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The role of peripheral immune cells in the CNS in steady state and disease

Abstract

The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These myeloid cells in the CNS parenchyma and at CNS–periphery interfaces are highly specialized but also extremely plastic cells that immediately react to any changes in CNS homeostasis and become reactive in the context of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease. However, when the blood–brain barrier is impaired during CNS diseases such as multiple sclerosis or altered with cerebral ischemia, peripheral adaptive and innate immune cells, including monocytes, neutrophils, T cells and B cells, can enter the CNS, where they execute distinct cell-mediated effects. On the basis of these observations, we assess strategies for targeting peripheral immune cells to reduce CNS disease burden.

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Figure 1: The CNS immune system during homeostasis.
Figure 2: Histopathological characteristics of neuroinflammation versus neurodegeneration in humans.
Figure 3: Peripheral immune cells in the CNS immune system during disease.

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References

  1. Louveau, A., Harris, T.H. & Kipnis, J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36, 569–577 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Ransohoff, R.M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

    CAS  PubMed  Google Scholar 

  4. Földi, M. et al. New contributions to the anatomical connections of the brain and the lymphatic system. Acta Anat. 64, 498–505 (1966).

    PubMed  Google Scholar 

  5. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Engelhardt, B., Vajkoczy, P. & Weller, R.O. The movers and shapers in immune priviledge of the CNS. Nat. Immunol. http://dx.doi.org/10.1038/ni.3666 (2017).

  10. Whedon, J.M. & Glassey, D. Cerebrospinal fluid stasis and its clinical significance. Altern. Ther. Health Med. 15, 54–60 (2009).

    PubMed  PubMed Central  Google Scholar 

  11. Kivisäkk, P., Tucky, B., Wei, T., Campbell, J.J. & Ransohoff, R.M. Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy. BMC Immunol. 7, 14 (2006).

    PubMed  PubMed Central  Google Scholar 

  12. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10, 514–523 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  14. WHO Classification of Tumours of the Central Nervous System (eds. Louis, D.N., Ohgaki, H., Wiestler, O.D. & Cavenee, W.K. (International Agency for Research on Cancer, 2016).

  15. Neuropathology, a Reference Book of CNS Pathology, 2nd edition (eds. Ellison D. et al.) (Mosby, 2004).

  16. Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275 (2006).

    CAS  PubMed  Google Scholar 

  17. Filiano, A.J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Derecki, N.C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wolf, S.A. et al. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus. FASEB J. 23, 3121–3128 (2009).

    CAS  PubMed  Google Scholar 

  20. Olah, M. et al. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia 57, 1046–1061 (2009).

    PubMed  Google Scholar 

  21. Huang, G.J. et al. A genetic and functional relationship between T cells and cellular proliferation in the adult hippocampus. PLoS Biol. 8, e1000561 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Steinman, R.M. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1–22 (2012).

    CAS  PubMed  Google Scholar 

  23. Kamphuis, W., Kooijman, L., Schetters, S., Orre, M. & Hol, E.M. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease. Biochim. Biophys. Acta 1862, 1847–1860 (2016).

    CAS  PubMed  Google Scholar 

  24. Prodinger, C. et al. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol. 121, 445–458 (2011).

    CAS  PubMed  Google Scholar 

  25. 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).

    CAS  PubMed  Google Scholar 

  26. Bulloch, K. et al. 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 (2008).

    PubMed  Google Scholar 

  27. Anandasabapathy, N. et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208, 1695–1705 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dando, S.J., Naranjo Golborne, C., Chinnery, H.R., Ruitenberg, M.J. & McMenamin, P.G. A case of mistaken identity: CD11c-eYFP(+) cells in the normal mouse brain parenchyma and neural retina display the phenotype of microglia, not dendritic cells. Glia 64, 1331–1349 (2016).

    PubMed  Google Scholar 

  29. Herz, J., Johnson, K.R. & McGavern, D.B. Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells. J. Exp. Med. 212, 1153–1169 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014).

    CAS  PubMed  Google Scholar 

  31. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  33. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hagemeyer, N. et al. Transcriptome-based profiling of yolk sac-derived macrophages reveals a role for Irf8 in macrophage maturation. EMBO J. 35, 1730–1744 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu, J. et al. Temporal-spatial resolution fate mapping reveals distinct origins for embryonic and adult microglia in zebrafish. Dev. Cell 34, 632–641 (2015).

    CAS  PubMed  Google Scholar 

  37. Shemer, A., Erny, D., Jung, S. & Prinz, M. Microglia plasticity during health and disease: an immunological perspective. Trends Immunol. 36, 614–624 (2015).

