kim BS, Kim K, Eo SK (2009) Functional modulation of dendritic cells and macrophages by Japanese encephalitis virus through MyD88 adaptor molecule-dependent and -independent pathways. J Immunol 183(4):2462–2474

    PubMed  CAS  Google Scholar 

  4. Ali S, Curtin JF, Zirger JM, Xiong W, King GD, Barcia C, Liu C, Puntel M, Goverdhana S, Lowenstein PR, Castro MG (2004) Inflammatory and anti-glioma effects of an adenovirus expressing human soluble Fms-like tyrosine kinase 3 ligand (hsFlt3L): treatment with hsFlt3L inhibits intracranial glioma progression. Mol Ther 10(6):1071–1084

    PubMed  CAS  Google Scholar 

  5. Anandasabapathy N, Victora GD, Meredith M, Feder R, Dong B, Kluger C, Yao K, Dustin ML, Nussenzweig MC, Steinman RM, Liu K (2011) Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J Exp Med 208(8):1695–1705

    PubMed  CAS  Google Scholar 

  6. Axtell RC, Steinman L (2009) Gaining entry to an uninflamed brain. Nat Immunol 10(5):453–455

    PubMed  CAS  Google Scholar 

  7. Bachy V, Ballerini C, Gourdain P, Prignon A, Iken S, Antoine N, Rosset M, Carnaud C (2010) Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie. J Gen Virol 91(Pt 3):809–820

    PubMed  CAS  Google Scholar 

  8. 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

    PubMed  CAS  Google Scholar 

  9. Barclay AN, Brown MH (2006) The SIRP family of receptors and immune regulation. Nat Rev Immunol 6(6):457–464

    PubMed  CAS  Google Scholar 

  10. Bauer J, Huitinga I, Zhao W, Lassmann H, Hickey WF, Dijkstra CD (1995) The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis. Glia 15(4):437–446

    PubMed  CAS  Google Scholar 

  11. Baumjohann D, Lutz MB (2006) Non-invasive imaging of dendritic cell migration in vivo. Immunobiology 211(6–8):587–597

    PubMed  CAS  Google Scholar 

  12. Becher B, Antel JP (1996) Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia 18(1):1–10

    PubMed  CAS  Google Scholar 

  13. Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28(1):5–11

    PubMed  CAS  Google Scholar 

  14. Bechmann I, Kwidzinski E, Kovac AD, Simburger E, Horvath T, Gimsa U, Dirnagl U, Priller J, Nitsch R (2001) Turnover of rat brain perivascular cells. Exp Neurol 168(2):242–249

    PubMed  CAS  Google Scholar 

  15. Bechmann I, Priller J, Kovac A, Bontert M, Wehner T, Klett FF, Bohsung J, Stuschke M, Dirnagl U, Nitsch R (2001) Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14(10):1651–1658

    PubMed  CAS  Google Scholar 

  16. Belz GT, Nutt SL (2012) Transcriptional programming of the dendritic cell network. Nat Rev Immunol 12(2):101–113

    PubMed  CAS  Google Scholar 

  17. Billingham RE, Boswell T (1953) Studies on the problem of corneal homografts. Proc R Soc Lond B Biol Sci 141(904):392–406

    PubMed  CAS  Google Scholar 

  18. Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T-cell tolerance. J Exp Med 196(12):1627–1638

    PubMed  CAS  Google Scholar 

  19. Bousso P (2008) T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol 8(9):675–684

    PubMed  CAS  Google Scholar 

  20. Brehin AC, Mouries J, Frenkiel MP, Dadaglio G, Despres P, Lafon M, Couderc T (2008) Dynamics of immune cell recruitment during West Nile encephalitis and identification of a new CD19+ B220-BST-2+ leukocyte population. J Immunol 180(10):6760–6767

    PubMed  CAS  Google Scholar 

  21. Brown EJ, Frazier WA (2001) Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 11(3):130–135

    PubMed  CAS  Google Scholar 

  22. Buller KM (2001) Role of circumventricular organs in pro-inflammatory cytokine-induced activation of the hypothalamic-pituitary–adrenal axis. Clin Exp Pharmacol Physiol 28(7):581–589

    PubMed  CAS  Google Scholar 

  23. 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(5):687–710

    PubMed  Google Scholar 

  24. Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, Schwartz M (2006) Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci USA 103(31):11784–11789

    PubMed  CAS  Google Scholar 

  25. Cao S, Li Y, Ye J, Yang X, Chen L, Liu X, Chen H (2011) Japanese encephalitis virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. Virol J 8:39

