_:b611582595 "3"^^ . . _:b54525977 "Clearance of tracers that enter the brain from the CSF appears to be via paravenous flow either into the CSF or possibly to cervical lymph nodes [>>62<<]. The immunological significance of the convective tracer influx/glymphatic system [62, 113] is unclear. Fluid and tissue metabolites in this system appear to drain back into the CSF and may reach lymph nodes via the CSF." . _:b611582594 "3"^^ . _:b54525980 . _:b611582605 "3"^^ . _:b611582693 . _:b611582604 "3"^^ . . . _:b54526054 . _:b611582607 "3"^^ . _:b611582500 . _:b611582899 . . _:b611582606 "3"^^ . . _:b611582601 "3"^^ . . . _:b611582600 "3"^^ . . _:b54525829 . _:b54526007 "Encephalitogenic T cells have also been shown to directly extravasate via the leptomeningeal microvessels into the subarachnoid space [13, >>118<<] (Fig.\u00A05b)." . _:b611582603 "3"^^ . _:b54526071 . _:b611582447 . _:b611582602 "3"^^ . . _:b611582779 . _:b611582613 "3"^^ . _:b611582741 . _:b611582612 "3"^^ . _:b611582561 . . _:b611582615 "3"^^ . _:b611582614 "3"^^ . . _:b54525827 . . _:b611582816 . _:b611582609 "3"^^ . _:b611582608 "3"^^ . . . _:b611582611 "3"^^ . _:b611582610 "3"^^ . _:b611582621 "3"^^ . _:b611582620 "3"^^ . _:b611582628 . . _:b611582623 "3"^^ . _:b611582622 "3"^^ . _:b54526046 "between these steps serve as checkpoints, in which the molecular keys required for immune cells to breach the glia limitans and to enter the CNS parenchyma are dependent upon local recognition of CNS antigens by the invading T cells [>>38<<]." . _:b611582617 "3"^^ . . _:b611582616 "3"^^ . . . _:b611582619 "3"^^ . _:b611582618 "3"^^ . _:b611582629 "3"^^ . . _:b611582773 . _:b611582628 "3"^^ . . . _:b611582631 "3"^^ . . _:b611582795 . _:b611582869 . . _:b611582630 "3"^^ . . _:b611582481 . . _:b611582625 "3"^^ . . _:b611582624 "3"^^ . _:b611582800 . _:b611582737 . _:b611582627 "3"^^ . _:b54525904 "Injection of larger volumes (2\u00A0\u03BCL) of tracer into the striatum of the mouse brain results in the passage of tracer into CSF in the ventricles [>>15<<].Fig." . . . _:b611582626 "3"^^ . _:b611582458 . _:b611582637 "3"^^ . _:b54525991 "Previous studies have provided direct evidence for the migration of low numbers of encephalitogenic T-cell blast across the BBB in the spinal cord within several hours after transfer [>>56<<, 134]. However, recent studies performed in a Lewis rat model of EAE have shown that the majority of intravenously inoculated encephalitogenic T-cell blasts do not directly cross CNS microvessels, but rather accumulate in the lung [43," . _:b611582636 "3"^^ . _:b611582504 . _:b611582639 "3"^^ . _:b611582638 "3"^^ . . . _:b611582479 . . _:b611582633 "3"^^ . . _:b54525971 "Cerebral hypoperfusion in a mouse model of Alzheimer\u2019s disease leads to accelerated accumulation of A\u03B2 in the walls of leptomeningeal vessels and this can be reversed by phosphodiesterase inhibitor and vasodilator Cilostazol [>>102<<]. Thus, experimental evidence again suggests that the interplay between the strength of pulsations and vasomotion may be key to the efficient perivascular clearance along basement membranes." . _:b611582728 . _:b611582632 "3"^^ . _:b611583063 . . _:b611582635 "3"^^ . _:b54526031 . _:b611583078 . _:b611582634 "3"^^ . _:b611582645 "2"^^ . _:b611582468 . _:b54525967 "As the route of drainage is within basement membranes [24], it is possible that the valve-like action results from changes in the orientation of the molecules within the basement membranes [>>122<<]. As vessels age, they become arteriosclerotic, stiff, and less elastic, particularly in humans, and such stiffening may interfere with perivascular drainage of ISF and soluble metabolites in elderly individuals [59, 139]." . . _:b611582542 . _:b611582644 "3"^^ . . _:b611583074 . _:b611582647 "2"^^ . _:b54525831 . _:b611582646 "2"^^ . _:b611582967 . _:b611582641 "3"^^ . _:b611583108 . _:b611582640 "3"^^ . _:b611582440 . _:b611582643 "3"^^ . _:b611582885 . _:b611582667 . _:b611582642 "3"^^ . _:b54525911 "The movement of water mixed with the movement of soluble metabolites results in the flow of ISF [>>2<<, 3]. ISF drains from the ECS of the CNS parenchyma by entering capillary basement membranes and then draining along the basement membranes of cerebral arteries by bulk flow, as indicated by physiological tracer experiments [24]. Bulk flow" . _:b611582653 "2"^^ . _:b54526023 "the leptomeningeal environment are in regular contact with these cells that constitutively express MHC class II molecules on their membrane surfaces and thus are able to present myelin antigens to the pathogenic effector T cells [13, >>70<<, 99]. In fact, live cell-imaging studies with activation-driven biosensors are able to demonstrate that T cells recognize their cognate antigen on these APC [80, 92] (the cognate antigen is the antigen that the T cell first encountered" . _:b611582640 . _:b611582652 "2"^^ . . _:b611582655 "2"^^ . _:b611582654 "2"^^ . _:b611582649 "2"^^ . . _:b611582553 . _:b611582648 "2"^^ . . _:b611582651 "2"^^ . . . . _:b611582650 "2"^^ . . _:b611582970 . _:b611582661 "2"^^ . _:b54525860 . . _:b611582660 "2"^^ . . _:b611582663 "2"^^ . _:b54525858 . _:b611582776 . _:b611582662 "2"^^ . . _:b54525859 . _:b611582657 "2"^^ . . _:b611582656 "2"^^ . . _:b611583031 . _:b611582739 . _:b611582659 "2"^^ . _:b611582632 . _:b611582658 "2"^^ . _:b611582669 "2"^^ . . _:b611582668 "2"^^ . _:b611582671 "2"^^ . _:b611582827 . _:b611582670 "2"^^ . _:b54525992 "Previous studies have provided direct evidence for the migration of low numbers of encephalitogenic T-cell blast across the BBB in the spinal cord within several hours after transfer [56, >>134<<]. However, recent studies performed in a Lewis rat model of EAE have shown that the majority of intravenously inoculated encephalitogenic T-cell blasts do not directly cross CNS microvessels, but rather accumulate in the lung [43, 100]." . . _:b611582665 "2"^^ . . _:b611582664 "2"^^ . _:b54525902 "This intramural perivascular drainage route is outlined in the human brain by deposits of amyloid \u03B2 (A\u03B2) in basement membranes in cerebral amyloid angiopathy (CAA) associated with age and with Alzheimer\u2019s disease [>>25<<, 141]. Injection of larger volumes (2\u00A0\u03BCL) of tracer into the striatum of the mouse brain results in the passage of tracer into CSF in the ventricles [15].Fig." . _:b611582667 "2"^^ . _:b611582558 . . _:b611582666 "2"^^ . . _:b611582677 "2"^^ . . _:b611583061 . _:b611582676 "2"^^ . . . . _:b611582679 "2"^^ . _:b611582678 "2"^^ . _:b54525953 . . _:b611582673 "2"^^ . _:b54525928 . _:b611582672 "2"^^ . _:b54525955 . . _:b54525919 "These authors injected minute amounts of radioiodinated serum albumin tracer into various regions of the rat brain and showed that the tracer drained to cervical lymph nodes along the walls of cerebral arteries [>>33<<]. The speed of drainage to lymph nodes was comparable to that of lymphatic drainage elsewhere in the body. Only 10\u201315\u00A0% of tracer injected into the caudate nucleus or internal capsule passed into the CSF, although this figure was higher" . _:b611582564 . _:b611582675 "2"^^ . . _:b611582674 "2"^^ . _:b611582761 . _:b611582438 . _:b611582685 "2"^^ . . _:b611582508 . "10.1007%2Fs00401-016-1606-5" . _:b611582684 "2"^^ . _:b611582792 . _:b611582687 "2"^^ . . _:b611582686 "2"^^ . _:b611582681 "2"^^ . . _:b611582680 "2"^^ . . _:b611582683 "2"^^ . _:b611582682 "2"^^ . _:b611582693 "2"^^ . _:b54526002 . _:b611582961 . . _:b611582692 "2"^^ . _:b54525948 "When particles in the range of 15\u00A0nm\u20131\u00A0\u03BCm are injected into grey matter in the brain, they do not drain along intramural basement membranes, but track along the outside of arteries and separate the glia limitans from the vessel walls [>>24<<, 147]. It was concluded from these studies that it was very unlikely that, due to their size, APC would be able to track along intramural arterial basement membranes from the brain to cervical lymph nodes [24]." . . _:b611582695 "2"^^ . . _:b611582694 "2"^^ . _:b611583062 . _:b611583089 . _:b611582689 "2"^^ . . _:b54526034 "In this case, T-cell adhesion to the endothelium and subsequent crawling was significantly reduced by blocking the function of \u03B14\u03B21-integrins, but not LFA-1 [>>13<<]. In addition, it has been proposed that the other adhesion molecules, such as ninjurin-1, ALCAM, and MCAM, participate in T-cell migration across the BBB [61]. A recent in vitro study showed that extensive crawling of encephalitogenic T" . _:b611582649 . _:b54525891 . _:b611582688 "2"^^ . _:b54526041 . _:b611582691 "2"^^ . _:b54526004 . _:b54525960 "Epigenetic modifications of the proteins that constitute the extracellular matrix appear to have a role in the properties of the cerebrovascular basement membranes [>>83<<] and may be involved in the impaired drainage of fluid and solutes from the brain associated with hyperlipidaemia [53]." . _:b611582690 "2"^^ . _:b611582854 . . . _:b54526015 "endothelial BBB or the epithelial blood\u2013CSF barrier, T cells will encounter APC that are resident in the CNS and strategically localized in perivenular spaces and in CSF drained spaces right behind these brain barriers (summarized in [>>39<<, 111]). While the perivascular spaces around post-capillary venules harbour rare DCs [48], large numbers of macrophages are found in the subarachnoid spaces [13]." . _:b611582586 . _:b611582701 "2"^^ . _:b54525913 "ISF drains from the ECS of the CNS parenchyma by entering capillary basement membranes and then draining along the basement membranes of cerebral