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Cited by 346Barrier Structure and Function StudiesNeuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research Studies

The anatomy and immunology of vasculature in the central nervous system

Open access
Mastorakos, Panagiotis, McGavern, Dorian·2019·Science Immunology
DOI 10.1126/sciimmunol.aav0492PMC PMC6816468
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Abstract

This review discusses the immunology of central nervous system vasculature from a neuroanatomical perspective.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes the anatomy of central nervous system (CNS) vasculature and its associated barriers, arguing that structural differences between parenchymal, meningeal, choroid plexus, and circumventricular vascular beds dictate where and how CNS immune responses begin. It then applies this framework to autoimmune disease, traumatic injury, ischemia, and infection.

Key findings

  • CNS barriers are anatomically heterogeneous rather than a single BBB: dura mater vessels are fenestrated and lack tight junctions (extravasation of solutes up to 43 kDa), the arachnoid mater is a ~200-μm sealed membrane with tight junctions and efflux pumps, and pial/leptomeningeal vessels have tight junctions but no astrocytic foot processes, with some paracellular gaps of 2.8 nm.
  • The glia limitans is the rate-limiting barrier to parenchymal entry: astrocytic endfeet cover >99% of the vascular surface, molecules of 0.8–70 kDa penetrate it to varying degrees while 150–2000 kDa molecules are confined to the perivascular space, and the ~20-nm gaps between endfeet likely set the diffusion cutoff.
  • Immune surveillance is compartmentalized: only ~15% of interstitial fluid is secreted into CSF, particulates (0.2–1.0 μm) injected into parenchyma remain trapped while the same particulates in CSF egress to cervical lymph nodes, explaining why intracerebral BCG or influenza virus fails to elicit adaptive immunity. Steady-state leukocyte traffic is largely restricted to meninges, choroid plexus, and CVOs, with parenchymal entry requiring antigen recognition by perivascular APCs.
  • In pathology, entry routes and mechanisms differ: EAE autoreactive T cells enter preferentially via leptomeningeal vessels and choroid plexus (CCR6/CCL20-dependent), with MMP-mediated cleavage of dystroglycan as the rate-limiting step into parenchyma; after ischemia, neutrophils accumulate in leptomeningeal space but are confined by the glia limitans until MMP activity degrades it; in cerebral malaria, parasite-specific CD8+ T cells engaging cerebrovascular endothelium cause fatal edema, preventable by anti–LFA-1 and anti–VLA-4 antibodies.

Methods

  • Narrative review; no primary data, experiments, or systematic search strategy are reported.
  • Synthesizes anatomical, ultrastructural, single-cell transcriptomic, immunohistochemical, and in vivo imaging literature across human and rodent (mouse, rat, primate) studies, organized by anatomical compartment (arterial supply, meninges, choroid plexus, CVOs, blood-CNS interface) and by pathophysiological state (cytokines, EAE/MS, TBI, ischemia, infection).
  • No stated inclusion criteria, databases, or quantitative synthesis.

Limitations

  • Stated in the text: the role of intraparenchymal convective flow (the glymphatic system) "remains controversial"; it is "unclear whether astrocytic coverage is complete"; and after TBI it is "unclear whether the anatomy is ever completely restored to its original configuration."
  • Stated in the text: the authors note that multiple preclinical and clinical trials have failed to improve ischemic stroke outcomes by preventing leukocyte diapedesis, "indicating that our knowledge of the inflammatory response to this condition is incomplete."
  • Evident from the text: as a narrative review, it presents no systematic evidence appraisal, and several mechanistic claims rest on specific animal models (e.g., PLP139-151 and MOG35-55 EAE, MCAO, LCMV, Plasmodium berghei ANKA) whose translational relevance to human disease is not systematically assessed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/sciimmunol.aav0492

Cites

154 of 154 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 147 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The CNS parenchyma does not have a conventional lymphatic drainage system.

    “Although the CNS parenchyma does not have a conventional lymphatic drainage system (3), lymphatics have been discovered in the dura mater and just outside holes in the skull bone (4-9).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Galea I, Bechmann I, Perry VH, What is immune privilege (not)? Trends Immunol. 28, 12– 18 (2007). 17129764 source

      Not checked in the free run.

  • Premisecitation

    Lymphatics have been discovered in the dura mater and just outside holes in the skull bone.

    “Although the CNS parenchyma does not have a conventional lymphatic drainage system (3), lymphatics have been discovered in the dura mater and just outside holes in the skull bone (4-9).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [4] Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J, Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337– 341 (2015). 26030524 PMC4506234 source

      Not checked in the free run.