    PubMed  CAS  Google Scholar 

  26. Carson MJ, Reilly CR, Sutcliffe JG, Lo D (1998) Mature microglia resemble immature antigen-presenting cells. Glia 22(1):72–85

    PubMed  CAS  Google Scholar 

  27. Chow A, Brown BD, Merad M (2011) Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11(11):788–798

    PubMed  CAS  Google Scholar 

  28. Ciavarra RP, Stephens A, Nagy S, Sekellick M, Steel C (2006) Evaluation of immunological paradigms in a virus model: are dendritic cells critical for antiviral immunity and viral clearance? J Immunol 177(1):492–500

    PubMed  CAS  Google Scholar 

  29. Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4(4):399–418

    PubMed  Google Scholar 

  30. Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65(3):199–203

    PubMed  Google Scholar 

  31. Courret N, Darche S, Sonigo P, Milon G, Buzoni-Gatel D, Tardieux I (2006) CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain. Blood 107(1):309–316

    PubMed  CAS  Google Scholar 

  32. Coyle PK, Rizvi S (2010) Clinical neuroimmunology: multiple sclerosis and related disorders. Current clinical neurology, Humana

    Google Scholar 

  33. 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(4):269–276

    PubMed  CAS  Google Scholar 

  34. D’Agostino PM, Kwak C, Vecchiarelli HA, Toth JG, Miller JM, Masheeb Z, McEwen BS, Bulloch K (2012) Viral-induced encephalitis initiates distinct and functional CD103+ CD11b+ brain dendritic cell populations within the olfactory bulb. Proc Natl Acad Sci USA 109(16):6175–6180

    PubMed  Google Scholar 

  35. Daffis S, Samuel MA, Suthar MS, Gale M Jr, Diamond MS (2008) Toll-like receptor 3 has a protective role against West Nile virus infection. J Virol 82(21):10349–10358

    PubMed  CAS  Google Scholar 

  36. Daffis S, Suthar MS, Szretter KJ, Gale M Jr, Diamond MS (2009) Induction of IFN-beta and the innate antiviral response in myeloid cells occurs through an IPS-1-dependent signal that does not require IRF-3 and IRF-7. PLoS Pathog 5(10):e1000607

    PubMed  Google Scholar 

  37. Danielyan L, Schafer R, von Ameln-Mayerhofer A, Bernhard F, Verleysdonk S, Buadze M, Lourhmati A, Klopfer T, Schaumann F, Schmid B, Koehle C, Proksch B, Weissert R, Reichardt HM, van den Brandt J, Buniatian GH, Schwab M, Gleiter CH, Frey WH 2nd (2011) Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 14(1):3–16

    PubMed  CAS  Google Scholar 

  38. Danielyan L, Schafer R, von Ameln-Mayerhofer A, Buadze M, Geisler J, Klopfer T, Burkhardt U, Proksch B, Verleysdonk S, Ayturan M, Buniatian GH, Gleiter CH, Frey WH II (2009) Intranasal delivery of cells to the brain. Eur J Cell Biol 88(6):315–324

    PubMed  CAS  Google Scholar 

  39. DeBoy CA, Rus H, Tegla C, Cudrici C, Jones MV, Pardo CA, Small D, Whartenby KA, Calabresi PA (2010) FLT-3 expression and function on microglia in multiple sclerosis. Exp Mol Pathol 89(2):109–116

    PubMed  CAS  Google Scholar 

  40. Dellmann HD (1998) Structure of the subfornical organ: a review. Microsc Res Tech 41(2):85–97

    PubMed  CAS  Google Scholar 

  41. Deshpande P, King IL, Segal BM (2007) Cutting edge: CNS CD11c+ cells from mice with encephalomyelitis polarize Th17 cells and support CD25+ CD4+ T cell-mediated immunosuppression, suggesting dual roles in the disease process. J Immunol 178(11):6695–6699

    PubMed  CAS  Google Scholar 

  42. Dilger RN, Johnson RW (2008) Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 84(4):932–939

    PubMed  CAS  Google Scholar 

  43. Elmquist JK, Breder CD, Sherin JE, Scammell TE, Hickey WF, Dewitt D, Saper CB (1997) Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J Comp Neurol 381(2):119–129