arteries by bulk flow, as indicated by physiological tracer experiments [>>24<<]. Bulk flow of ISF also occurs along the white matter fibre tracts [2]. Functionally, the ECS provides a pathway for the diffusion and exchange of ions and molecules between cells; the movement of ISF through the ECS surrounding the cells" . _:b611582428 . _:b611582700 "2"^^ . . _:b611582703 "2"^^ . _:b611582476 . . _:b611582715 . _:b54526023 . _:b611582702 "2"^^ . _:b54525861 . . _:b611582697 "2"^^ . _:b611582696 "2"^^ . _:b54526054 "relationships between lymphatic drainage of the brain and neurological disease" . _:b611582699 "2"^^ . _:b54526063 "It was concluded from this study [>>136<<] that the type and frequencies of CNS antigens within the cervical lymph nodes are determined by the type and extent of CNS damage." . _:b611582698 "2"^^ . . _:b611582709 "2"^^ . _:b611583008 . _:b611582831 . . _:b54525904 . _:b611582708 "2"^^ . _:b611582957 . . _:b611582711 "2"^^ . _:b611582725 . . . _:b611582710 "2"^^ . _:b611582724 . _:b611582762 . _:b611582703 . _:b611582705 "2"^^ . _:b611582727 . _:b54525918 . . _:b611582704 "2"^^ . _:b611583016 . _:b54525917 "Diffusion through the ECS and bulk flow of ISF along perivascular drainage routes changes with age and in Alzheimer\u2019s disease [>>54<<, 87]." . _:b611582726 . _:b611582707 "2"^^ . _:b54526044 . _:b54526037 "Similar mechanisms for trafficking across the BBB have also been shown for myeloid cells, including DC; this applies especially to the predominant role for \u03B14-integrins [>>42<<, 63]. These findings have been translated to clinical use by treating relapsing-remitting MS with the humanized anti-\u03B14-integrin antibody natalizumab [127]." . _:b611582509 . _:b611582721 . _:b611582706 "2"^^ . _:b611582485 . _:b611582720 . _:b611582747 . _:b611582717 "2"^^ . . _:b611582723 . _:b611582716 "2"^^ . _:b611582918 . _:b611582722 . _:b611582719 "2"^^ . _:b611582616 . _:b611582733 . _:b611582718 "2"^^ . _:b54526039 . _:b611582732 . . _:b611582713 "2"^^ . _:b611582735 . _:b611582802 . _:b611582712 "2"^^ . _:b54526043 . . _:b611582734 . _:b54525849 "Such intramural perivascular basement membrane pathways are not large enough to allow the traffic of APC to regional lymph nodes and this may be a key factor in inducing immune privilege in the parenchyma of the CNS [24, >>26<<].Fig." . _:b611582715 "2"^^ . _:b611582729 . _:b54525912 . _:b611582714 "2"^^ . _:b54526009 "With the ventricular CSF, the CD4+ Th17 cells seem to travel to the leptomeningeal (subarachnoid) spaces, where they accumulate and trigger neuroinflammation [>>111<<, 112] (Fig." . _:b611582501 . _:b611582728 . _:b611582677 . _:b611582725 "2"^^ . _:b611582457 . _:b611582731 . _:b611582724 "2"^^ . . . _:b611582730 . _:b611583114 . _:b611582727 "2"^^ . _:b611582741 . . _:b611582726 "2"^^ . . _:b611582740 . _:b611582721 "2"^^ . _:b611582617 . _:b611582743 . _:b611582720 "2"^^ . _:b54525981 "the CNS parenchyma are fourfold: (1) transformation into another functional subset, e.g., adoptively transferred Th17 cells changing into Th1 or IFN-gamma producing cells, or Th1* (IFN-gamma and IL-17 producing cells) or even Th2 cells [>>23<<], (2) eventual demise in situ and uptake by phagocytic cells, (3) long-term residence, that is presumably rare, and (4) emigration to secondary lymphoid organs." . _:b611582723 . _:b611582742 . _:b611582723 "2"^^ . _:b611582460 . _:b611582737 . _:b611582686 . . _:b611582722 "2"^^ . _:b611582736 . _:b611582490 . _:b611582733 "2"^^ . _:b611582739 . . _:b611582732 "2"^^ . _:b54526052 . _:b611582738 . _:b611582735 "2"^^ . _:b611582749 . _:b54526066 "restricted pathway for the elimination of ISF and solutes from its parenchyma to cervical lymph nodes that serves not only an immunological function but is also a pathway for the elimination of soluble metabolites from the brain [>>25<<]. This system of elimination fails with age [54], and this appears to be a major factor in the aetiology of CAA and Alzheimer\u2019s disease." . _:b54525999 "These studies indicate that, in addition to the cervical lymph nodes and the gut [>>18<<], the lung can also serve as a location, where autoreactive T cells potentially become re-activated." . _:b611582734 "2"^^ . _:b611582748 . _:b54526062 "In MS, neuronal antigens were present in pro-inflammatory antigen-presenting cells in cervical lymph nodes, whereas the majority of cells containing myelin were anti-inflammatory [>>136<<]. This may reflect a different origin of the cells or different drainage mechanisms." . _:b611582729 "2"^^ . . _:b54526016 "BBB or the epithelial blood\u2013CSF barrier, T cells will encounter APC that are resident in the CNS and strategically localized in perivenular spaces and in CSF drained spaces right behind these brain barriers (summarized in [39, >>111<<]). While the perivascular spaces around post-capillary venules harbour rare DCs [48], large numbers of macrophages are found in the subarachnoid spaces [13]." . _:b611582751 . _:b611582728 "2"^^ . _:b611582750 . _:b611582731 "2"^^ . _:b611582745 . . _:b611582730 "2"^^ . _:b54525968 "As vessels age, they become arteriosclerotic, stiff, and less elastic, particularly in humans, and such stiffening may interfere with perivascular drainage of ISF and soluble metabolites in elderly individuals [>>59<<, 139]." . _:b611582870 . _:b611582744 . _:b611582741 "2"^^ . _:b54525995 "blasts were found to profoundly reprogram their gene expression profile, i.e., they upregulated a migratory program involving adhesion molecules, motility factors, and chemokine receptors, but down-regulated their activation program [>>100<<]. These newly-gained migratory properties enabled that these T cells to efficiently cross the BBB [13, 68]." . _:b611582769 . _:b611582747 . . _:b611582740 "2"^^ . _:b54525838 . _:b611582746 . _:b611582743 "2"^^ . _:b611582577 . _:b611582675 . _:b54525920 . . _:b611582757 . _:b611582742 "2"^^ . _:b54525858 "Very recently, in back-to-back studies, the next generation sequencing was used to assess B-cell receptor repertoire in MS in peripheral blood versus CSF [>>104<<] and in brain versus cervical lymph nodes [82, 128]." . _:b611582844 . _:b611582756 . _:b54525969 "As vessels age, they become arteriosclerotic, stiff, and less elastic, particularly in humans, and such stiffening may interfere with perivascular drainage of ISF and soluble metabolites in elderly individuals [59, >>139<<]." . _:b611582737 "2"^^ . . _:b611582759 . . _:b611582736 "2"^^ . _:b611582669 . _:b611582758 . _:b611582498 . _:b611582739 "2"^^ . . . . _:b611582753 . _:b611582435 . _:b611582738 "2"^^ . _:b611582495 . . _:b54526038 . _:b611582752 . _:b611582749 "2"^^ . _:b611582434 . _:b611582755 . _:b54525973 "When horseradish peroxidase or fluorescent tracers are infused into the cerebral CSF, they enter the surface of the brain along the outer aspects of penetrating arteries and mix with ISF in the ECS of the brain parenchyma [62, >>113<<]. Entry of tracers in the CSF into the brain is along basement membranes between the outer pial coating of the artery and glia limitans [91] (Fig.\u00A04) and appears to be driven by arterial pulsations [62, 113]. Mixing of CSF with ISF is" . _:b611582748 "2"^^ . _:b611582754 . . _:b611582751 "2"^^ . . _:b611582765 . _:b611582999 . . _:b611582750 "2"^^ . _:b611582764 . _:b611582745 "2"^^ . . _:b611582767 . _:b611582744 "2"^^ . . _:b611582766 . _:b611582747 "2"^^ . _:b54526027 . _:b54525846 "In contrast to CSF, ISF drains from the brain parenchyma to cervical lymph nodes along very narrow, restricted pathways that comprise 100\u2013150\u00A0nm-thick basement membranes in the walls of cerebral capillaries, arterioles, and arteries [>>24<<, 26] (Fig.\u00A01)." . _:b611582761 . _:b611582746 "2"^^ . _:b611582760 . _:b611582757 "2"^^ . _:b611582763 . _:b611582756 "2"^^ . _:b54525951 . _:b611582762 . _:b611582759 "2"^^ . . _:b54525850 _:b54525852 . _:b54525850 _:b54525853 . _:b611582773 . _:b54525850 _:b54525854 . . _:b54526030 . _:b54525850 _:b54525855 . _:b611582758 "2"^^ . _:b611582772 . _:b611582639 . _:b611582753 "2"^^ . _:b54525850 _:b54525851 . _:b611582775 . _:b611582752 "2"^^ . _:b611582774 . _:b611582755 "2"^^ . _:b611582769 . _:b611582754 "2"^^ . . _:b611582768 . _:b611582765 "2"^^ . _:b54525850 _:b54525860 . _:b54525850 _:b54525861 . _:b611582771 . _:b54525850 _:b54525862 . . _:b611582764 "2"^^ . . _:b54525850 _:b54525856 . _:b54525850 _:b54525857 . _:b611582770 . _:b54525864 "the brain, spinal cord and parts of the eye, specialized lymphatic vessels begin as blind-ended capillaries and allow the free uptake of excess protein-rich ISF via discontinuous button-like junctions between lymphatic endothelial cells [>>6<<] (Fig.