    • cites [5] Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K, A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med 212, 991– 999 (2015). 26077718 PMC4493418 source

      Not checked in the free run.

    • cites [6] Mascagni P, Vasorum Lymphaticorum Corporis Humani Historia et Ichnographia (P. Carli, 1787).

      Not checked in the free run.

    • cites [7] Waggener JD, Beggs J, The membranous coverings of neural tissues: An electron microscopy study. J. Neuropathol. Exp. Neurol 26, 412– 426 (1967). 6027438 source

      Not checked in the free run.

    • cites [8] Andres KH, von Düring M, Muszynski K, Schmidt RF, Nerve fibres and their terminals of the dura mater encephali of the rat. Anat. Embryol 175, 289– 301 (1987). 3826655 source

      Not checked in the free run.

    • cites [9] Ma Q, Ineichen BV, Detmar M, Proulx ST, Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat. Commun 8, 1434 (2017). 29127332 PMC5681558 source

      Not checked in the free run.

  • Interpretationcitation

    The development of robust immune reactions against parenchymal antigens depends on their entry into fluid spaces, which promotes egress into draining lymph nodes.

    “These findings show that the development of robust immune reactions against parenchymal antigens depends on their entry into fluid spaces, which promotes egress into draining lymph nodes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Murphy JB, Sturm E, Conditions determining the transplantability of tissues in the brain. J. Exp. Med 38, 183– 197 (1923). 19868782 PMC2128434 source

      Not checked in the free run.

  • Interpretationreasoning

    The elaborate barrier system between the brain parenchyma and circulation combined with restricted afferent and efferent communication with lymphatic tissue limits immune surveillance of the CNS relative to other peripheral tissues.

    “The elaborate barrier system between the brain parenchyma and circulation combined with restricted afferent and efferent communication with lymphatic tissue limits immune surveillance of the CNS relative to other peripheral tissues.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The blood-CSF barrier within the choroid plexus has fundamentally different properties than those of the BBB.

    “The blood-CSF barrier within the choroid plexus has fundamentally different properties than those of the BBB.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 44
  • Classified as probably not a substantial claim. 3
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    CNS immune responses differ based on anatomical location, with a clear distinction between responses that develop in fluid spaces and membranous lining (meninges) relative to the parenchyma.

    “CNS immune responses differ based on anatomical location, and a clear distinction exists between responses that develop in the fluid spaces and membranous lining (or meninges) relative to the parenchyma (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Engelhardt B, Vajkoczy P, Weller RO, The movers and shapers in immune privilege of the CNS. Nat. Immunol 18, 123– 131 (2017). 28092374 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mouse sarcoma cells grow rapidly when injected into the brain parenchyma of rats but are immunologically rejected when placed close to a ventricle.

    “early studies demonstrated that mouse sarcoma cells grow rapidly when injected into the brain parenchyma of rats but were immunologically rejected when placed close to a ventricle [a space filled with cerebrospinal fluid (CSF)] (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Murphy JB, Sturm E, Conditions determining the transplantability of tissues in the brain. J. Exp. Med 38, 183– 197 (1923). 19868782 PMC2128434 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the cortex, a packed barrier of endothelial cells, basement membrane, and glia limitans surrounds penetrating arteries, leaving little to no fluid-filled space, whereas the lenticulostriate branches in the basal ganglia are surrounded by a larger perivascular space.

    “For example, in the cortex, a packed barrier of endothelial cells, basement membrane, and glia limitans surrounds penetrating arteries, leaving little to no fluid-filled space, whereas the lenticulostriate branches in the basal ganglia are surrounded by a larger perivascular space (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Morris AWJ, MacGregor Sharp M, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO, Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 131, 725– 736 (2016). 26975356 PMC4835509 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages in the choroid plexus and dura mater turn over and receive some input from peripheral blood monocytes during adulthood.

    “This contrasts with macrophages in the choroid plexus and dura mater, which do turn over and receive some input from peripheral blood monocytes during adulthood (71-73).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [71] Goldmann T, Wieghofer P, Costa Jordão MJ, Prutek F, Hagemeyer N, Frenzel K, Amann L, Staszewski O, Kierdorf K, Krueger M, Locatelli G, Hochgerner H, Zeiser R, Epelman S, Geissmann F, Priller J, Rossi FMV, Bechmann I, Kerschensteiner M, Linnarsson S, Jung S, Prinz M, Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol 17, 797– 805 (2016). 27135602 PMC4968048 source

      Not checked in the free run.