    PubMed  CAS  Google Scholar 

  44. 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

    PubMed  CAS  Google Scholar 

  45. Felger JC, Abe T, Kaunzner UW, Gottfried-Blackmore A, Gal-Toth J, McEwen BS, Iadecola C, Bulloch K (2010) Brain dendritic cells in ischemic stroke: time course, activation state, and origin. Brain Behav Immun 24(5):724–737

    PubMed  CAS  Google Scholar 

  46. Fischer HG, Bonifas U, Reichmann G (2000) Phenotype and functions of brain dendritic cells emerging during chronic infection of mice with Toxoplasma gondii. J Immunol 164(9):4826–4834

    PubMed  CAS  Google Scholar 

  47. Fischer HG, Reichmann G (2001) Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 166(4):2717–2726

    PubMed  CAS  Google Scholar 

  48. Flores-Langarica A, Sebti Y, Mitchell DA, Sim RB, MacPherson GG (2009) Scrapie pathogenesis: the role of complement C1q in scrapie agent uptake by conventional dendritic cells. J Immunol 182(3):1305–1313

    PubMed  CAS  Google Scholar 

  49. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28(1):12–18

    PubMed  CAS  Google Scholar 

  50. Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20(3):269–287

    PubMed  CAS  Google Scholar 

  51. Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ (2010) Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 10(6):453–460

    PubMed  CAS  Google Scholar 

  52. Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, Hashimoto D, Price J, Yin N, Bromberg J, Lira SA, Stanley ER, Nussenzweig M, Merad M (2009) The origin and development of nonlymphoid tissue CD103+ DCs. J Exp Med 206(13):3115–3130

    PubMed  CAS  Google Scholar 

  53. 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(4):797–801

    PubMed  CAS  Google Scholar 

  54. Gottfried-Blackmore A, Kaunzner UW, Idoyaga J, Felger JC, McEwen BS, Bulloch K (2009) Acute in vivo exposure to interferon-gamma enables resident brain dendritic cells to become effective antigen presenting cells. Proc Natl Acad Sci USA 106(49):20918–20923

    PubMed  CAS  Google Scholar 

  55. Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A, Browman DT, Chenouard N, de Chaumont F, Martino A, Enninga J, Olivo-Marin JC, Mannel D, Zurzolo C (2009) Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol 11(3):328–336

    PubMed  CAS  Google Scholar 

  56. Graeber MB, Streit WJ, Buringer D, Sparks DL, Kreutzberg GW (1992) Ultrastructural location of major histocompatibility complex (MHC) class II positive perivascular cells in histologically normal human brain. J Neuropathol Exp Neurol 51(3):303–311

    PubMed  CAS  Google Scholar 

  57. Gregerson DS, Sam TN, McPherson SW (2004) The antigen-presenting activity of fresh, adult parenchymal microglia and perivascular cells from retina. J Immunol 172(11):6587–6597

    PubMed  CAS  Google Scholar 

  58. 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(3):328–334

    PubMed  CAS  Google Scholar 

  59. Grodums EI (1976) Ultrastructure of mouse periventricular and choroid plexus tissues in experimental vesicular stomatitis virus infection. Arch Virol 51(1–2):75–85

    PubMed  CAS  Google Scholar 

  60. Hanly A, Petito CK (1998) HLA-DR-positive dendritic cells of the normal human choroid plexus: a potential reservoir of HIV in the central nervous system. Hum Pathol 29(1):88–93

    PubMed  CAS  Google Scholar 

  61. Hart DN, Fabre JW (1981) Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med 154(2):347–361

    PubMed  CAS  Google Scholar 

  62. Hayashi K, Ohta S, Kawakami Y, Toda M (2009) Activation of dendritic-like cells and neural stem/progenitor cells in injured spinal cord by GM-CSF. Neurosci Res 64(1):96–103

    PubMed  CAS  Google Scholar 

  63. Hayashi T, Nagai S, Fujii H, Baba Y, Ikeda E, Kawase T, Koyasu S (2009) Critical roles of NK and CD8+ T cells in central nervous system listeriosis. J Immunol 182(10):6360–6368

    PubMed  CAS  Google Scholar 

  64. Helft J, Ginhoux F, Bogunovic M, Merad M (2010) Origin and functional heterogeneity of non-lymphoid tissue dendritic cells in mice. Immunol Rev 234(1):55–75

    PubMed  CAS  Google Scholar 

  65. Her Z, Malleret B, Chan M, Ong EK, Wong SC, Kwek DJ, Tolou H, Lin RT, Tambyah PA, Renia L, Ng LF (2010) Active infection of human blood monocytes by Chikungunya virus triggers an innate immune response. J Immunol 184(10):5903–5913