\u00A02a). Once within the lymphatic vessels, tissue fluid is referred to as lymph." . _:b54525850 _:b54525858 . _:b611582767 "2"^^ . _:b54525850 _:b54525859 . _:b611582781 . _:b611582766 "2"^^ . _:b54526057 . _:b611582780 . _:b611582884 . _:b611582761 "2"^^ . _:b611582783 . _:b611582760 "2"^^ . . _:b611582782 . _:b611582763 "2"^^ . _:b54525873 "Both CSF and ISF drain to lymph nodes and are involved in immunological reactions within the CNS [34, 74, >>106<<]." . _:b611582777 . _:b611582762 "2"^^ . _:b54525925 . _:b611582776 . _:b611582773 "2"^^ . . . _:b611582779 . _:b611582772 "2"^^ . _:b54525970 "Ischaemic stroke as well as amyloid accumulation results in a failure of perivascular clearance of solutes in the affected hemisphere [>>10<<]. Cerebral hypoperfusion in a mouse model of Alzheimer\u2019s disease leads to accelerated accumulation of A\u03B2 in the walls of leptomeningeal vessels and this can be reversed by phosphodiesterase inhibitor and vasodilator Cilostazol [102]." . _:b611582778 . _:b611582775 "2"^^ . _:b611582789 . _:b611582774 "2"^^ . _:b611582788 . _:b54526029 "Lack of T-cell activation by leptomeningeal macrophages will lead to T-cell detachment and their release into the CSF which flows largely driven by respiration rather than the cardiac cycle [>>37<<, 118] in this space." . _:b611582769 "2"^^ . _:b611582791 . . _:b611582768 "2"^^ . _:b611582614 . _:b611582790 . _:b611582583 . _:b611582771 "2"^^ . _:b54525826 _:b54525836 . _:b54526026 "In fact, live cell-imaging studies with activation-driven biosensors are able to demonstrate that T cells recognize their cognate antigen on these APC [80, >>92<<] (the cognate antigen is the antigen that the T cell first encountered and which bound to its receptor and resulted in the cell proliferation and differentiation that generated the population of T cells sensitized to that antigen)." . _:b54525826 _:b54525837 . _:b54525826 _:b54525838 . _:b611582785 . _:b54525826 _:b54525839 . _:b611582770 "2"^^ . _:b54525826 _:b54525832 . . _:b54525826 _:b54525833 . _:b54525826 _:b54525834 . _:b611582784 . _:b54525826 _:b54525835 . _:b611582524 . _:b611582781 "2"^^ . _:b54525826 _:b54525828 . _:b54525826 _:b54525829 . _:b611582902 . _:b611582719 . _:b54525826 _:b54525830 . _:b611582787 . _:b54525826 _:b54525831 . _:b611582780 "2"^^ . _:b611582786 . _:b54525826 _:b54525827 . _:b611582783 "2"^^ . _:b611582797 . _:b54525826 "introduction" . . _:b611582782 "2"^^ . _:b54525826 _:b54525848 . . _:b54525826 _:b54525849 . _:b611582796 . _:b611582777 "2"^^ . _:b54525826 _:b54525844 . _:b54525826 _:b54525845 . _:b611583052 . _:b54525826 _:b54525846 . . _:b611582799 . _:b54525826 _:b54525847 . _:b611582889 . _:b611582776 "2"^^ . _:b54525826 _:b54525840 . _:b611582604 . . _:b54525826 _:b54525841 . _:b54526032 "Subsequent polarization and extended crawling of the T cells against the direction of flow have been shown in vitro to be mediated by LFA-1 interaction with endothelial ICAM-1 and ICAM-2 as in other vascular beds [>>1<<]." . _:b54525826 _:b54525842 . _:b611582789 . _:b611582798 . _:b54525826 _:b54525843 . _:b611582779 "2"^^ . . _:b54525868 _:b54525908 . _:b54525994 . _:b54525868 _:b54525909 . _:b54525868 _:b54525910 . _:b611582793 . _:b54525868 _:b54525911 . _:b611582778 "2"^^ . _:b54525868 _:b54525904 . _:b54525995 . _:b54525868 _:b54525905 . _:b54525868 _:b54525906 . _:b611582792 . _:b54525868 _:b54525907 . _:b611582789 "2"^^ . _:b54525868 _:b54525916 . _:b54525868 _:b54525917 . _:b54525868 _:b54525918 . . _:b611582795 . _:b54525868 _:b54525919 . _:b611582788 "2"^^ . _:b54525868 _:b54525912 . _:b54525868 _:b54525913 . _:b611583070 . _:b54525868 _:b54525914 . _:b611582794 . _:b54525868 _:b54525915 . . _:b611582791 "2"^^ . _:b54525868 _:b54525892 . _:b54525868 _:b54525893 . _:b54525868 _:b54525894 . _:b611582805 . _:b54525868 _:b54525895 . _:b611582790 "2"^^ . _:b54525868 _:b54525888 . _:b54525868 _:b54525889 . _:b54525929 "of desmosomes and small nexus junctions, are reflected from the surface of the brain and spinal cord to coat arteries and veins in the SAS, thus separating CSF in the subarachnoid space from the CNS and perivascular compartments [>>95<<, 137] (Fig.\u00A04). Furthermore, leptomeningeal cells form a perivascular sheath around arteries, as they enter the brain." . _:b54525868 _:b54525890 . _:b611582804 . _:b54525868 _:b54525891 . _:b611582785 "2"^^ . _:b54525868 _:b54525900 . _:b54525868 _:b54525901 . _:b54525868 _:b54525902 . _:b611582807 . _:b54525868 _:b54525903 . _:b611582784 "2"^^ . _:b611582642 . _:b54525868 _:b54525896 . _:b54525868 _:b54525897 . . _:b54525868 _:b54525898 . _:b611582806 . _:b54525868 _:b54525899 . _:b611583106 . _:b611582964 . _:b611582787 "2"^^ . _:b54525868 _:b54525940 . _:b54525868 _:b54525941 . . _:b54525868 _:b54525942 . _:b611582801 . _:b54525868 _:b54525943 . _:b611582786 "2"^^ . _:b54525868 _:b54525936 . _:b54525868 _:b54525937 . _:b54525868 _:b54525938 . _:b611582437 . _:b611582800 . _:b54525868 _:b54525939 . _:b611582797 "2"^^ . _:b54525868 _:b54525948 . . _:b54525868 _:b54525949 . _:b54525868 _:b54525950 . _:b611582803 . _:b54525868 _:b54525951 . _:b611582796 "2"^^ . _:b54525868 _:b54525944 . _:b54525868 _:b54525945 . _:b54525868 _:b54525946 . _:b611582802 . _:b54525868 _:b54525947 . _:b611582799 "2"^^ . _:b54525868 _:b54525924 . _:b54525868 _:b54525925 . . _:b54525868 _:b54525926 . _:b611582813 . _:b611582453 . _:b54525868 _:b54525927 . _:b611582798 "2"^^ . _:b54525868 _:b54525920 . _:b54525868 _:b54525921 . . . _:b611582812 . . _:b54525868 _:b54525922 . _:b54525868 _:b54525923 . _:b611582793 "2"^^ . _:b54525868 _:b54525932 . _:b54525868 _:b54525933 . _:b611582502 . _:b54525868 _:b54525934 . _:b611582815 . . _:b54525868 _:b54525935 . . . _:b611582792 "2"^^ . _:b54525868 _:b54525928 . _:b54525963 "that perivascular transport only occurs in living animals and ceases immediately after cardiac arrest suggests that pulsations in artery walls may generate the motive force for the transport of ISF and solutes out of the brain [>>24<<]. Furthermore, mathematical models indicate that perivascular transport of ISF and solutes may be driven by the contrary (reflection) waves that follow each pulse wave [119]." . _:b54525868 _:b54525929 . _:b54525852 "of cervical lymph nodes to detrimental immunity in multiple sclerosis (MS) and EAE may seem rather obvious, it is important to point out that the cervical lymph nodes clearly can also mediate the induction of tolerance [88, >>143<<]. For example, the injection of myelin basic protein into the CSF induces tolerance and prevents the subsequent induction of EAE [49]." . _:b54525868 _:b54525930 . _:b611582814 . . . _:b54525868 _:b54525931 . _:b611582795 "2"^^ . . . _:b611582809 . _:b611582794 "2"^^ . _:b54526074 . . . _:b611582808 . _:b611582805 "2"^^ . _:b611582811 . _:b611582804 "2"^^ . _:b611582794 . _:b611582906 . _:b611582810 . _:b611582807 "2"^^ . _:b54525863 _:b54525864 . _:b54525863 _:b54525865 . . _:b54525863 _:b54525866 . _:b611582962 . _:b611582821 . _:b54525863 _:b54525867 . _:b611582806 "2"^^ . _:b54525999 . _:b54525989 "In this case, autoreactive effector T cells that are normal constituents of the immune repertoire [>>103<<, 120] are activated in lymph nodes draining the skin." . . _:b611582820 . _:b611582801 "2"^^ . _:b54526049 "Interaction between PSGL-1 and P-selectin has been shown to contribute to the recruitment of human CD8 T cells in leptomeningeal brain vessels [>>14<<]. Recent development of mouse models of CNS autoimmunity driven by CD8 T cells has led to the identification of the first molecular mechanisms involved in cytotoxic CD8 T-cell migration into the CNS and has shown that these mechanisms are" . . _:b611582823 . _:b611582800 "2"^^ . _:b54526068 "Elimination of A\u03B2 from the brain entails absorption into the blood, degradation by enzymes, such as neprilysin, and drainage, along intramural perivascular routes with ISF to lymph nodes [>>25<<]. With age and Alzheimer\u2019s disease, insoluble fibrillary A\u03B2 is deposited in intramural basement membranes of capillaries and arteries of the brain as CAA. Age-related changes in cerebral arteries impair intramural perivascular drainage of" . . _:b611582822 . . _:b611582803 "2"^^ . _:b54525868 _:b54525876 . _:b54525868 _:b54525877 . _:b54525868 _:b54525878 . _:b611582817 . . _:b54525868 _:b54525879 . _:b611582802 "2"^^ . _:b54525868 _:b54525872 . _:b54525868 _:b54525873 . . _:b54525868 _:b54525874 . _:b611582930 . _:b611582816 . _:b54525868 _:b54525875 . _:b611583099 . _:b611582813 "2"^^ . _:b54525868 _:b54525884 . _:b54525868 _:b54525885 . _:b54525868 _:b54525886 . _:b611582819 . _:b54525868 _:b54525887 . _:b611583035 . _:b611582812 "2"^^ . . _:b54525868 _:b54525880 . _:b54525868 _:b54525881 . _:b54525868 _:b54525882 . _:b611582818 . _:b54525868 _:b54525883 . _:b611583091 . _:b611582815 "2"^^ . . _:b611582829 . _:b611582814 "2"^^ . _:b611582828 . _:b611582809 "2"^^ . _:b611583036 . _:b54526017 . _:b54525868 _:b54525869 . . _:b54525868 _:b54525870 . _:b611582831 . _:b54525868 _:b54525871 . _:b54525931 "Venous perivascular spaces communicate with the subpial space, as veins tend to lack a complete perivascular coat of leptomeningeal cells [>>146<<]." . _:b611582808 "2"^^ . _:b611582830 . _:b611582811 "2"^^ . . _:b611582825 . _:b611582810 "2"^^ . . _:b611582824 . _:b611582821 "2"^^ . _:b611583051 . . _:b611583023 . . . _:b611582827 . _:b611582820 "2"^^ . . . _:b611582826 . _:b611582823 "2"^^ . _:b54526069 . _:b611582672 . _:b54525841 "CSF drains from the subarachnoid space into lymphatic vessels in the nasal mucosa, in the dura mater, and into lymphatics associated with the sheaths of cranial and spinal nerve roots [11, >>33<<, 69, 81]. The nasal and dural routes appear to allow the traffic of APC to lymph nodes [66, 81]; CSF compartments, (the ventricles and subarachnoid space), do not exhibit the same immune privilege as the parenchyma of the CNS. In contrast" . . _:b611582837 . _:b611582822 "2"^^ . . _:b611582836 . _:b611582817 "2"^^ . _:b611583005 . _:b54526067 . _:b611582839 . _:b611582816 "2"^^ . _:b611582838 . _:b611582819 "2"^^ . _:b54525944 "4) [90, >>137<<, 146]. The drainage route for ISF and solutes is along pathways within the tunica media of arteries and not along perivascular spaces (Fig." . . _:b611582833 . _:b611582818 "2"^^ . _:b611582832 . _:b611582829 "2"^^ . . _:b611582835 . _:b611582635 . _:b611582828 "2"^^ . _:b611582834 . _:b611582831 "2"^^ . _:b611582982 . _:b611582845 . _:b611582830 "2"^^ . . _:b611582844 . . _:b611582825 "2"^^ . _:b611582847 . _:b611582824 "2"^^ . _:b611582984 . . _:b611582846 . _:b611582827 "2"^^ . _:b611582841 . _:b611582826 "2"^^ . _:b611582976 . . _:b611582840 . _:b611582837 "2"^^ . . _:b611582691 . _:b611582843 . _:b611582836 "2"^^ . . _:b611582998 . _:b611582876 . _:b611582842 . _:b611582839 "2"^^ . _:b611582965 . _:b611582853 . _:b611582838 "2"^^ . . . _:b611582852 . _:b611582833 "2"^^ . . _:b611582855 . . _:b611582832 "2"^^ . _:b611582854 . _:b611582835 "2"^^ . _:b611582849 . _:b611582834 "2"^^ . _:b611582848 . _:b611582845 "2"^^ . _:b611582851 . _:b611582844 "2"^^ . _:b54525976 "Mixing of CSF with ISF is dependent upon the presence of astrocytic aquaporin 4 [>>62<<]. Clearance of tracers that enter the brain from the CSF appears to be via paravenous flow either into the CSF or possibly to cervical lymph nodes [62]. The immunological significance of the convective tracer influx/glymphatic system [62," . _:b611582783 . _:b611582850 . _:b611582847 "2"^^ . _:b611582518 . _:b54525883 "Lymph vessels of the dura mater were probably described first by Mascagni in 1787 in his study \u201CDe lymphaticis profundis capitis et colli\u201D [>>21<<], and since then, functional drainage by this route has been demonstrated by Schwalbe et al. [121], Andres et al. [9], Cserr and Knopf [34], Kida et al. [69], and more recently by Aspelund et al. [11] and by Louveau et al. [81]." . _:b611582861 . _:b611582846 "2"^^ . _:b611582860 . _:b611582841 "2"^^ . _:b611582520 . _:b611582436 . _:b611582863 . _:b611582840 "2"^^ . _:b54525933 "The pia mater prevents particles and erythrocytes [60] and, probably, neurotransmitters [>>41<<] in the CSF from entering perivascular compartments of the brain, but the exact degree of selective permeability to solutes of the pia mater and underlying glia limitans is not known." . _:b611583095 . . _:b611582862 . _:b611582843 "2"^^ . _:b611582857 . . _:b611582842 "2"^^ . . _:b611582856 . _:b611582853 "2"^^ . . _:b611582859 . _:b611582852 "2"^^ . . _:b611582858 . _:b611582855 "2"^^ . _:b611582869 . _:b611582854 "2"^^ . _:b611582868 . _:b611582849 "2"^^ . _:b611582871 . _:b611582848 "2"^^ . _:b611582575 . _:b611582870 . _:b611582851 "2"^^ . . _:b54526055 . _:b611582865 . _:b611582850 "2"^^ . _:b611582864 . _:b611582861 "2"^^ . _:b611582867 . _:b611582860 "2"^^ . _:b54525910 "The gaps are interconnected and are filled with ISF; they represent the extracellular spaces (ECS) and are in direct continuity with the basement membranes of capillaries [>>89<<]. The most significant exchange between blood and CNS occurs at the capillary level. Cerebral capillary endothelial cells are connected by highly complex and continuous tight junctions and form the BBB. While crossing the BBB requires" . _:b611582866 . _:b611582863 "2"^^ . _:b54525921 . . _:b611582877 . . _:b611582862 "2"^^ . . _:b611582876 . _:b611582857 "2"^^ . _:b54525856 . _:b611582879 . . _:b611582856 "2"^^ . _:b611582835 . _:b611582878 . _:b611582757 . _:b611582859 "2"^^ . _:b54525903 "This intramural perivascular drainage route is outlined in the human brain by deposits of amyloid \u03B2 (A\u03B2) in basement membranes in cerebral amyloid angiopathy (CAA) associated with age and with Alzheimer\u2019s disease [25, >>141<<]. Injection of larger volumes (2\u00A0\u03BCL) of tracer into the striatum of the mouse brain results in the passage of tracer into CSF in the ventricles [15].Fig." . _:b611582873 . _:b611582858 "2"^^ . _:b54525936 "as shown by the enlarged perivascular spaces that develop with age around arteries in the basal ganglia [109] and white matter [140]; the perivascular spaces are enclosed by two layers of leptomeninges in these regions of the brain [>>109<<]. Arteries in the cortex, on the other hand, have only one layer of encompassing leptomeningeal cells and do not have perivascular space [146] (Fig." . . _:b611582872 . _:b611582869 "2"^^ . . . _:b611582875 . _:b611582868 "2"^^ . _:b54525844 "The nasal and dural routes appear to allow the traffic of APC to lymph nodes [>>66<<, 81]; CSF compartments, (the ventricles and subarachnoid space), do not exhibit the same immune privilege as the parenchyma of the CNS." . . _:b611582874 . . _:b611582871 "2"^^ . _:b611582885 . _:b611582870 "2"^^ . _:b54525961 . _:b611582884 . _:b611582865 "2"^^ . . _:b611582996 . _:b611582887 . _:b611582864 "2"^^ . _:b611582866 . _:b54525989 . _:b611582886 . _:b611582867 "2"^^ . _:b611582881 . . _:b611582866 "2"^^ . _:b611582880 . . _:b611582877 "2"^^ . _:b611582883 . _:b611582876 "2"^^ . _:b611582882 . . _:b54526007 . _:b611582879 "2"^^ . . _:b611582893 . _:b611582925 . _:b611582878 "2"^^ . _:b611582892 . _:b611582873 "2"^^ . _:b54525958 . . _:b611582784 . _:b611582895 . _:b611582872 "2"^^ . _:b611582894 . _:b611582875 "2"^^ . _:b611582494 . _:b611582889 . _:b611582874 "2"^^ . _:b54525964 "Furthermore, mathematical models indicate that perivascular transport of ISF and solutes may be driven by the contrary (reflection) waves that follow each pulse wave [>>119<<]. The contrary wave travels in the reverse direction to the major pulse wave and in the reverse direction to the flow of blood. If the contrary wave does act as the motive force for the drainage of ISF and solutes, then the model dictates" . . _:b611582888 . . _:b611582885 "2"^^ . . _:b54525966 "As the route of drainage is within basement membranes [>>24<<], it is possible that the valve-like action results from changes in the orientation of the molecules within the basement membranes [122]." . _:b611582891 . . . _:b611582884 "2"^^ . _:b611582890 . _:b611582887 "2"^^ . _:b611582759 . _:b611582901 . _:b611582886 "2"^^ . . _:b611582890 . _:b611582900 . _:b54525864 . _:b611582881 "2"^^ . _:b611582903 . _:b611582880 "2"^^ . _:b611582902 . _:b611582883 "2"^^ . _:b611582517 . _:b611582880 . _:b611582897 . _:b611582882 "2"^^ . _:b611582896 . _:b611582893 "2"^^ . _:b611582899 . . _:b611582892 "2"^^ . _:b611582898 . _:b611582895 "2"^^ . . _:b611582909 . . _:b611582894 "2"^^ . _:b611582955 . _:b611582908 . _:b611582889 "2"^^ . _:b611582771 . . _:b611582911 . . _:b611582888 "2"^^ . _:b54525857 "This follows up on studies by the same group demonstrating brain antigens in cervical lymph nodes of patients with stroke; there is some correlation between antigen load, type, and clinical outcome [>>108<<]. Very little evidence of MS or encephalitis has emerged following" . _:b611582910 . _:b611582891 "2"^^ . _:b54525983 . _:b611582905 . _:b611582489 . _:b611582890 "2"^^ . _:b611582904 . _:b611582901 "2"^^ . . _:b54526011 "In healthy individuals, it is mostly central memory T cells and B cells and low numbers of innate immune cells that are detected in the CSF [>>7<<, 46, 71, 111]. This further underscores the ability of activated T and B cells to breach the outer brain barriers in the absence of neuroinflammation and perform immunosurveillance of the CNS by entering the CSF spaces." . . _:b611582589 . _:b611582907 . _:b611582550 . _:b611582900 "2"^^ . _:b54525958 . _:b611582626 . _:b611582906 . _:b611582903 "2"^^ . . _:b611582917 . _:b54525888 "colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et al. [121], Andres et al. [9], Cserr and Knopf [34], Kida et al. [69], and more recently by Aspelund et al. [11] and by Louveau et al. [>>81<<].\u00A0Although it has been suggested that lymphatic vessels in the dura drain fluid, solutes, and cells from the brain parenchyma, no such drainage has been demonstrated and the anatomical pathways for such drainage have not been demonstrated." . _:b611582902 "2"^^ . _:b611582916 . _:b611582897 "2"^^ . _:b611582919 . _:b54525959 "It is also possible to block the perivascular drainage pathways along arterial basement membranes acutely as demonstrated by the impairment of drainage when Immune complexes lodge in arterial basement membranes [>>27<<]. Epigenetic modifications of the proteins that constitute the extracellular matrix appear to have a role in the properties of the cerebrovascular basement membranes [83] and may be involved in the impaired drainage of fluid and solutes" . _:b611582896 "2"^^ . _:b611583049 . _:b611582918 . _:b611582899 "2"^^ . _:b611582913 . _:b611582898 "2"^^ . _:b611582912 . _:b611582909 "2"^^ . _:b54526036 "vitro study showed that extensive crawling of encephalitogenic T cells against the blood flow is a unique characteristic when low levels of ICAM-1 are expressed on the BBB allowing the T cells to find sites for paracellular diapedesis [>>1<<]. Inflammatory stimuli increased the cell surface levels of ICAM-1 on the BBB endothelium, which abrogated extended T-cell crawling and allowed the T cells to cross the BBB via transcellular routes." . . _:b611582949 . _:b611582915 . . _:b611582908 "2"^^ . . _:b611582914 . _:b54525943 . _:b611582911 "2"^^ . _:b54525860 "Stern and colleagues [>>128<<] found B-cell populations with sequences closely resembling the germline, dubbed founder events, which were highly represented in both the CNS and cervical lymph nodes." . . _:b611582925 . _:b611582910 "2"^^ . _:b611582584 . _:b611582924 . _:b611582905 "2"^^ . . _:b611582891 . _:b54525838 "during neurological disorders combined with cytokine activation of microglial cells leads to expression of MHC class I and class II molecules on their surfaces and subsequent presentation of antigen to receptive T lymphocytes [13, >>70<<, 80]. The adaptive response depends upon the presentation of antigen to lymphocytes by antigen-presenting cells (APC)." . _:b611582927 . _:b611582904 "2"^^ . . _:b54526010 . . _:b611582926 . _:b611582907 "2"^^ . _:b611582652 . _:b611582921 . _:b611582580 . _:b611582978 . _:b611582906 "2"^^ . _:b54526008 . _:b611582588 . _:b611582920 . . _:b611582917 "2"^^ . _:b611582513 . . _:b611582923 . _:b611582916 "2"^^ . _:b611582685 . _:b54526012 "In healthy individuals, it is mostly central memory T cells and B cells and low numbers of innate immune cells that are detected in the CSF [7, >>46<<, 71, 111]. This further underscores the ability of activated T and B cells to breach the outer brain barriers in the absence of neuroinflammation and perform immunosurveillance of the CNS by entering the CSF spaces." . . _:b54525925 "The capillary basement membrane is in direct communication with the brain extracellular spaces and encircles pericytes [>>142<<] that are responsible for the regulation of capillary diameter and of cerebral blood flow in response to neural activity [16]." . _:b611582922 . _:b611582758 . _:b611582919 "2"^^ . _:b611582933 . _:b611582918 "2"^^ . _:b611582536 . _:b611583081 . _:b611582932 . _:b54525915 . _:b611582913 "2"^^ . . _:b611583006 . . _:b611582935 . _:b611582912 "2"^^ . _:b611583009 . . . . _:b611582934 . _:b611582722 . _:b611582915 "2"^^ . . _:b611582929 . _:b611582914 "2"^^ . _:b611582928 . _:b54525893 . _:b611582925 "2"^^ . _:b611582426 . _:b611582931 . _:b611582924 "2"^^ . _:b611582930 . _:b611582927 "2"^^ . _:b611582459 . _:b611582941 . _:b611582610 . _:b611582926 "2"^^ . _:b611583022 . _:b611582940 . _:b611582921 "2"^^ . _:b611583096 . . _:b611582943 . _:b54526048 . _:b611582920 "2"^^ . _:b54525916 "Functionally, the ECS provides a pathway for the diffusion and exchange of ions and molecules between cells; the movement of ISF through the ECS surrounding the cells of nervous system depends on diffusion [96, >>130<<]. Diffusion through the ECS and bulk flow of ISF along perivascular drainage routes changes with age and in Alzheimer\u2019s disease [54, 87]." . _:b611582942 . _:b611582629 . _:b611582923 "2"^^ . . _:b611582926 . _:b611582937 . _:b611582922 "2"^^ . _:b611582936 . _:b611582933 "2"^^ . _:b611582654 . . _:b611582655 . _:b611582939 . . _:b611583066 . _:b611582932 "2"^^ . _:b54525932 . _:b611582735 . _:b611582938 . _:b611582935 "2"^^ . _:b611582560 . _:b611583001 . _:b611582662 . _:b54525865 . . _:b611582949 . _:b611582732 . _:b611582934 "2"^^ . _:b54525940 "drainage of ISF and solutes from the brain parenchyma, minute quantities (0.5\u00A0\u03BCL) of fluorescent dextran 3KDa or ovalbumin 49KDa were injected into the grey matter of the caudate putamen in the centre of the mouse cerebral hemisphere [>>24<<]. By 5\u00A0min after injection, tracers had spread diffusely through the ECS, but tracer was also present in the walls of blood vessels." . . _:b611582948 . _:b611582929 "2"^^ . _:b611582951 . _:b611582928 "2"^^ . _:b54525845 "The nasal and dural routes appear to allow the traffic of APC to lymph nodes [66, >>81<<]; CSF compartments, (the ventricles and subarachnoid space), do not exhibit the same immune privilege as the parenchyma of the CNS." . . _:b611582950 . _:b611582931 "2"^^ . _:b611582993 . _:b611582945 . _:b611583004 . _:b611582930 "2"^^ . _:b611582944 . _:b611582941 "2"^^ . _:b611582947 . . _:b54525927 "artery on the surface of the brain (leptomeningeal artery) has an endothelium separated from layers of smooth muscle cells by basement membrane, an intimal layer of extracellular matrix, and, frequently, an internal elastic lamina [>>138<<, 144]. As an artery enters the cerebral cortex, it loses its internal elastic lamina and its tunica adventitia to become an arteriole (Fig." . _:b611582940 "2"^^ . . . _:b611582946 . _:b611582943 "2"^^ . _:b54526033 "Crawling of encephalitogenic T cells against the direction of blood flow on the luminal side of spinal cord meningeal vessels in vivo has first been observed during the initiation phase of EAE in a Lewis rat EAE model [>>13<<]. In this case, T-cell adhesion to the endothelium and subsequent crawling was significantly reduced by blocking the function of \u03B14\u03B21-integrins, but not LFA-1 [13]." . . _:b611582957 . _:b611582942 "2"^^ . _:b611582864 . _:b54526061 "However, the resulting infiltration of immune cells into the CNS does not occur until weeks after the insult [79, >>132<<]." . . _:b611582956 . _:b611583030 . _:b611582937 "2"^^ . _:b54525967 . _:b611582959 . _:b611582883 . _:b611582936 "2"^^ . _:b611582958 . _:b611582939 "2"^^ . _:b611582953 . _:b611582839 . _:b611582938 "2"^^ . _:b611582952 . _:b611582949 "2"^^ . _:b54525931 . _:b611582955 . _:b611582948 "2"^^ . _:b611582682 . _:b611582432 . _:b611582954 . _:b611582951 "2"^^ . _:b611582965 . _:b611582950 "2"^^ . _:b54526024 . _:b611582964 . _:b611582945 "2"^^ . _:b611582967 . _:b611582944 "2"^^ . _:b611582974 . . _:b611582966 . _:b611582947 "2"^^ . _:b611582961 . _:b611582946 "2"^^ . _:b611582680 . _:b611582960 . _:b611582957 "2"^^ . _:b611582777 . _:b611582963 . _:b611582956 "2"^^ . _:b54525998 "Epidemiological studies suggest that infections of the respiratory tract play an important role in triggering relapses in MS, i.e., relapses in MS regularly follow inflammation of the respiratory tract [>>124<<]. Therefore, it is quite conceivable that stimulatory environmental factors might directly elicit a pathogenic response of autoimmune T cells within the lung. These studies indicate that, in addition to the cervical lymph nodes and the" . _:b611582962 . _:b611582959 "2"^^ . _:b54525937 . _:b611582973 . _:b611582958 "2"^^ . _:b611582972 . _:b611582953 "2"^^ . . _:b611582975 . _:b611582952 "2"^^ . _:b611582974 . _:b611582955 "2"^^ . _:b611582847 . _:b611582448 . . _:b611582969 . _:b611582954 "2"^^ . _:b611582968 . _:b611582965 "2"^^ . . _:b611582971 . . _:b611582964 "2"^^ . _:b611582970 . _:b611582905 . _:b611582967 "2"^^ . _:b54525945 . _:b611582469 . . _:b611582966 "2"^^ . . _:b611582468 . _:b611582961 "2"^^ . . _:b611582471 . _:b611582960 "2"^^ . . _:b611582470 . _:b611582963 "2"^^ . _:b611582465 . _:b54525895 . _:b611582962 "2"^^ . _:b611583068 . _:b611582510 . . _:b611582464 . _:b611582973 "2"^^ . _:b611582467 . _:b611582972 "2"^^ . _:b611582466 . _:b611582975 "2"^^ . _:b54525980 "pathways for the migration of antigen-presenting cells from the cns to regional lymph nodes" . _:b611583072 . _:b611582477 . _:b611582634 . _:b611582974 "2"^^ . . _:b611582476 . . _:b611582700 . _:b611582969 "2"^^ . . . _:b611582479 . _:b611582968 "2"^^ . _:b611582488 . _:b611582478 . . _:b611582971 "2"^^ . _:b611582969 . . . _:b611582473 . _:b611582970 "2"^^ . . _:b611582472 . _:b611582475 . _:b54525872 . _:b611582474 . _:b54525896 "Moreover, myelin and axonal epitopes have been found in deep cervical lymph nodes after axonal injury and (autoimmune) demyelination [36, >>40<<, 79, 93]. Although it can be emphasised that APC may drain with CSF to lymph nodes by various routes, the migration of APC from brain parenchyma with ISF along narrow intramural periarterial pathways is highly unlikely (see section on" . _:b611582492 . _:b611582485 . . _:b611582484 . _:b54526064 "There is no evidence from clinical experience in MS that cervical lymph nodes are enlarged or reactive, but this does not appear to have been pursued by systematic imaging [>>40<<]. However, there is great promise and opportunity in the development of advanced imaging methods both in experimental animals, and in humans." . . _:b611582487 . _:b611582486 . _:b54525994 "However, recent studies performed in a Lewis rat model of EAE have shown that the majority of intravenously inoculated encephalitogenic T-cell blasts do not directly cross CNS microvessels, but rather accumulate in the lung [43, >>100<<]. In the lung and its draining lymph nodes, the T-cell blasts were found to profoundly reprogram their gene expression profile, i.e., they upregulated a migratory program involving adhesion molecules, motility factors, and chemokine" . . _:b611582481 . . . _:b611582480 . . _:b611582483 . _:b611582793 . _:b611582647 . _:b54525957 "In these mice, the amount of A\u03B2 in the cervical lymph nodes reflects the degree of production of mutant A\u03B2 in the brain parenchyma [>>105<<]." . _:b611582807 . _:b611582482 . . _:b611582493 . . . _:b611583059 . _:b611582492 . . _:b611582495 . . _:b611582470 . _:b611582494 . _:b611582796 . _:b611582489 . _:b54526060 "However, the resulting infiltration of immune cells into the CNS does not occur until weeks after the insult [>>79<<, 132]." . . _:b54525837 . _:b611582488 . . _:b611582491 . . _:b611582490 . _:b611582915 . . _:b54525900 . _:b611582501 . . _:b611582429 . _:b611582467 . _:b611582500 . . _:b611582917 . _:b611582503 . _:b611582724 . _:b611582502 . . . _:b611582497 . _:b54525844 . . _:b611582496 . _:b611582718 . _:b611582840 . _:b611582499 . . . _:b611582498 . . _:b54525988 "routes and molecular mechanisms involved in the trafficking of immune cells from secondary immune organs into the CNS is mostly derived from studies in murine EAE, an animal model for MS that is focussed mainly on the spinal cord [>>39<<]. EAE can be induced by subcutaneous immunization of susceptible mice or rats with neuroantigens emulsified in adjuvants." . _:b611582509 . _:b611582975 . _:b611582585 . . _:b611582508 . _:b611582781 . _:b611582511 . _:b611582510 . _:b611582514 . _:b611582505 . _:b611582704 . _:b611582504 . _:b611582507 . _:b611582919 . _:b54525965 "contrary wave does act as the motive force for the drainage of ISF and solutes, then the model dictates that some form of valve-like action is required to prevent reflux during the passage of the major pulse wave along the