    • cites [72] Rua R, Lee JY, Silva AB, Swafford IS, Maric D, Johnson KR, McGavern DB, Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat. Immunol 20, 407– 419 (2019). 30886419 PMC6481670 source

      Not checked in the free run.

    • cites [73] Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, Vandamme N, De Schepper S, Van Isterdael G, Scott CL, Aerts J, Berx G, Boeckxstaens GE, Vandenbroucke RE, Vereecke L, Moechars D, Guilliams M, Van Ginderachter JA, Saeys Y, Movahedi K, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci 22, 1021– 1035 (2019). 31061494 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postcapillary venules and veins have a more pronounced CSF-filled perivascular space than other types of parenchymal blood vessels, and these spaces support a lot of immune activity.

    “Postcapillary venules and veins have a more pronounced CSF-filled perivascular space than the other types of parenchyma blood vessels (15), and these spaces support a lot of immune activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Zhang ET, Inman CB, Weller RO, Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J. Anat 170, 111– 123 (1990). 2254158 PMC1257067

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fluorescent tracers (3-kDa dextran and 40-kDa ovalbumin) move from the brain parenchyma along basement membranes, whereas particulates (0.2 to 1.0 μm in diameter) remain trapped in the parenchyma.

    “In fact, fluorescent tracers (3-kDa dextran and 40-kDa ovalbumin) were shown to move from the brain parenchyma along basement membranes, whereas particulates (0.2 to 1.0 μm in diameter) remained trapped in the parenchyma.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JAR, Perry VH, Weller RO, Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: Significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol. Appl. Neurobiol 34, 131– 144 (2008). 18208483 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The meningeal vasculature is a major point of entry into the CNS and should be considered separately from vasculature that traverses the CNS parenchyma.

    “The meningeal vasculature is a major point of entry into the CNS and should be considered separately from those that traverse the CNS parenchyma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Subarachnoid and pial vessels restrict extravasation of leukocytes, but migration across these vessels is more efficient relative to parenchymal vessels because meningeal endothelial cells constitutively express P-selectin during steady state.

    “Subarachnoid and pial vessels also restrict extravasation of leukocytes; however, migration across these vessels is more efficient relative to parenchymal vessels (86). This is because meningeal, unlike parenchymal, vascular endothelial cells constitutively express P-selectin during steady state, which is stored in Weibel-Palade bodies, allowing rapid release to the endothelial surface (79, 86).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Carrithers MD, Visintin I, Kang SJ, Janeway CA Jr., Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain 123 (Pt. 6), 1092– 1101 (2000). 10825349 source

      Not checked in the free run.

    • cites [79] Barkalow FJ, Goodman MJ, Gerritsen ME, Mayadas TN, Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion. Blood 88, 4585– 4593 (1996). 8977250 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ependymal cells overlying choroid plexus vessels have tight junctions and form a blood-CSF barrier composed of transmembrane proteins such as occludin, claudin-1, claudin-2, and claudin-11.

    “However, ependymal cells overlying these vessels do have tight junctions and are tasked with forming a blood-CSF barrier composed of transmembrane proteins such as occludin, claudin-1, claudin-2, and claudin-11 (52, 53).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Cserr HF, Bundgaard M, Blood-brain interfaces in vertebrates: A comparative approach. Am. J. Physiol 246, R277– R288 (1984). 6367490

      Not checked in the free run.

    • cites [53] Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B, Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci. Lett 307, 77– 80 (2001). 11427304 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most macrophages residing in the leptomeninges and perivascular spaces are derived from early yolk sac-derived erythromyeloid progenitors, and during steady state, these cells have minimal turnover.

    “Like microglia, most macrophages residing in the leptomeninges and perivascular spaces are derived from early yolk sac–derived erythromyeloid progenitors, and during steady state, these cells have minimal turnover.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [71] Goldmann T, Wieghofer P, Costa Jordão MJ, Prutek F, Hagemeyer N, Frenzel K, Amann L, Staszewski O, Kierdorf K, Krueger M, Locatelli G, Hochgerner H, Zeiser R, Epelman S, Geissmann F, Priller J, Rossi FMV, Bechmann I, Kerschensteiner M, Linnarsson S, Jung S, Prinz M, Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol 17, 797– 805 (2016). 27135602 PMC4968048 source

      Not checked in the free run.

    • cites [72] Rua R, Lee JY, Silva AB, Swafford IS, Maric D, Johnson KR, McGavern DB, Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat. Immunol 20, 407– 419 (2019). 30886419 PMC6481670 source

      Not checked in the free run.