    PubMed  CAS  Google Scholar 

  66. Hesske L, Vincenzetti C, Heikenwalder M, Prinz M, Reith W, Fontana A, Suter T (2010) Induction of inhibitory central nervous system-derived and stimulatory blood-derived dendritic cells suggests a dual role for granulocyte-macrophage colony-stimulating factor in central nervous system inflammation. Brain 133(Pt 6):1637–1654

    PubMed  Google Scholar 

  67. Hickey WF (1991) Migration of hematogenous cells through the blood–brain barrier and the initiation of CNS inflammation. Brain Pathol 1(2):97–105

    PubMed  CAS  Google Scholar 

  68. Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239(4837):290–292

    PubMed  CAS  Google Scholar 

  69. Hickman HD, Takeda K, Skon CN, Murray FR, Hensley SE, Loomis J, Barber GN, Bennink JR, Yewdell JW (2008) Direct priming of antiviral CD8+ T cells in the peripheral interfollicular region of lymph nodes. Nat Immunol 9(2):155–165

    PubMed  CAS  Google Scholar 

  70. Hogg N, Takacs L, Palmer DG, Selvendran Y, Allen C (1986) The p150,95 molecule is a marker of human mononuclear phagocytes: comparison with expression of class II molecules. Eur J Immunol 16(3):240–248

    PubMed  CAS  Google Scholar 

  71. http://clinicaltrials.gov/ct2/results?term=glioblastoma+multiforme+immunotherapy. Accessed 4 Apr 2012

  72. http://www.cdc.gov/meningitis/bacterial.html. Accessed 23 Mar 2012

  73. http://www.cdc.gov/ncidod/dvbid/arbor/arbdet.htm. Accessed 29 Feb 2012

  74. Huneycutt BS, Plakhov IV, Shusterman Z, Bartido SM, Huang A, Reiss CS, Aoki C (1994) Distribution of vesicular stomatitis virus proteins in the brains of BALB/c mice following intranasal inoculation: an immunohistochemical analysis. Brain Res 635(1–2):81–95

    PubMed  CAS  Google Scholar 

  75. Jain P, Coisne C, Enzmann G, Rottapel R, Engelhardt B (2010) Alpha4beta1 integrin mediates the recruitment of immature dendritic cells across the blood–brain barrier during experimental autoimmune encephalomyelitis. J Immunol 184(12):7196–7206

    PubMed  CAS  Google Scholar 

  76. John B, Ricart B, Tait Wojno ED, Harris TH, Randall LM, Christian DA, Gregg B, De Almeida DM, Weninger W, Hammer DA, Hunter CA (2011) Analysis of behavior and trafficking of dendritic cells within the brain during toxoplasmic encephalitis. PLoS Pathog 7(9):e1002246

    PubMed  CAS  Google Scholar 

  77. Joiner KA, Dubremetz JF (1993) Toxoplasma gondii: a protozoan for the nineties. Infect Immun 61(4):1169–1172

    PubMed  CAS  Google Scholar 

  78. 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(1):31–39

    PubMed  CAS  Google Scholar 

  79. Karman J, Chu HH, Co DO, Seroogy CM, Sandor M, Fabry Z (2006) Dendritic cells amplify T cell-mediated immune responses in the central nervous system. J Immunol 177(11):7750–7760

    PubMed  CAS  Google Scholar 

  80. Karman J, Ling C, Sandor M, Fabry Z (2004) Initiation of immune responses in brain is promoted by local dendritic cells. J Immunol 173(4):2353–2361

    PubMed  CAS  Google Scholar 

  81. Kaunzner UW, Miller MM, Gottfried-Blackmore A, Gal-Toth J, Felger JC, McEwen BS, Bulloch K (2012) Accumulation of resident and peripheral dendritic cells in the aging CNS. Neurobiol Aging 33(4):681–693 e681

    Google Scholar 

  82. Kaushik DK, Gupta M, Basu A (2012) Microglial response to viral challenges: every silver lining comes with a cloud. Front Biosci 17:2187–2205

    Google Scholar 

  83. Keizer GD, Borst J, Visser W, Schwarting R, de Vries JE, Figdor CG (1987) Membrane glycoprotein p150,95 of human cytotoxic T cell clone is involved in conjugate formation with target cells. J Immunol 138(10):3130–3136