vessel wall [>>119<<]. As the route of drainage is within basement membranes [24], it is possible that the valve-like action results from changes in the orientation of the molecules within the basement membranes [122]." . _:b611582506 . . _:b54525840 "CSF drains from the subarachnoid space into lymphatic vessels in the nasal mucosa, in the dura mater, and into lymphatics associated with the sheaths of cranial and spinal nerve roots [>>11<<, 33, 69, 81]." . . _:b611582517 . _:b611582525 . _:b611582516 . . _:b611582814 . _:b611582519 . _:b54525990 "In this case, autoreactive effector T cells that are normal constituents of the immune repertoire [103, >>120<<] are activated in lymph nodes draining the skin." . _:b611582518 . . _:b611582513 . . _:b54525834 "If foreign tissue grafted into the brain enters the ventricles, it is rejected [>>45<<, 85]." . _:b611582756 . _:b611582512 . _:b611582760 . _:b611582419 . _:b611582515 . _:b54525839 "during neurological disorders combined with cytokine activation of microglial cells leads to expression of MHC class I and class II molecules on their surfaces and subsequent presentation of antigen to receptive T lymphocytes [13, 70, >>80<<]. The adaptive response depends upon the presentation of antigen to lymphocytes by antigen-presenting cells (APC)." . _:b611582514 . . _:b54525987 . _:b611582525 . . _:b54526040 . _:b611582524 . _:b611582527 . _:b54525983 "Using a chronic-relapsing EAE model in Biozzi ABH mice, van Zwam et al. [>>135<<] surgically removed a total of thirteen lymph nodes draining the CNS:" . _:b611582612 . _:b611582526 . _:b54525997 "These newly-gained migratory properties enabled that these T cells to efficiently cross the BBB [13, >>68<<]. Interestingly, encephalitogenic T cells were also shown to persist as long-lived memory cells within the lung tissue, where they could be stimulated to gain the competence to enter the CNS and trigger autoimmune disease within the CNS." . _:b611582521 . . _:b611582520 . _:b611582523 . _:b54525897 "Moreover, myelin and axonal epitopes have been found in deep cervical lymph nodes after axonal injury and (autoimmune) demyelination [36, 40, >>79<<, 93]. Although it can be emphasised that APC may drain with CSF to lymph nodes by various routes, the migration of APC from brain parenchyma with ISF along narrow intramural periarterial pathways is highly unlikely (see section on" . _:b54525991 . _:b611582522 . . _:b611582533 . . _:b611582532 . . . _:b611582535 . _:b54526019 . . _:b611582452 . _:b611582636 . _:b611582534 . _:b611582453 . _:b611582454 . _:b611582455 . _:b611582448 . _:b54525920 "Only 10\u201315\u00A0% of tracer injected into the caudate nucleus or internal capsule passed into the CSF, although this figure was higher for tracer injected into the midbrain [>>131<<]." . _:b611582449 . _:b611582529 . _:b611582450 . _:b611582451 . . _:b611582460 . _:b611582701 . . _:b611582528 . _:b611582461 . _:b611582462 . _:b611582463 . _:b611582456 . _:b611582692 . _:b611582457 . _:b611582531 . _:b611582458 . _:b611582459 . _:b54525870 "The other fluid is ISF in the extracellular spaces of the brain and spinal cord parenchyma and amounts to 280\u00A0mL in humans [>>19<<]. Both CSF and ISF drain to lymph nodes and are involved in immunological reactions within the CNS [34, 74, 106]." . _:b54525847 . _:b611582608 . . _:b611582436 . _:b611582437 . _:b611582530 . _:b611582624 . . _:b611582438 . _:b611582439 . _:b611582432 . _:b611582433 . _:b611582698 . _:b611582541 . _:b611582434 . _:b611582671 . _:b611582435 . _:b611582444 . _:b611582445 . _:b54525959 . _:b611582540 . _:b611582446 . _:b611582447 . _:b611582440 . _:b611582441 . _:b611582543 . _:b611582442 . _:b611582443 . _:b611582420 . _:b611582421 . _:b611582542 . _:b611582422 . _:b611582963 . _:b611582423 . _:b54525985 . _:b611582537 . _:b611582709 . _:b611582418 . _:b611582419 . _:b611582428 . _:b611582429 . _:b611582536 . _:b611582430 . _:b611582431 . _:b611582424 . _:b611582425 . _:b611582539 . _:b611582426 . _:b611582427 . _:b611582768 . _:b611582538 . . _:b54525874 "A further proportion of CSF drains to regional lymph nodes via nasal lymphatics and dural lymphatics and via lymphatic vessels associated with cranial and spinal nerve roots [>>11<<, 33, 65, 69, 81] (Fig." . . _:b611582549 . _:b611582425 . . _:b611582548 . _:b611582551 . _:b611582944 . _:b54525923 . _:b611582550 . . _:b611582519 . . _:b611582545 . _:b54525849 . _:b611582544 . _:b611582603 . _:b611582547 . _:b611582546 . _:b611582557 . _:b611582522 . _:b54525926 "basement membrane is in direct communication with the brain extracellular spaces and encircles pericytes [142] that are responsible for the regulation of capillary diameter and of cerebral blood flow in response to neural activity [>>16<<]." . . _:b611583012 . _:b611582556 . _:b611582559 . . _:b54525832 "privileged sites as those in which: \u201Cgrafts transplanted to them are in some way partially or fully exempted from the normal rigours imposed by their histocompatibility status\u201D is a definition of a state of relative tolerance [12, >>45<<]. One further point that has been emphasised is that immune privilege does not apply to the meninges and CSF spaces [45]." . . _:b611582422 . _:b611582558 . _:b611582754 . _:b611582553 . _:b611582742 . _:b54526065 "Progress in sonography, computed tomography, and magnetic resonance imaging could yield useful insights (reviewed in [>>75<<]), facilitated by the fact that cervical lymph nodes are relatively near to the skin." . _:b611582552 . . . _:b54526011 . _:b611582555 . _:b54525975 "4) and appears to be driven by arterial pulsations [62, >>113<<]. Mixing of CSF with ISF is dependent upon the presence of astrocytic aquaporin 4 [62]." . _:b611582591 . _:b611582554 . _:b611582565 . _:b611582564 . . _:b611582567 . . . _:b611583020 . _:b611582566 . _:b611582532 . _:b611582561 . . . _:b611582881 . _:b611582560 . _:b54526040 "(MMP-2) and MMP-9 in perivascular and leptomeningeal myeloid cells leading to the cleavage of astrocyte dystroglycan which anchors the astrocyte foot processes to the parenchymal basement membrane of the glia limitans [>>4<<]. At the same time, the scavenger receptor CXCR7 is upregulated on the inflamed BBB endothelium leading to downregulation in the levels of the chemokine CXCL12 in the perivascular spaces which further facilitates mobilization of CXCR4+ T" . . _:b611582563 . . _:b611583058 . _:b611582562 . _:b54525867 . _:b611582573 . _:b54525903 . _:b611582572 . . . _:b54525842 "CSF drains from the subarachnoid space into lymphatic vessels in the nasal mucosa, in the dura mater, and into lymphatics associated with the sheaths of cranial and spinal nerve roots [11, 33, >>69<<, 81]. The nasal and dural routes appear to allow the traffic of APC to lymph nodes [66, 81]; CSF compartments, (the ventricles and subarachnoid space), do not exhibit the same immune privilege as the parenchyma of the CNS. In contrast to" . _:b54526059 . _:b611582575 . _:b611582863 . _:b611582596 . . _:b54526058 . _:b611582574 . . _:b611583042 . _:b611583094 . _:b611582569 . _:b611582568 . _:b611582491 . . _:b611582571 . _:b611582570 . _:b611582808 . _:b611582581 . _:b611583084 . _:b54526027 "The resulting antigen-specific activation of the T cells is not only of relevance for the adherence of the T cells to the leptomeningeal milieu [>>118<<], but also for the consecutive expression of pro-inflammatory cytokine by the effector T cells that constitutes a crucial signal for the initiation of the parenchymal invasion of immune cells and the clinical autoimmune process [67]." . _:b611582580 . . . . _:b611582583 . . _:b611582582 . _:b611583119 . _:b54525981 . _:b611582577 . _:b611582576 . _:b611582579 . . . _:b611582578 . _:b54525969 . _:b54525915 "Functionally, the ECS provides a pathway for the diffusion and exchange of ions and molecules between cells; the movement of ISF through the ECS surrounding the cells of nervous system depends on diffusion [>>96<<, 130]. Diffusion through the ECS and bulk flow of ISF along perivascular drainage routes changes with age and in Alzheimer\u2019s disease [54, 87]." . _:b611582641 . _:b611582589 . . _:b611582588 . . . . _:b611582591 . _:b611582590 . . _:b611582585 . . _:b611582584 . . _:b611582587 . _:b611582586 . _:b611583065 . _:b611582535 . _:b611582597 . . _:b611582596 . _:b611582475 . _:b611582599 . _:b611582645 . _:b54525950 "It was concluded from these studies that it was very unlikely that, due to their size, APC would be able to track along intramural arterial basement membranes from the brain to cervical lymph nodes [>>24<<]." . _:b611582708 . _:b611582709 . _:b611582598 . _:b611582710 . _:b611582711 . . _:b611582704 . _:b611582705 . _:b611582593 . _:b611582706 . _:b611582707 . _:b54526056 . _:b611582716 . _:b611582689 . _:b611582592 . _:b611582717 . _:b611582718 . _:b611582719 . _:b611582712 . _:b611582713 . . _:b611582595 . _:b611582714 . _:b611582715 . _:b611582692 . _:b611582693 . _:b611582594 . _:b611582694 . _:b611582695 . . _:b611582688 . _:b611582689 . _:b611582605 . _:b611582690 . _:b611583111 . _:b611582691 . _:b611582700 . _:b611582701 . _:b611582604 . _:b611582702 . _:b611582703 . _:b611582696 . . _:b611582480 . _:b611582607 . _:b611582697 . _:b611582698 . _:b611583104 . _:b611582699 . . _:b611582676 . _:b611582677 . _:b611582606 . _:b611582678 . . _:b611582679 . _:b611582672 . _:b611582673 . _:b611582601 . _:b611582674 . _:b611582675 . _:b611582684 . _:b611582685 . _:b611582600 . _:b611582686 . _:b611582687 . _:b611582680 . _:b611582681 . _:b54525916 . _:b611582603 . _:b611582682 . . _:b611582683 . _:b611582660 . _:b611582661 . _:b611582817 . _:b611582602 . _:b611582662 . _:b611582663 . _:b54526041 "on the inflamed BBB endothelium leading to downregulation in the levels of the chemokine CXCL12 in the perivascular spaces which further facilitates mobilization of CXCR4+ T cells from the perivascular space into the CNS parenchyma [>>31<<]. In the CSF, CXCL12 acts as a homeostatic chemokine that maintains the expression of its ligand CXCR4 by immune cells, keeping them in the subarachnoid space; this may be relevant for immune surveillance." . . _:b611582656 . _:b611582822 . _:b611582657 . _:b611582613 . . _:b611582658 . _:b611582659 . _:b611582668 . _:b611582669 . _:b611583055 . _:b611582612 . _:b611582670 . _:b611582671 . . _:b611582664 . _:b611582665 . _:b611582615 . _:b611582433 . _:b611582666 . _:b611582667 . _:b611582644 . _:b611582645 . _:b611582614 . . _:b611582646 . _:b611582647 . _:b54525993 . _:b611582640 . _:b611582641 . _:b611582466 . _:b611582609 . _:b611582642 . _:b611582643 . _:b611582901 . . _:b611582652 . _:b611582938 . _:b611582653 . _:b611582608 . _:b611582654 . _:b611582655 . _:b611582648 . _:b611582649 . _:b611582611 . _:b611582650 . . _:b611582651 . _:b611582628 . _:b611582629 . _:b611582610 . _:b611582740 . _:b611582630 . _:b611582633 . _:b611582631 . _:b54526012 . _:b611582624 . _:b611582625 . _:b611582893 . _:b611582621 . _:b611582626 . _:b54526067 "This system of elimination fails with age [>>54<<], and this appears to be a major factor in the aetiology of CAA and Alzheimer\u2019s disease." . . _:b611582627 . _:b611582636 . _:b611582637 . _:b611582980 . _:b611582620 . _:b611582638 . _:b54525901 "extracellular spaces (ECS) and then rapidly enter the basement membranes of cerebral capillaries and drain directly via basement membranes in the tunica media of arterioles and arteries out of the brain to cervical lymph nodes [24, 26, >>33<<] (Figs.\u00A01, 2c, 3, 4)." . _:b611582639 . _:b611582632 . _:b611582633 . _:b611582623 . _:b611582634 . _:b611582635 . _:b611582986 . _:b611582612 . . _:b611582622 . _:b611582613 . . . _:b611582614 . _:b611582615 . _:b54525907 "Tracer experiments and mathematical models show that ISF is eliminated from the brain by bulk flow along white matter fibre tracts and along perivascular pathways [>>32<<, 119]." . _:b611582608 . _:b611582609 . _:b611582617 . _:b611582610 . _:b611582611 . _:b611582620 . _:b611582621 . _:b611582616 . _:b611582622 . _:b611582623 . . _:b611582616 . _:b611582617 . _:b54526070 . _:b611582619 . _:b611582618 . _:b611582843 . _:b611582619 . _:b611582596 . _:b611582597 . _:b611583037 . _:b611582618 . . _:b611582598 . . _:b611582599 . . _:b611582592 . _:b611582593 . _:b611582629 . _:b611582594 . _:b611582595 . _:b611582604 . _:b611582605 . _:b611582628 . _:b611582523 . . _:b611582606 . _:b611582607 . _:b611582600 . _:b54526064 . _:b611582601 . _:b611582631 . _:b611582602 . _:b611582603 . _:b54525870 . _:b611582580 . _:b54525926 . _:b611582849 . _:b611582581 . _:b611582630 . _:b611582582 . _:b54525891 "Several studies have also demonstrated efflux of T cells and APC from the CSF into deep cervical lymph nodes [47, >>50<<, 51, 66, 101]." . _:b611582583 . _:b611582576 . _:b54525880 "This pathway was demonstrated in humans in 1912 [148] and has more recently been confirmed in more detail in rats and other mammals, including humans [65, 69]. CSF from the spinal subarachnoid space drains to lumbar lymph nodes [>>69<<]." . _:b611582577 . _:b54525990 . _:b611582625 . _:b611582578 . _:b611582579 . _:b611582588 . _:b611582589 . _:b611582624 . _:b611582590 . _:b611582591 . _:b54525869 . _:b611582555 . _:b611582584 . _:b611582585 . _:b611582627 . _:b611582586 . _:b611582587 . _:b611582564 . _:b611582565 . _:b611582626 . _:b611582566 . . _:b611582567 . _:b611582560 . _:b611582561 . _:b611582888 . _:b611582637 . _:b611582562 . _:b611582563 . _:b611582572 . _:b611582573 . _:b611582636 . _:b611582574 . . _:b611582575 . _:b611582568 . _:b611582569 . _:b611582639 . _:b611582570 . _:b54525954 "[123, 131] together with the presence of lymph nodes within the carotid sheath just below the base of the skull in humans strongly suggest that ISF and solutes leave artery walls in the neck to drain to adjacent cervical lymph nodes [>>30<<]. Quantitative studies of lymphatic drainage from the brain have shown that the speed of drainage is comparable to lymphatic drainage from other organs [131]." . . _:b611582571 . _:b611582820 . _:b611582548 . _:b54526025 "In fact, live cell-imaging studies with activation-driven biosensors are able to demonstrate that T cells recognize their cognate antigen on these APC [>>80<<, 92] (the cognate antigen is the antigen that the T cell first encountered and which bound to its receptor and resulted in the cell proliferation and differentiation that generated the population of T cells sensitized to that antigen)." . _:b611582549 . _:b54526008 "express the chemokine receptor CCR6 would appear to initiate EAE by crossing the blood\u2013CSF barrier in the choroid plexus by engaging CCL20, which is produced by choroid plexus epithelial cells, but not by endothelial cells of the BBB [>>112<<]. With the ventricular CSF, the CD4+ Th17 cells seem to travel to the leptomeningeal (subarachnoid) spaces, where they accumulate and trigger neuroinflammation [111, 112] (Fig." . _:b54525908 . _:b611582638 . _:b611582550 . _:b611582551 . _:b54525875 "A further proportion of CSF drains to regional lymph nodes via nasal lymphatics and dural lymphatics and via lymphatic vessels associated with cranial and spinal nerve roots [11, >>33<<, 65, 69, 81] (Fig." . _:b611582544 . _:b611582545 . _:b611582633 . _:b611582546 . _:b54526060 . _:b611582547 . _:b611582556 . _:b611582557 . _:b611582632 . _:b611582558 . _:b611582559 . _:b611582552 . _:b611582553 . _:b611582635 . _:b611582554 . _:b611582555 . _:b611582907 . _:b611582532 . . _:b611582634 . _:b611582533 . _:b611582534 . _:b611582535 . _:b611582528 . _:b611582529 . _:b611582645 . _:b611582530 . _:b54526045 "in the cerebral cortex suggests that the diffusion of soluble agents may either pass from CSF into brain [57], or agents, such as cytokines, may defuse from the brain into the CSF and attract inflammatory cells to the subarachnoid space [>>8<<]." . . . _:b611582531 . _:b611582540 . _:b611582832 . _:b611582541 . _:b611582825 . _:b611582644 . _:b611582542 . _:b54526042 . . _:b611582543 . . _:b611582536 . _:b611582537 . _:b611582647 . . . _:b611582538 . _:b611582539 . _:b611582516 . _:b611582517 . _:b611582646 . _:b611582518 . _:b611582519 . _:b611582512 . _:b611582421 . _:b611582513 . _:b611582641 . _:b611582514 . _:b611582515 . _:b611582524 . _:b611582525 . _:b611582640 . _:b611582526 . _:b54525902 . _:b611582527 . _:b611582520 . _:b611582521 . _:b611582643 . _:b611582522 . _:b611582523 . _:b54525854 . _:b611582500 . _:b611582501 . _:b611582642 . _:b611582502 . _:b611582503 . _:b611582496 . _:b611582497 . _:b611582653 . _:b611582498 . _:b611582499 . _:b54525852 . _:b611582508 . _:b611582509 . _:b611582652 . _:b611582510 . . _:b611582511 . _:b611582504 . . . _:b611582505 . _:b611582655 . _:b611582506 . _:b611582507 . _:b611582484 . _:b611582485 . _:b611582654 . _:b611582486 . _:b611582487 . _:b54526002 "Live cell-imaging studies have provided evidence for the migration of encephalitogenic CD4+ Th 1 cells across leptomeningeal vessels associated with the spinal cord and the brain [13, >>107<<, 134]. Migration is achieved by engaging constitutively expressed VCAM-1 on the BBB endothelium with activated \u03B14\u03B21-integrins expressed on the surface of the activated CD4+ Th1 cells [107, 134] (Fig." . _:b611582480 . _:b611582481 . _:b611582649 . _:b611582482 . _:b611582483 . _:b611582492 . . _:b54526037 . _:b611582648 . _:b611582493 . . _:b611582494 . _:b611582495 . _:b611582898 . _:b611582488 . . _:b611582489 . _:b611582651 . _:b611582490 . _:b611582491 . _:b611582468 . _:b611582469 . _:b611582650 . . _:b611582470 . _:b611582471 . _:b611582464 . _:b611582465 . _:b611582661 . _:b611582466 . _:b611582467 . _:b611582476 . _:b611582512 . . _:b611582660 . _:b611582477 . _:b611582478 . _:b611582479 . _:b611582472 . _:b611582449 . _:b611582663 . _:b611582473 . _:b611582474 . _:b54525943 "the artery wall [24]. This defined the drainage route for ISF as an intramural perivascular pathway. In the normal brain, there are no actual \u201Cperivascular spaces\u201D around arteries, as they enter the cerebral cortex (Fig.\u00A04) [>>90<<, 137, 146]. The drainage route for ISF and solutes is along pathways within the tunica media of arteries and not along perivascular spaces (Fig." . _:b611582475 . _:b611582941 . _:b611582964 . _:b611582965 . _:b611582662 . _:b611582966 . _:b611582850 . _:b611582967 . _:b611582960 . _:b611582961 . _:b611582657 . _:b611582962 . _:b611582963 . _:b611582972 . _:b611582720 . _:b611582656 . _:b611582973 . _:b611582974 . _:b611582975 . _:b611582968 . _:b611582969 . _:b611582659 . _:b611582970 . _:b611582971 . . _:b611582948 . . _:b611582658 . _:b611582949 . _:b611582950 . _:b611583015 . _:b611582951 . _:b611582944 . _:b611582945 . _:b611582669 . _:b611582946 . . _:b611582947 . _:b611582956 . _:b611582957 . _:b611582668 . _:b611582744 . _:b611582958 . _:b611582959 . _:b54525972 "When horseradish peroxidase or fluorescent tracers are infused into the cerebral CSF, they enter the surface of the brain along the outer aspects of penetrating arteries and mix with ISF in the ECS of the brain parenchyma [>>62<<, 113]. Entry of tracers in the CSF into the brain is along basement membranes between the outer pial coating of the artery and glia limitans [91] (Fig.