    • cites [73] Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, Vandamme N, De Schepper S, Van Isterdael G, Scott CL, Aerts J, Berx G, Boeckxstaens GE, Vandenbroucke RE, Vereecke L, Moechars D, Guilliams M, Van Ginderachter JA, Saeys Y, Movahedi K, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci 22, 1021– 1035 (2019). 31061494 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Molecules from 0.8 to 70 kDa penetrate the glia limitans to varying degrees, whereas molecules from 150 to 2000 kDa are confined within the perivascular space.

    “Molecules from 0.8 to 70 kDa have been shown to penetrate the glia limitans to varying degrees, whereas molecules from 150 to 2000 kDa are confined within the perivascular space (18, 39, 40).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Hannocks M-J, Pizzo ME, Huppert J, Deshpande T, Abbott NJ, Thorne RG, Sorokin L, Molecular characterization of perivascular drainage pathways in the murine brain. J. Cereb. Blood Flow Metab 38, 669– 686 (2018). 29283289 PMC5888861 source

      Not checked in the free run.

    • cites [39] Bedussi B, van Lier MGJTB, Bartstra JW, de Vos J, Siebes M, VanBavel E, Bakker ENTP, Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system. Fluids Barriers CNS 12, 23 (2015). 26435380 PMC4593194 source

      Not checked in the free run.

    • cites [40] Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M, A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med 4, 147ra111 (2012). PMC3551275 22896675 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leukocyte migration across the BBB is limited to very few activated CD8+ and CD4+ T cells but not innate immune cells.

    “In fact, leukocyte migration across the BBB is limited to very few activated CD8+ and CD4+ T cells but not innate immune cells (80).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Engelhardt B, Ransohoff RM, Capture, crawl, cross: The T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579– 589 (2012). 22926201 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glia limitans and basement membranes create a barrier between circulating components of the immune system and the CNS parenchyma, a division that is integral to the neuroimmune axis.

    “The glia limitans and basement membranes also create a barrier between circulating components of the immune system and the CNS parenchyma, a division that is integral to the neuroimmune axis (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Horng S, Therattil A, Moyon S, Gordon A, Kim K, Argaw AT, Hara Y, Mariani JN, Sawai S, Flodby P, Crandall ED, Borok Z, Sofroniew MV, Chapouly C, John GR, Astrocytic tight junctions control inflammatory CNS lesion pathogenesis. J. Clin. Invest 127, 3136– 3151 (2017). 28737509 PMC5531407 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated T cells can enter the perivascular space independent of antigen specificity, but are unable to traverse the astrocytic basement membrane and glia limitans.

    “Activated T cells can enter the perivascular space independent of antigen specificity (82), but are unable to traverse the astrocytic basement membrane and glia limitans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Kawakami N, Nägerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flügel A, Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J. Exp. Med 201, 1805– 1814 (2005). 15939794 PMC2213265 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The inner and outer basement membranes of parenchymal capillaries are directly apposed and have minimal space for perivascular fluid, limiting the ability of immune cells to traffic from the brain parenchyma to draining lymph nodes.

    “As noted previously, the inner and outer basement membranes of parenchymal capillaries are directly apposed and have minimal space for perivascular fluid. This limits the ability of immune cells to traffic from the brain parenchyma to draining lymph nodes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The glia limitans separates the brain parenchyma from the CSF/perivascular spaces and plays a major role in compartmentalizing CNS immune reactions.

    “The glia limitans separates the brain parenchyma from the CSF/perivascular spaces and plays a major role in compartmentalizing CNS immune reactions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Endothelial cells comprising blood vessels in the dura mater lack tight junctions and allow extravasation of solutes as large as 43 kDa.

    “For example, endothelial cells comprising blood vessels in the dura mater lack tight junctions and allow extravasation of solutes as large as 43 kDa (Fig. 1A) (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Balin BJ, Broadwell RD, Salcman M, El-Kalliny M, Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J. Comp. Neurol 251, 260– 280 (1986). 3782501 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Astrocytic endfeet cover >99% of the vascular surface and densely surround tight junctions, creating an additional barrier that limits entry into the CNS parenchyma.

    “They cover >99% of the vascular surface and densely surround tight junctions, creating an additional barrier that limits entry into the CNS parenchyma (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Kacem K, Lacombe P, Seylaz J, Bonvento G, Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: A confocal microscopy study. Glia 23, 1– 10 (1998). 9562180

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated T cells need to recognize cognate antigen presented by perivascular APCs to enter the CNS parenchyma; otherwise, they undergo apoptosis or reenter the circulation.