    PubMed  CAS  Google Scholar 

  84. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553

    PubMed  CAS  Google Scholar 

  85. Kida S, Steart PV, Zhang ET, Weller RO (1993) Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes, microglia and macrophages. Acta Neuropathol 85(6):646–652

    PubMed  CAS  Google Scholar 

  86. Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM (2003) 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(14):8389–8394

    PubMed  Google Scholar 

  87. Koh L, Zakharov A, Johnston M (2005) Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res 2:6

    PubMed  Google Scholar 

  88. Koido S, Ohana M, Liu C, Nikrui N, Durfee J, Lerner A, Gong J (2004) Dendritic cells fused with human cancer cells: morphology, antigen expression, and T cell stimulation. Clin Immunol 113(3):261–269

    PubMed  CAS  Google Scholar 

  89. Kostulas N, Li HL, Xiao BG, Huang YM, Kostulas V, Link H (2002) Dendritic cells are present in ischemic brain after permanent middle cerebral artery occlusion in the rat. Stroke 33(4):1129–1134

    PubMed  Google Scholar 

  90. Lambert H, Hitziger N, Dellacasa I, Svensson M, Barragan A (2006) Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination. Cell Microbiol 8(10):1611–1623

    PubMed  CAS  Google Scholar 

  91. Lassmann H, Schmied M, Vass K, Hickey WF (1993) Bone marrow derived elements and resident microglia in brain inflammation. Glia 7(1):19–24

    PubMed  CAS  Google Scholar 

  92. Lauterbach H, Zuniga EI, Truong P, Oldstone MB, McGavern DB (2006) Adoptive immunotherapy induces CNS dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection. J Exp Med 203(8):1963–1975

    PubMed  CAS  Google Scholar 

  93. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170

    PubMed  CAS  Google Scholar 

  94. Li Y, Xu M, Chen L, Zhu J, Ye J, Liu X, Sun Y, Chen H, Cao S (2009) Evaluation of murine bone marrow-derived dendritic cells loaded with inactivated virus as a vaccine against Japanese encephalitis virus. Vaccine 27(43):6004–6010

    PubMed  CAS  Google Scholar 

  95. Lindquist RL, Shakhar G, Dudziak D, Wardemann H, Eisenreich T, Dustin ML, Nussenzweig MC (2004) Visualizing dendritic cell networks in vivo. Nat Immunol 5(12):1243–1250

    PubMed  CAS  Google Scholar 

  96. Ling C, Sandor M, Fabry Z (2003) In situ processing and distribution of intracerebrally injected OVA in the CNS. J Neuroimmunol 141(1–2):90–98

    PubMed  CAS  Google Scholar 

  97. Liu J, Johnson TV, Lin J, Ramirez SH, Bronich TK, Caplan S, Persidsky Y, Gendelman HE, Kipnis J (2007) T cell independent mechanism for copolymer-1-induced neuroprotection. Eur J Immunol 37(11):3143–3154

    PubMed  CAS  Google Scholar 

  98. Liu K, Nussenzweig MC (2010) Origin and development of dendritic cells. Immunol Rev 234(1):45–54

    PubMed  CAS  Google Scholar 

  99. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, Chu FF, Randolph GJ, Rudensky AY, Nussenzweig M (2009) In vivo analysis of dendritic cell development and homeostasis. Science 324(5925):392–397

    PubMed  CAS  Google Scholar 

  100. Liu XF, Fawcett JR, Thorne RG, DeFor TA, Frey WH 2nd (2001) Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci 187(1–2):91–97

    PubMed  CAS  Google Scholar 

  101. Lundh B, Kristensson K, Norrby E (1987) Selective infections of olfactory and respiratory epithelium by vesicular stomatitis and Sendai viruses. Neuropathol Appl Neurobiol 13(2):111–122

    PubMed  CAS  Google Scholar 

  102. Mabbott NA, MacPherson GG (2006) Prions and their lethal journey to the brain. Nat Rev Microbiol 4(3):201–211

    PubMed  CAS  Google Scholar 

  103. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15(11):1311–1333

    PubMed  CAS  Google Scholar 

  104. Matozaki T, Murata Y, Okazawa H, Ohnishi H (2009) Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol 19(2):72–80

    PubMed  CAS  Google Scholar 

  105. Matyszak MK, Perry VH (1996) A comparison of leucocyte responses to heat-killed bacillus Calmette-Guerin in different CNS compartments. Neuropathol Appl Neurobiol 22(1):44–53