    CAS  PubMed  Google Scholar 

  38. Kivisäkk, P. et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann. Neurol. 65, 457–469 (2009).

    PubMed  PubMed Central  Google Scholar 

  39. Brendecke, S.M. & Prinz, M. Do not judge a cell by its cover--diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation. Semin. Immunopathol. 37, 591–605 (2015).

    CAS  PubMed  Google Scholar 

  40. Fantin, A. et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829–840 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. Wolburg, H. & Paulus, W. Choroid plexus: biology and pathology. Acta Neuropathol. 119, 75–88 (2010).

    PubMed  Google Scholar 

  43. Goldmann, T. et al. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16, 1618–1626 (2013).

    CAS  PubMed  Google Scholar 

  44. Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

    PubMed  Google Scholar 

  45. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    CAS  PubMed  Google Scholar 

  46. Ajami, B., Bennett, J.L., Krieger, C., McNagny, K.M. & Rossi, F.M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).

    CAS  PubMed  Google Scholar 

  47. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    CAS  PubMed  Google Scholar 

  48. Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).

    PubMed  Google Scholar 

  49. Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2011).

    PubMed  PubMed Central  Google Scholar 

  50. Goldmann, T. et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 34, 1612–1629 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Meuwissen, M.E. et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J. Exp. Med. 213, 1163–1174 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Biber, K., Möller, T., Boddeke, E. & Prinz, M. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat. Rev. Drug Discov. 15, 110–124 (2016).

    CAS  PubMed  Google Scholar 

  53. Möhle, L. et al. Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep. 15, 1945–1956 (2016).

    PubMed  Google Scholar 

  54. Baruch, K., Kertser, A., Porat, Z. & Schwartz, M. Cerebral nitric oxide represses choroid plexus NFκB-dependent gateway activity for leukocyte trafficking. EMBO J. 34, 1816–1828 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Obermeier, B., Daneman, R. & Ransohoff, R.M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584–1596 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Meyer-Luehmann, M. & Prinz, M. Myeloid cells in Alzheimer's disease: culprits, victims or innocent bystanders? Trends Neurosci. 38, 659–668 (2015).

    CAS  PubMed  Google Scholar 

  57. Togo, T. et al. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J. Neuroimmunol. 124, 83–92 (2002).

    CAS  PubMed  Google Scholar 

  58. Brochard, V. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009).

    CAS  PubMed  Google Scholar 

  59. Heneka, M.T. et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14, 388–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).

    CAS  PubMed  Google Scholar 

  61. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Naj, A.C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Guerreiro, R.J. et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 70, 78–84 (2013).

    PubMed  PubMed Central  Google Scholar 

  66. Replogle, J.M. et al. A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann. Neurol. 77, 469–477 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chan, G. et al. CD33 modulates TREM2: convergence of Alzheimer loci. Nat. Neurosci. 18, 1556–1558 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Takahashi, K., Prinz, M., Stagi, M., Chechneva, O. & Neumann, H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 4, e124 (2007).

    PubMed  PubMed Central  Google Scholar 

  69. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Jay, T.R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212, 287–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    CAS  PubMed  Google Scholar 

  73. Cros, J. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33, 375–386 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bien-Ly, N. et al. Lack of widespread BBB disruption in Alzheimer's disease models: focus on therapeutic antibodies. Neuron 88, 289–297 (2015).

    CAS  PubMed  Google Scholar 

  75. Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).

    CAS  PubMed  Google Scholar 

  76. Kierdorf, K., Katzmarski, N., Haas, C.A. & Prinz, M. Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS One 8, e58544 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Simard, A.R., Soulet, D., Gowing, G., Julien, J.P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489–502 (2006).

    CAS  PubMed  Google Scholar 

  78. Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159–11171 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).

    CAS  PubMed  Google Scholar 

  80. Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5, e13693 (2010).

    PubMed  PubMed Central  Google Scholar 

  81. Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nat. Med. 18, 1812–1819 (2012).

    CAS  PubMed  Google Scholar 

  82. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 9, 857–865 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Heneka, M.T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

    CAS  PubMed  Google Scholar 

  84. Zenaro, E. et al. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).

    CAS  PubMed  Google Scholar 

  85. Gabbita, S.P. et al. Oral TNFα modulation alters neutrophil infiltration, improves cognition and diminishes tau and amyloid pathology in the 3xTgAD mouse model. PLoS One 10, e0137305 (2015).