    “In addition, activated T cells need to recognize cognate antigen presented by perivascular APCs to enter the CNS parenchyma (65, 84); otherwise, they undergo apoptosis or reenter the circulation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B, Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med 11, 328– 334 (2005). 15735653 source

      Not checked in the free run.

    • cites [84] Lodygin D, Odoardi F, Schläger C, Körner H, Kitz A, Nosov M, van den Brandt J, Reichardt HM, Haberl M, Flügel A, A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nat. Med 19, 784– 790 (2013). 23624600 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The arachnoid mater keeps the dura mater separate from the underlying subarachnoid space, which contains CSF.

    “Similarly, the arachnoid mater keeps the dura mater separate from the underlying subarachnoid space, which contains CSF.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CXCL12 expression is elevated during EAE and is not confined to the abluminal surface of blood vessels.

    “CXCL12 expression is elevated during EAE as well and is not confined to the abluminal surface of blood vessels (114).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] McCandless EE, Piccio L, Woerner BM, Schmidt RE, Rubin JB, Cross AH, Klein RS, Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am. J. Pathol 172, 799– 808 (2008). 18276777 PMC2258272 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CNS is affected by cytokines through a variety of mechanisms, including direct transfer across the BBB, stimulation of CVOs, nerve stimulation, or release from infiltrating or resident immune cells.

    “The CNS is affected by cytokines (97), and this can occur through a variety of different mechanisms, including direct transfer across the BBB, stimulation of CVOs, nerve stimulation, or release from infiltrating or resident immune cells, among others (98).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [97] Ching S, Zhang H, Belevych N, He L, Lai W, Pu X.-a., Jaeger LB, Chen Q, Quan N, Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J. Neurosci 27, 10476– 10486 (2007). 17898219 PMC6673171 source

      Not checked in the free run.

    • cites [98] Banks WA, Blood-brain barrier transport of cytokines: A mechanism for neuropathology. Curr. Pharm. Des 11, 973– 984 (2005). 15777248 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationnone given

    Peripheral immune cells can traverse the BBB only after acquiring the ability to move from the perivascular space across the glia limitans.

    “However, they can traverse the BBB during pathophysiological conditions (such as autoimmune disease, injury, stroke, or infection) but only after acquiring the ability to move from the perivascular space across the glia limitans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Early CD4+ T cell extravasation was observed primarily through leptomeningeal vasculature in the Lewis rat model of EAE, as well as the choroid plexus in the MOG35-55 model and, to a lesser extent, postcapillary venules in the CNS parenchyma.

    “Early CD4+ T cell extravasation was observed primarily through leptomeningeal vasculature in the Lewis rat model of EAE (66) as well as the choroid plexus in the MOG35-55 model (118) and, to a less extent, postcapillary venules in the CNS parenchyma.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Bartholomäus I, Kawakami N, Odoardi F, Schläger C, Miljkovic D, Ellwart JW, Klinkert WEF, Flügel-Koch C, Issekutz TB, Wekerle H, Flügel A, Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94– 98 (2009). 19829296 source

      Not checked in the free run.

    • cites [118] Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F, 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). 19305396 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CNS barriers are composed of biological materials and are not absolute.

    “All these barriers are composed of biological materials and are by no means absolute, but they do compartmentalize peripheral immune cells until the barriers are breached.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acute lymphoblastic leukemia cells never traverse the BBB but do enter the subarachnoid space.

    “These cancer cells never traverse the BBB but do enter the subarachnoid space (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, Ridge SM, Jablonski EM, Therrien J, Tannheimer S, McCall CM, Chenn A, Sipkins DA, Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 560, 55– 60 (2018). 30022166 PMC10257142 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During CNS autoimmune disease, the process of diapedesis involves T cell interactions with endothelial selectins through P-selectin glycoprotein ligand-1 (PSGL-1), although the requirement for selectins is not absolute.

    “Similar to steady state, the process of diapedesis during CNS autoimmune disease involves T cell interactions with endothelial selectins through P-selectin glycoprotein ligand–1 (PSGL-1), although the requirement for selectins is not absolute.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Piccio L, Rossi B, Scarpini E, Laudanna C, Giagulli C, Issekutz AC, Vestweber D, Butcher EC, Constantin G, Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: Critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric Gi-linked receptors. J. Immunol 168, 1940– 1949 (2002). 11823530 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    EAE is often used as a model for human multiple sclerosis (MS) and to study autoreactive immune cell traffic into the CNS.