    PubMed  CAS  Google Scholar 

  106. Matyszak MK, Perry VH (1996) The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 74(2):599–608

    PubMed  CAS  Google Scholar 

  107. McGavern DB, Kang SS (2011) Illuminating viral infections in the nervous system. Nat Rev Immunol 11(5):318–329

    PubMed  CAS  Google Scholar 

  108. 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

    PubMed  CAS  Google Scholar 

  109. McMenamin PG (1999) Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 405(4):553–562

    PubMed  CAS  Google Scholar 

  110. Medawar PB (1944) The behaviour and fate of skin autografts and skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. J Anat 78(Pt 5):176–199

    PubMed  CAS  Google Scholar 

  111. Medawar PB (1945) A second study of the behaviour and fate of skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. J Anat 79(Pt 4):157–176

    Google Scholar 

  112. Medawar PB (1948) 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(1):58–69

    PubMed  CAS  Google Scholar 

  113. Meerburg BG, Kijlstra A (2009) Changing climate-changing pathogens: Toxoplasma gondii in North-Western Europe. Parasitol Res 105(1):17–24

    PubMed  Google Scholar 

  114. Metlay JP, Witmer-Pack MD, Agger R, Crowley MT, Lawless D, Steinman RM (1990) The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies. J Exp Med 171(5):1753–1771

    PubMed  CAS  Google Scholar 

  115. Miller SD, McMahon EJ, Schreiner B, Bailey SL (2007) Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 1103:179–191

    PubMed  CAS  Google Scholar 

  116. Mineharu Y, King GD, Muhammad AK, Bannykh S, Kroeger KM, Liu C, Lowenstein PR, Castro MG (2011) Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design. Clin Cancer Res 17(14):4705–4718

    PubMed  CAS  Google Scholar 

  117. Mix E, Meyer-Rienecker H, Hartung HP, Zettl UK (2010) Animal models of multiple sclerosis—potentials and limitations. Prog Neurobiol 92(3):386–404

    PubMed  Google Scholar 

  118. Mix E, Meyer-Rienecker H, Zettl UK (2008) Animal models of multiple sclerosis for the development and validation of novel therapies—potential and limitations. J Neurol 255(Suppl 6):7–14

    PubMed  CAS  Google Scholar 

  119. Mohan J, Hopkins J, Mabbott NA (2005) Skin-derived dendritic cells acquire and degrade the scrapie agent following in vitro exposure. Immunology 116(1):122–133

    PubMed  CAS  Google Scholar 

  120. Nagra G, Koh L, Zakharov A, Armstrong D, Johnston M (2006) Quantification of cerebrospinal fluid transport across the cribriform plate into lymphatics in rats. Am J Physiol Regul Integr Comp Physiol 291(5):R1383–1389

    PubMed  CAS  Google Scholar 

  121. Newman TA, Galea I, van Rooijen N, Perry VH (2005) Blood-derived dendritic cells in an acute brain injury. J Neuroimmunol 166(1–2):167–172

    PubMed  CAS  Google Scholar 

  122. Okada K, Yamasoba T, Kiyono H (2011) Craniofacial mucosal immune system: importance of its unique organogenesis and function in the development of a mucosal vaccine, vol 72. Recent advances in tonsils and mucosal barriers of the upper airways. In: Proceedings of the 7th International Symposium on Tonsils and Mucosal Barriers of the Upper Airways, 2010, Asahikawa, Japan. Karger, Basel, New York

  123. Ou R, Zhang M, Huang L, Flavell RA, Koni PA, Moskophidis D (2008) Regulation of immune response and inflammatory reactions against viral infection by VCAM-1. J Virol 82(6):2952–2965

    PubMed  CAS  Google Scholar 

  124. 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(6):593–604

    PubMed  CAS  Google Scholar 

  125. Pashenkov M, Huang YM, Kostulas V, Haglund M, Soderstrom M, Link H (2001) Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 124(Pt 3):480–492

    PubMed  CAS  Google Scholar 

  126. Pashenkov M, Soderstrom M, Huang YM, Link H (2002) Cerebrospinal fluid affects phenotype and functions of myeloid dendritic cells. Clin Exp Immunol 128(2):379–387

    PubMed  CAS  Google Scholar 

  127. Pashenkov M, Teleshova N, Kouwenhoven M, Smirnova T, Jin YP, Kostulas V, Huang YM, Pinegin B, Boiko A, Link H (2002) Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol 122(1–2):106–116