    PubMed  PubMed Central  Google Scholar 

  86. Hemmer, B., Kerschensteiner, M. & Korn, T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol. 14, 406–419 (2015).

    CAS  PubMed  Google Scholar 

  87. Dendrou, C.A., Fugger, L. & Friese, M.A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15, 545–558 (2015).

    CAS  PubMed  Google Scholar 

  88. Croxford, A.L., Spath, S. & Becher, B. GM-CSF in neuroinflammation: licensing myeloid cells for tissue damage. Trends Immunol. 36, 651–662 (2015).

    CAS  PubMed  Google Scholar 

  89. Chard, D.T. et al. Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain 125, 327–337 (2002).

    CAS  PubMed  Google Scholar 

  90. Popescu, B.F. & Lucchinetti, C.F. Pathology of demyelinating diseases. Annu. Rev. Pathol. 7, 185–217 (2012).

    CAS  PubMed  Google Scholar 

  91. Bielekova, B. et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J. Immunol. 172, 3893–3904 (2004).

    CAS  PubMed  Google Scholar 

  92. van Zwam, M. et al. Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE. J. Mol. Med. (Berl) 87, 273–286 (2009).

    CAS  Google Scholar 

  93. Villares, R. et al. CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues. Eur. J. Immunol. 39, 1671–1681 (2009).

    CAS  PubMed  Google Scholar 

  94. Steinman, L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13, 139–145 (2007).

    CAS  PubMed  Google Scholar 

  95. Tzartos, J.S. et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 172, 146–155 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Frisullo, G. et al. IL17 and IFNgamma production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis. Cytokine 44, 22–25 (2008).

    CAS  PubMed  Google Scholar 

  97. Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567 (2011).

    CAS  PubMed  Google Scholar 

  98. Noster, R. et al. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci. Transl. Med. 6, 241ra80 (2014).

    PubMed  Google Scholar 

  99. Segal, B.M. et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 7, 796–804 (2008).

    CAS  PubMed  Google Scholar 

  100. Polman, C.H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    CAS  PubMed  Google Scholar 

  101. Ji, Q., Castelli, L. & Goverman, J.M. MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8+ T cells. Nat. Immunol. 14, 254–261 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Willing, A. et al. CD8+ MAIT cells infiltrate into the CNS and alterations in their blood frequencies correlate with IL-18 serum levels in multiple sclerosis. Eur. J. Immunol. 44, 3119–3128 (2014).

    CAS  PubMed  Google Scholar 

  103. Frischer, J.M. et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175–1189 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. Stern, J.N. et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci. Transl. Med. 6, 248ra107 (2014).

    PubMed  PubMed Central  Google Scholar 

  105. 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).

    CAS  PubMed  Google Scholar 

  106. Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Pikor, N.B. et al. Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity 43, 1160–1173 (2015).

    CAS  PubMed  Google Scholar 

  108. Greter, M., Lelios, I. & Croxford, A.L. Microglia versus myeloid cell nomenclature during brain inflammation. Front. Immunol. 6, 249 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. Goldmann, T. & Prinz, M. Role of microglia in CNS autoimmunity. Clin. Dev. Immunol. 2013, 208093 (2013).

    PubMed  PubMed Central  Google Scholar 

  110. Heppner, F.L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146–152 (2005).

    CAS  PubMed  Google Scholar 

  111. Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. King, I.L., Dickendesher, T.L. & Segal, B.M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Croxford, A.L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015).

    CAS  PubMed  Google Scholar 

  114. Chamorro, Á. et al. The immunology of acute stroke. Nat. Rev. Neurol. 8, 401–410 (2012).

    CAS  PubMed  Google Scholar 

  115. Fu, Y., Liu, Q., Anrather, J. & Shi, F.D. Immune interventions in stroke. Nat. Rev. Neurol. 11, 524–535 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    CAS  PubMed  Google Scholar 

  117. Gelderblom, M. et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40, 1849–1857 (2009).

    PubMed  Google Scholar 

  118. Jin, R., Yang, G. & Li, G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J. Leukoc. Biol. 87, 779–789 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Enzmann, G. et al. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol. 125, 395–412 (2013).

    PubMed  Google Scholar 

  120. Petito, C.K., Olarte, J.P., Roberts, B., Nowak, T.S. Jr . & Pulsinelli, W.A. Selective glial vulnerability following transient global ischemia in rat brain. J. Neuropathol. Exp. Neurol. 57, 231–238 (1998).