    “Experimental autoimmune encephalomyelitis (EAE) is often used as a model for human multiple sclerosis (MS) and to study autoreactive immune cell traffic into the CNS (107).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Lassmann H, Models of multiple sclerosis: New insights into pathophysiology and repair. Curr. Opin. Neurol 21, 242– 247 (2008). 18451705 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Astrocytes secrete MMP-2 from their endfeet, and pro-MMP-9 and pro-MMP-3 are produced by endothelial cells, microglia, and pericytes.

    “Astrocytes secrete MMP-2 from their endfeet, and pro–MMP-9 and pro–MMP-3 are produced by endothelial cells, microglia, and pericytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Yang Y, Rosenberg GA, Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 1623, 30– 38 (2015). 25916577 PMC4569515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This alarmin detection triggers a rapid inflammatory response characterized by inflammasome assembly, nuclear factor-κβ signaling, resident immune cell activation, cytokine and chemokine production, and recruitment of peripheral myelomonocytic cells.

    “This, in turn, triggers a rapid inflammatory response characterized by inflammasome assembly, nuclear factor-κβ signaling, resident immune cell activation, cytokine and chemokine production (such as IL-6, TNFα, CXCL1, CXCL2, and CCL2), and recruitment of peripheral myelomonocytic cells, among others (Fig. 4) (130).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J, Neuroimmunology of traumatic brain injury: Time for a paradigm shift. Neuron 95, 1246– 1265 (2017). 28910616 PMC5678753 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depletion of these monocytes has a negative impact on stroke outcome and increases the incidence of hemorrhagic transformation.

    “However, depletion of these cells has a negative impact on stroke outcome and increases the incidence of hemorrhagic transformation (146).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Gliem M, Mausberg AK, Lee J-I, Simiantonakis I, van Rooijen N, Hartung H-P, Jander S, Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann. Neurol 71, 743– 752 (2012). 22718543 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MCAM+ effector T cells migrate more efficiently across the BBB than MCAM-negative counterparts through homotypic binding with MCAM on vascular endothelial cells and interactions with laminin-411.

    “MCAM+ effector T cells migrate more efficiently across the BBB than their MCAM-negative counterparts and appear to do so through homotypic binding with MCAM expressed on vascular endothelial cells (123) and through interactions with laminin-411 (124).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [123] Larochelle C, Cayrol R, Kebir H, Alvarez JI, Lécuyer M-A, Ifergan I, Viel É, Bourbonnière L, Beauseigle D, Terouz S, Hachehouche L, Gendron S, Poirier J, Jobin C, Duquette P, Flanagan K, Yednock T, Arbour N, Prat A, Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain 135, 2906– 2924 (2012). 22975388 source

      Not checked in the free run.

    • cites [124] Flanagan K, Fitzgerald K, Baker J, Regnstrom K, Gardai S, Bard F, Mocci S, Seto P, You M, Larochelle C, Prat A, Chow S, Li L, Vandevert C, Zago W, Lorenzana C, Nishioka C, Hoffman J, Botelho R, Willits C, Tanaka K, Johnston J, Yednock T, Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS. PLOS ONE 7, e40443 (2012). 22792325 PMC3391262 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although expression of P-selectin can be up-regulated in meningeal and parenchymal vessels during inflammation, the delayed availability of this protein in the CNS leads to slower leukocyte recruitment kinetics when compared with the periphery.

    “Although expression of P-selectin can be up-regulated in meningeal and parenchymal vessels during inflammation, the delayed availability of this protein in the CNS leads to slower leukocyte recruitment kinetics when compared with the periphery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upon extravasation, autoreactive T cells interact with peptide-MHC II-bearing APCs in perivascular spaces, triggering up-regulation of chemokines that recruit myeloid cells and release of TNFα that increases production of MMP-2 and MMP-9 by resident and recruited myeloid cells.

    “Upon extravasation, the autoreactive T cells interact with peptide–major histocompatibility complex (MHC) II–bearing APCs (such as DCs) in the perivascular spaces, triggering up-regulation of chemokines that recruit myeloid cells and release of TNFα that increases production of metalloproteinases MMP-2 and MMP-9 by resident and recruited myeloid cells (Fig. 4) (65, 67, 84, 119, 120).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [65] Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B, Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med 11, 328– 334 (2005). 15735653 source

      Not checked in the free run.

    • cites [67] Mundt S, Mrdjen D, Utz SG, Greter M, Schreiner B, Becher B, Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci. Immunol 4, eaau8380 (2019). 30679199 source

      Not checked in the free run.