    PubMed  CAS  Google Scholar 

  128. Pellegatta S, Poliani PL, Stucchi E, Corno D, Colombo CA, Orzan F, Ravanini M, Finocchiaro G (2010) Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment. Neuro Oncol 12(4):377–388

    PubMed  CAS  Google Scholar 

  129. Peters A, Palay SL, Webster Hd (1976) The fine structure of the nervous system: the neurons and supporting cells. Saunders, Philadelphia

    Google Scholar 

  130. Platten M, Steinman L (2005) Multiple sclerosis: trapped in deadly glue. Nat Med 11(3):252–253

    PubMed  CAS  Google Scholar 

  131. Postigo AA, Corbi AL, Sanchez-Madrid F, de Landazuri MO (1991) Regulated expression and function of CD11c/CD18 integrin on human B lymphocytes. Relation between attachment to fibrinogen and triggering of proliferation through CD11c/CD18. J Exp Med 174(6):1313–1322

    PubMed  CAS  Google Scholar 

  132. Press R, Nennesmo I, Kouwenhoven M, Huang YM, Link H, Pashenkov M (2005) Dendritic cells in the cerebrospinal fluid and peripheral nerves in Guillain–Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. J Neuroimmunol 159(1–2):165–176

    PubMed  CAS  Google Scholar 

  133. 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

    PubMed  CAS  Google Scholar 

  134. Prodinger C, Bunse J, Kruger M, Schiefenhovel F, Brandt C, Laman JD, Greter M, Immig K, Heppner F, Becher B, Bechmann I (2011) CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 121(4):445–458

    PubMed  CAS  Google Scholar 

  135. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216(4542):136–144

    PubMed  CAS  Google Scholar 

  136. Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev 30(1):77–105

    PubMed  CAS  Google Scholar 

  137. Ramagopalan SV, Knight JC, Ebers GC (2009) Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol 22(3):219–225

    PubMed  CAS  Google Scholar 

  138. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10(5):514–523

    PubMed  CAS  Google Scholar 

  139. Reichmann G, Schroeter M, Jander S, Fischer HG (2002) Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J Neuroimmunol 129(1–2):125–132

    PubMed  CAS  Google Scholar 

  140. Rodriguez Boulan E, Sabatini DD (1978) Asymmetric budding of viruses in epithelial monlayers: a model system for study of epithelial polarity. Proc Natl Acad Sci USA 75(10):5071–5075

    PubMed  CAS  Google Scholar 

  141. Rosicarelli B, Serafini B, Sbriccoli M, Lu M, Cardone F, Pocchiari M, Aloisi F (2005) Migration of dendritic cells into the brain in a mouse model of prion disease. J Neuroimmunol 165(1–2):114–120

    PubMed  CAS  Google Scholar 

  142. Rosset MB, Sacquin A, Lecollinet S, Chaigneau T, Adam M, Crespeau F, Eloit M (2009) Dendritic cell-mediated-immunization with xenogenic PrP and adenoviral vectors breaks tolerance and prolongs mice survival against experimental scrapie. PLoS One 4(3):e4917

    PubMed  Google Scholar 

  143. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11(11):775–787

    PubMed  CAS  Google Scholar 

  144. Santambrogio L, Belyanskaya SL, Fischer FR, Cipriani B, Brosnan CF, Ricciardi-Castagnoli P, Stern LJ, Strominger JL, Riese R (2001) Developmental plasticity of CNS microglia. Proc Natl Acad Sci USA 98(11):6295–6300

    PubMed  CAS  Google Scholar 

  145. Schiltz JC, Sawchenko PE (2002) Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci 22(13):5606–5618

    PubMed  CAS  Google Scholar 

  146. Schulz M, Engelhardt B (2005) The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res 2:8

    PubMed  Google Scholar 

  147. Serot JM, Foliguet B, Bene MC, Faure GC (1997) Ultrastructural and immunohistological evidence for dendritic-like cells within human choroid plexus epithelium. NeuroReport 8(8):1995–1998

    PubMed  CAS  Google Scholar 

  148. Serrats J, Schiltz JC, Garcia-Bueno B, van Rooijen N, Reyes TM, Sawchenko PE (2010) Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65(1):94–106

    PubMed  CAS  Google Scholar 

  149. Sethi S, Kerksiek KM, Brocker T, Kretzschmar H (2007) Role of the CD8+ dendritic cell subset in transmission of prions. J Virol 81(9):4877–4880