    CAS  PubMed  Google Scholar 

  121. Henning, E.C. et al. Feridex preloading permits tracking of CNS-resident macrophages after transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 29, 1229–1239 (2009).

    CAS  PubMed  Google Scholar 

  122. Stroh, A. et al. Tracking of systemically administered mononuclear cells in the ischemic brain by high-field magnetic resonance imaging. Neuroimage 33, 886–897 (2006).

    PubMed  Google Scholar 

  123. Li, T. et al. Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke. Brain 136, 3578–3588 (2013).

    PubMed  Google Scholar 

  124. Schilling, M. et al. Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp. Neurol. 196, 290–297 (2005).

    CAS  PubMed  Google Scholar 

  125. Clausen, B.H. et al. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J. Neuroinflammation 5, 46 (2008).

    PubMed  PubMed Central  Google Scholar 

  126. Lalancette-Hébert, M., Gowing, G., Simard, A., Weng, Y.C. & Kriz, J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci. 27, 2596–2605 (2007).

    PubMed  PubMed Central  Google Scholar 

  127. Dimitrijevic, O.B., Stamatovic, S.M., Keep, R.F. & Andjelkovic, A.V. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38, 1345–1353 (2007).

    CAS  PubMed  Google Scholar 

  128. Yilmaz, G., Arumugam, T.V., Stokes, K.Y. & Granger, D.N. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 113, 2105–2112 (2006).

    PubMed  Google Scholar 

  129. Kleinschnitz, C. et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115, 3835–3842 (2010).

    CAS  PubMed  Google Scholar 

  130. Shichita, T. et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat. Med. 15, 946–950 (2009).

    CAS  PubMed  Google Scholar 

  131. Gelderblom, M. et al. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood 120, 3793–3802 (2012).

    CAS  PubMed  Google Scholar 

  132. Benakis, C. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat. Med. 22, 516–523 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Liesz, A. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009).

    CAS  PubMed  Google Scholar 

  134. Li, P. et al. Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann. Neurol. 74, 458–471 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kleinschnitz, C. et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood 121, 679–691 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Doyle, K.P. et al. B-lymphocyte-mediated delayed cognitive impairment following stroke. J. Neurosci. 35, 2133–2145 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ren, X. et al. Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J. Neurosci. 31, 8556–8563 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Planas, A.M. et al. Brain-derived antigens in lymphoid tissue of patients with acute stroke. J. Immunol. 188, 2156–2163 (2012).

    CAS  PubMed  Google Scholar 

  139. Doyle, K.P. & Buckwalter, M.S. Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia? Brain Behav. Immun. S0889-1591(16)30366-X (2016).

  140. Ankeny, D.P., Guan, Z. & Popovich, P.G. B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. J. Clin. Invest. 119, 2990–2999 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Magliozzi, R., Columba-Cabezas, S., Serafini, B. & Aloisi, F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 148, 11–23 (2004).

    CAS  PubMed  Google Scholar 

  142. Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).

    PubMed  Google Scholar 

  143. Römer, C. et al. Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke. J. Neurosci. 35, 7777–7794 (2015).

    PubMed  PubMed Central  Google Scholar 

  144. Meisel, C., Schwab, J.M., Prass, K., Meisel, A. & Dirnagl, U. Central nervous system injury-induced immune deficiency syndrome. Nat. Rev. Neurosci. 6, 775–786 (2005).

    CAS  PubMed  Google Scholar 

  145. Prass, K. et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J. Exp. Med. 198, 725–736 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Stanley, D. et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat. Med. 22, 1277–1284 (2016).

    CAS  PubMed  Google Scholar 

  147. Wong, C.H., Jenne, C.N., Lee, W.Y., Léger, C. & Kubes, P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334, 101–105 (2011).

    CAS  PubMed  Google Scholar 

  148. Engel, O. et al. Cholinergic pathway suppresses pulmonary innate immunity facilitating pneumonia after stroke. Stroke 46, 3232–3240 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. F. Fernández-Klett and D. Erny for the artwork. M.P. and J.P. are coordinators of the DFG-funded collaborative research center SFB/TRR167 (NeuroMac). In addition, M.P. is supported by the BMBF-funded competence network of multiple sclerosis (KKNMS) and the DFG (SFB 992, SFB 1160, Reinhart Koeselleck Grant). J.P. receives additional funding from the DFG (NeuroCure Cluster of Excellence, SFB TRR43), the BIH (CRG Proteostasis) and the BMBF (AERIAL).

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Prinz, M., Priller, J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 20, 136–144 (2017). https://doi.org/10.1038/nn.4475

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