    • cites [84] Lodygin D, Odoardi F, Schläger C, Körner H, Kitz A, Nosov M, van den Brandt J, Reichardt HM, Haberl M, Flügel A, A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nat. Med 19, 784– 790 (2013). 23624600 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models of TBI, reduced microvascular densities were observed in the brain within a day of injury, although the density returned to normal within 2 weeks, suggesting engagement of vascular repair mechanisms.

    “In animal models of TBI, reduced microvascular densities were observed in the brain within a day of injury, although the density returned to normal within 2 weeks, suggesting engagement of vascular repair mechanisms (129).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Park E, Bell JD, Siddiq IP, Baker AJ, An analysis of regional microvascular loss and recovery following two grades of fluid percussion trauma: A role for hypoxia-inducible factors in traumatic brain injury. J. Cereb. Blood Flow Metab 29, 575– 584 (2008). 19088740 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    After entering the CSF through the choroid plexus, CD4+ T cells accumulate in leptomeningeal spaces, suggesting that the choroid plexus might be one of the earliest CNS entry points for autoreactive T cells during EAE development.

    “After entering the CSF through the choroid plexus, CD4+ T cells accumulate in leptomeningeal spaces, suggesting that the choroid plexus might be one of the earliest CNS entry points for autoreactive T cells during the development of EAE (118).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F, 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). 19305396 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In contrast to most peripheral vasculature, blood vessels in the CNS parenchyma lack P-selectin in Weibel-Palade bodies and only express low levels of this protein under steady state.

    “In contrast to most peripheral vasculature, blood vessels in the CNS parenchyma lack P-selectin in Weibel-Palade bodies and only express low levels of this protein under steady state (79).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Barkalow FJ, Goodman MJ, Gerritsen ME, Mayadas TN, Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion. Blood 88, 4585– 4593 (1996). 8977250 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A number of preclinical and clinical trials have failed to improve ischemic stroke outcomes or lesion size by preventing leukocyte diapedesis, indicating that our knowledge of the inflammatory response to this condition is incomplete.

    “To date, a number of preclinical and clinical trials have failed to improve ischemic stroke outcomes or lesion size by preventing leukocyte diapedesis (142, 147), indicating that our knowledge of the inflammatory response to this condition is incomplete.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Enzmann G, Kargaran S, Engelhardt B, Ischemia-reperfusion injury in stroke: Impact of the brain barriers and brain immune privilege on neutrophil function. Ther. Adv. Neurol. Disord 11, 1756286418794184 (2018). 30181779 PMC6111395 source

      Not checked in the free run.

    • cites [147] Elkins J, Veltkamp R, Montaner J, Johnston SC, Singhal AB, Becker K, Lansberg MG, Tang W, Chang I, Muralidharan K, Gheuens S, Mehta L, Elkind MSV, Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): A randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 16, 217– 226 (2017). 28229893 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Up-regulation of hypoxia-inducible factor-1α after hypoxia leads to furin production, which activates MMP-14 that, in turn, activates MMP-2.

    “Up-regulation of hypoxia-inducible factor–1α after hypoxia leads to furin production, which activates MMP-14 that, in turn, activates MMP-2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Yang Y, Rosenberg GA, Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 1623, 30– 38 (2015). 25916577 PMC4569515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils are among the first peripheral immune cells recruited to the brain after an ischemic-reperfusion event and are thought to contribute to injury in at least some brain regions.

    “Neutrophils are among the first peripheral immunes recruited to the brain after an ischemic-reperfusion event and are thought to contribute to the injury in a least some brain regions (137).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Beray-Berthat V, Croci N, Plotkine M, Margaill I, Polymorphonuclear neutrophils contribute to infarction and oxidative stress in the cortex but not in the striatum after ischemia-reperfusion in rats. Brain Res. 987, 32– 38 (2003). 14499943 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNFα and IL-1β induce expression of pro-MMP-9 and pro-MMP-3, and the latter is responsible for activating MMP-9.

    “In addition, TNFα and IL-1β induce expression of pro–MMP-9 and pro–MMP-3, and the latter is responsible for activating MMP-9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Yang Y, Rosenberg GA, Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 1623, 30– 38 (2015). 25916577 PMC4569515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR4 is up-regulated after TBI and recognizes LPSs and endogenous proteins such as high-mobility group box 1 protein, heat shock proteins, and low-density lipoprotein.