    PubMed  CAS  Google Scholar 

  150. Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55(4):412–424

    PubMed  Google Scholar 

  151. Skarica M, Wang T, McCadden E, Kardian D, Calabresi PA, Small D, Whartenby KA (2009) Signal transduction inhibition of APCs diminishes Th17 and Th1 responses in experimental autoimmune encephalomyelitis. J Immunol 182(7):4192–4199

    PubMed  CAS  Google Scholar 

  152. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35

    PubMed  Google Scholar 

  153. Steel CD, Hahto SM, Ciavarra RP (2009) Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system. Virology 387(1):117–126

    PubMed  CAS  Google Scholar 

  154. Steinman RM (2007) Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat Med 13(10):1155–1159

    PubMed  CAS  Google Scholar 

  155. Steinman RM, Dhodapkar M (2001) Active immunization against cancer with dendritic cells: the near future. Int J Cancer 94(4):459–473

    PubMed  CAS  Google Scholar 

  156. Stevenson PG, Hawke S, Sloan DJ, Bangham CR (1997) The immunogenicity of intracerebral virus infection depends on anatomical site. J Virol 71(1):145–151

    PubMed  CAS  Google Scholar 

  157. Stichel CC, Luebbert H (2007) Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging 28(10):1507–1521

    PubMed  CAS  Google Scholar 

  158. Streit WJ (2006) Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 29(9):506–510

    PubMed  CAS  Google Scholar 

  159. Streit WJ, Graeber MB (1993) Heterogeneity of microglial and perivascular cell populations: insights gained from the facial nucleus paradigm. Glia 7(1):68–74

    PubMed  CAS  Google Scholar 

  160. Suthar MS, Ma DY, Thomas S, Lund JM, Zhang N, Daffis S, Rudensky AY, Bevan MJ, Clark EA, Kaja MK, Diamond MS, Gale M Jr (2010) IPS-1 is essential for the control of West Nile virus infection and immunity. PLoS Pathog 6(2):e1000757

    PubMed  Google Scholar 

  161. Tenter AM, Heckeroth AR, Weiss LM (2000) Toxoplasma gondii: from animals to humans. Int J Parasitol 30(12–13):1217–1258

    PubMed  CAS  Google Scholar 

  162. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH 2nd (2004) Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127(2):481–496

    PubMed  CAS  Google Scholar 

  163. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31(45):16064–16069

    PubMed  CAS  Google Scholar 

  164. Trifilo MJ, Lane TE (2004) The CC chemokine ligand 3 regulates CD11c+ CD11b+ CD8alpha− dendritic cell maturation and activation following viral infection of the central nervous system: implications for a role in T cell activation. Virology 327(1):8–15

    PubMed  CAS  Google Scholar 

  165. van Beek EM, Cochrane F, Barclay AN, van den Berg TK (2005) Signal regulatory proteins in the immune system. J Immunol 175(12):7781–7787

    PubMed  Google Scholar 

  166. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF (2006) Community-acquired bacterial meningitis in adults. N Engl J Med 354(1):44–53

    PubMed  Google Scholar 

  167. Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117(1):1–14

    PubMed  CAS  Google Scholar 

  168. Williams K, Alvarez X, Lackner AA (2001) Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 36(2):156–164

    PubMed  CAS  Google Scholar 

  169. Wuest TR, Carr DJ (2008) Dysregulation of CXCR3 signaling due to CXCL10 deficiency impairs the antiviral response to herpes simplex virus 1 infection. J Immunol 181(11):7985–7993

    PubMed  CAS  Google Scholar 

  170. Yang I, Han SJ, Kaur G, Crane C, Parsa AT (2010) The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17(1):6–10

    PubMed  Google Scholar 

  171. Zozulya AL, Ortler S, Lee J, Weidenfeller C, Sandor M, Wiendl H, Fabry Z (2009) Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS. J Neurosci 29(1):140–152

    PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Dr. Judit Gal Toth and Haley A. Vecchiarelli for contributing images used as figures in this review and for their comments and suggestions. Additionally, we are grateful to Drs. Bruce S. McEwen, Richard Hunter, and James M. Miller, as well as Changsoo Kwak and Zahrah Masheeb for their valuable recommendations. This work was supported by the Peter Deane Trust (K.B.).

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The authors have no conflicting financial interests.

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D’Agostino, P.M., Gottfried-Blackmore, A., Anandasabapathy, N. et al. Brain dendritic cells: biology and pathology. Acta Neuropathol 124, 599–614 (2012). https://doi.org/10.1007/s00401-012-1018-0

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