    “TLR4 is up-regulated after TBI and recognizes LPSs and endogenous proteins, such as high-mobility group box 1 protein, heat shock proteins, and low-density lipoprotein (132).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Lee H, Lee S, Cho I-H, Lee SJ, Toll-like receptors: Sensor molecules for detecting damage to the nervous system. Curr. Protein Pept. Sci 14, 33– 42 (2013). 23441900 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This combination of inflammatory events leads to tight junction and glia limitans degradation as well as leukocyte infiltration of the brain parenchyma and vasogenic edema.

    “This combination of inflammatory events leads to tight junction and glia limitans degradation as well as leukocyte infiltration of the brain parenchyma and vasogenic edema (Fig. 4) (145).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Yang Y, Rosenberg GA, Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 1623, 30– 38 (2015). 25916577 PMC4569515 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pro-inflammatory monocytes eventually follow neutrophils into the brain parenchyma and enter in a CCR2-dependent manner, eventually differentiating into Ly6Clow phagocytes.

    “Pro-inflammatory monocytes eventually follow neutrophils into the brain parenchyma and enter in a CCR2-dependent manner, eventually differentiating into Ly6Clow phagocytes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Gliem M, Mausberg AK, Lee J-I, Simiantonakis I, van Rooijen N, Hartung H-P, Jander S, Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann. Neurol 71, 743– 752 (2012). 22718543 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vascular repair was observed in the meninges after TBI and was dependent on the recruitment of nonclassical monocytes from the blood.

    “Vascular repair was also observed in the meninges after TBI and was dependent on the recruitment of nonclassical monocytes from the blood (127).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Russo MV, Latour LL, McGavern DB, Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury. Nat. Immunol 19, 442– 452 (2018). 29662169 PMC6426637 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Injection of anti-MCAM antibodies into mice reduces the severity of EAE, demonstrating the importance of MCAM in disease pathogenesis.

    “Injection of anti-MCAM antibodies into mice also reduces the severity of EAE, demonstrating the importance of this adhesion molecule in disease pathogenesis (122, 123).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [122] Duan H, Xing S, Luo Y, Feng L, Gramaglia I, Zhang Y, Lu D, Zeng Q, Fan K, Feng J, Yang D, Qin Z, Couraud P-O, Romero IA, Weksler B, Yan X, Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS. Sci. Rep 3, 1687 (2013). 23595028 PMC3629416 source

      Not checked in the free run.

    • cites [123] Larochelle C, Cayrol R, Kebir H, Alvarez JI, Lécuyer M-A, Ifergan I, Viel É, Bourbonnière L, Beauseigle D, Terouz S, Hachehouche L, Gendron S, Poirier J, Jobin C, Duquette P, Flanagan K, Yednock T, Arbour N, Prat A, Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain 135, 2906– 2924 (2012). 22975388 source

      Not checked in the free run.

46 of 46

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • It seems plausible that molecules within parasagittal dura structures may reach adjacent lymphatic vessels, and perhaps also vice versa.

    “it seems plausible that molecules within parasagittal dura structures may well reach adjacent lymphatic vessels, and perhaps also vice versa”

    From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [16]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. J. R. Youmans Neurological Surgery: A Comprehensive Reference Guide to the Diagnosis and Management of Neurosurgical Problems (Saunders ed. 3 1990).
  2. R. V. Krstić Die Gewebe des Menschen und der Säugetiere: ein Atlas zum Studium für Mediziner und Biologen (Springer-Verlag ed. 2 korrigierter Nachdruck der 1. Aufl. 1984).

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Related

Authors
Mastorakos, P., & McGavern, D.
Affiliations
National Institutes of Health (US)
Corresponding author
McGavern, Dorian
ORCID
Venue
Science Immunology
Publisher
American Association for the Advancement of Science (AAAS)
Published
2019-07-05
Volume
4
Issue
37
ISSN
2470-9468 (ISSN-L)
DOI
10.1126/sciimmunol.aav0492
PMC
PMC6816468
OpenAlex
W2958251376
Semantic Scholar
70285abeae706be27d3a748d5a0bf2f8e5b848c3
Cited by
333
References
154
Citations by year
2026: 35 · 2025: 53 · 2024: 49 · 2023: 47 · 2022: 61 · 2021: 55 · 2020: 29 · 2019: 3
FWCI
3.96
Type
journal article
Language
en
Open access
Locations
  • Science Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Neurological Disorders and Stroke (ZIA NS003112 10)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
cerebrovascular anatomy, central nervous system immune response, cerebrovascular injury, cerebral ischemia, central nervous system infection, blood-brain barrier
MeSH terms
Anatomy, Animals, Central Nervous System, Cerebral Arteries, Cerebrovascular Circulation, Humans, Neovascularization, Physiologic

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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