\u00A04) and appears to be driven by arterial pulsations [62, 113]. Mixing of CSF with ISF" . _:b611582952 . _:b611582644 . _:b611582671 . _:b611582953 . . _:b611582954 . _:b611582955 . _:b611582932 . _:b611582933 . _:b611582670 . _:b611582934 . _:b611582935 . _:b611582928 . _:b611582929 . _:b611582665 . _:b611582930 . _:b611582600 . _:b611582931 . _:b611582940 . _:b611582941 . _:b611582664 . _:b611582942 . _:b611582943 . _:b54525962 . _:b611582936 . _:b611582937 . _:b611582667 . . _:b611582938 . _:b611582939 . _:b611582916 . _:b611582917 . _:b611582666 . _:b611582918 . . _:b611582919 . _:b611582912 . _:b611582913 . _:b611582677 . _:b611582914 . _:b611582915 . _:b611582924 . _:b611582925 . _:b611582676 . _:b611582926 . _:b611582927 . _:b611582920 . _:b611582921 . _:b611582679 . _:b611582922 . _:b611582923 . . _:b611582900 . . _:b611582678 . _:b611582901 . _:b611582902 . . _:b611582903 . _:b611582896 . _:b611582659 . _:b611582673 . . _:b611582897 . _:b611582898 . _:b611582899 . . . _:b611582908 . . _:b54525894 "Several studies have also demonstrated efflux of T cells and APC from the CSF into deep cervical lymph nodes [47, 50, 51, 66, >>101<<]. Moreover, myelin and axonal epitopes have been found in deep cervical lymph nodes after axonal injury and (autoimmune) demyelination [36, 40, 79, 93]. Although it can be emphasised that APC may drain with CSF to lymph nodes by various" . _:b611582672 . _:b611582909 . _:b611582910 . _:b611582471 . _:b611582911 . _:b611582904 . . . _:b54525861 "First, in a transgenic spontaneous EAE model driven by CD4+ T cells against MOG92-106, in which germfree conditions abolish disease induction, the cervical lymph nodes feature an ongoing MOG-specific germinal centre reaction [>>18<<]. Second, work from Lloyd and Dennis Kasper on how polysaccharide A from Bacteroides fragilis protects against EAE demonstrates increased numbers of regulatory T cells in cervical lymph nodes [98]. These studies underscore the importance" . . _:b611582675 . _:b611582905 . _:b611582906 . . _:b611582907 . _:b611582884 . _:b54526006 "Encephalitogenic T cells have also been shown to directly extravasate via the leptomeningeal microvessels into the subarachnoid space [>>13<<, 118] (Fig.\u00A05b)." . _:b611582885 . _:b611582674 . _:b611582886 . _:b611582887 . _:b611582880 . _:b611582881 . _:b611582685 . _:b611582882 . . _:b611582883 . . _:b611582892 . _:b611582893 . _:b611582684 . _:b611582894 . _:b611582895 . _:b611582888 . _:b611582889 . _:b611582687 . _:b611582890 . _:b611582891 . _:b611582868 . _:b54526000 "that have directly addressed the early migratory steps of T cells into the CNS have mostly been performed in the framework of EAE and have suggested three potential routes of entry for encephalitogenic T cells into the CNS (reviewed in [>>39<<]) (Fig.\u00A05)." . _:b611582869 . _:b54525939 . _:b611582686 . . _:b611582870 . _:b611582529 . _:b611582871 . _:b611582864 . . _:b611582681 . _:b611582865 . . _:b611582866 . . . _:b611582867 . _:b611582876 . _:b611582877 . _:b611582934 . _:b611582680 . _:b611582878 . _:b611582879 . _:b611582872 . _:b611582873 . _:b611582683 . . _:b611582874 . _:b611582875 . . _:b54526072 "The original experiments demonstrating immune privilege in the brain showed that skin grafts directly implanted into the brain survived, but were rejected when similar grafts were placed on the skin [>>86<<]. However, if grafts extended into the ventricles and thus the CSF, they were rejected [86]." . _:b611582852 . _:b611582853 . _:b611582841 . _:b611582682 . _:b611582854 . _:b611582855 . _:b611582848 . _:b611582849 . _:b611582693 . _:b611582541 . _:b611582850 . _:b611582851 . . _:b611582860 . _:b611582861 . _:b611582692 . _:b611582526 . _:b611582862 . _:b611582863 . _:b611582856 . _:b611582857 . _:b611582695 . _:b611582858 . _:b611582859 . _:b611582836 . _:b54525878 "It is estimated that at least 50\u00A0% of CSF drains into lymphatics in some mammals, [>>33<<] but the proportion in humans is still unknown [65]." . . _:b611582694 . _:b611582837 . . _:b611582838 . _:b611582839 . _:b611582832 . _:b611582833 . _:b611582689 . _:b611582834 . _:b611582835 . _:b611582844 . _:b54525963 . _:b611582845 . _:b611582913 . _:b611582688 . _:b611582846 . . _:b611582847 . _:b611582840 . _:b611582841 . _:b611582691 . _:b611582599 . _:b611582842 . _:b611582843 . _:b611582661 . _:b611582820 . _:b611582821 . _:b611582690 . _:b611582822 . _:b611582823 . _:b54525977 . _:b611582816 . _:b611582817 . _:b611582701 . _:b611582818 . _:b611582819 . _:b54525976 . _:b611582981 "2"^^ . _:b611582828 . _:b611582829 . _:b611582700 . . _:b611582830 . _:b611582831 . _:b611582980 "2"^^ . _:b611582824 . _:b54525966 . _:b611582825 . _:b611582703 . _:b611582826 . _:b611582830 . _:b611582562 . _:b54525978 . _:b611582983 "2"^^ . _:b611582827 . _:b611582804 . _:b611582805 . _:b54525912 "The movement of water mixed with the movement of soluble metabolites results in the flow of ISF [2, >>3<<]. ISF drains from the ECS of the CNS parenchyma by entering capillary basement membranes and then draining along the basement membranes of cerebral arteries by bulk flow, as indicated by physiological tracer experiments [24]. Bulk flow of" . _:b611582702 . _:b611582806 . _:b611582807 . _:b54525932 "The pia mater prevents particles and erythrocytes [>>60<<] and, probably, neurotransmitters [41] in the CSF from entering perivascular compartments of the brain, but the exact degree of selective permeability to solutes of the pia mater and underlying glia limitans is not known." . _:b611582982 "2"^^ . . _:b611582800 . _:b611582801 . _:b611582697 . _:b611582802 . _:b611582803 . _:b611582977 "2"^^ . _:b611582812 . . _:b611582813 . _:b611582696 . _:b611582814 . _:b611582815 . _:b54525922 . _:b611582976 "2"^^ . _:b611582808 . _:b54525877 "A further proportion of CSF drains to regional lymph nodes via nasal lymphatics and dural lymphatics and via lymphatic vessels associated with cranial and spinal nerve roots [11, 33, 65, 69, >>81<<] (Fig.\u00A01). It is estimated that at least 50\u00A0% of CSF drains into lymphatics in some mammals, [33] but the proportion in humans is still unknown [65]." . _:b611582809 . _:b611582699 . _:b611582810 . _:b611582811 . _:b611582979 "2"^^ . . _:b611582788 . _:b611582789 . _:b611582698 . . _:b611582790 . _:b611582791 . _:b54525830 "As a sequel to the grafting experiments, it was shown that if the same allografts were subsequently grafted on to the skin, allografts in the brain were rapidly rejected [29, >>86<<]. It appears, therefore, that immunization in peripheral tissues precipitates immunological rejection of foreign tissue in the CNS. The description of immune privileged sites as those in which: \u201Cgrafts transplanted to them are in some way" . _:b611582978 "2"^^ . _:b611582784 . _:b611582785 . _:b611582709 . _:b611582786 . _:b611582787 . _:b611582989 "2"^^ . _:b611582796 . . _:b611582708 . _:b611582797 . _:b611582798 . _:b611582799 . _:b611582988 "2"^^ . . _:b611582792 . _:b611582793 . _:b611582711 . _:b611582794 . _:b611582795 . _:b611582991 "2"^^ . _:b611582772 . _:b611582773 . _:b611582710 . . _:b611582774 . _:b611582775 . _:b611582990 "2"^^ . _:b611582768 . _:b54525956 . _:b611582769 . _:b611582705 . _:b611582770 . _:b611582771 . _:b54525972 . _:b611582985 "2"^^ . _:b611582780 . _:b611582781 . . _:b611582704 . _:b611582782 . _:b611582783 . _:b611582984 "2"^^ . _:b611582776 . _:b611582646 . _:b611582777 . _:b611582707 . _:b611582778 . _:b611582779 . _:b54525974 . _:b611582987 "2"^^ . _:b611582756 . _:b611582757 . _:b611582706 . _:b611582758 . _:b611582759 . _:b54525984 "Furtado et al. [>>44<<] had similar results upon extirpation of deep and superficial cervical lymph nodes in a transgenic spontaneous EAE model, as did Phillips et al. [106] in a cryolesion-enhanced model of cerebral EAE." . _:b54525878 . _:b611582986 "2"^^ . _:b611582752 . _:b611582753 . _:b611582717 . _:b611582754 . _:b611582755 . _:b611582997 "2"^^ . _:b611582764 . _:b54525894 . _:b611582765 . _:b611582716 . _:b611582766 . _:b611582767 . _:b611582996 "2"^^ . _:b611582760 . _:b54525833 "One further point that has been emphasised is that immune privilege does not apply to the meninges and CSF spaces [>>45<<]. If foreign tissue grafted into the brain enters the ventricles, it is rejected [45, 85]." . _:b611582761 . _:b611582719 . _:b611582762 . . _:b54525875 . _:b611582999 "2"^^ . _:b611582763 . _:b611582740 . _:b611582741 . _:b611582718 . _:b611582742 . _:b611582743 . _:b611582998 "2"^^ . _:b611582736 . _:b611582737 . _:b611582713 . . _:b611582738 . _:b611582739 . _:b611582993 "2"^^ . _:b611582748 . _:b54526003 "Live cell-imaging studies have provided evidence for the migration of encephalitogenic CD4+ Th 1 cells across leptomeningeal vessels associated with the spinal cord and the brain [13, 107, >>134<<]. Migration is achieved by engaging constitutively expressed VCAM-1 on the BBB endothelium with activated \u03B14\u03B21-integrins expressed on the surface of the activated CD4+ Th1 cells [107, 134] (Fig." . _:b611582749 . _:b611582833 . _:b611582712 . . _:b611582782 . _:b611582750 . . _:b611582992 "2"^^ . _:b611582751 . _:b611582744 . _:b611582745 . _:b611582715 . _:b611582746 . _:b611582747 . _:b611582995 "2"^^ . _:b611582724 . _:b54525924 . _:b611582725 . _:b611582714 . _:b611582726 . _:b611582727 . _:b611582994 "2"^^ . . _:b611582720 . _:b611582721 . _:b611582722 . _:b611582723 . _:b611583005 "2"^^ . _:b611582732 . _:b611582733 . _:b54525956 . _:b611582734 . _:b611582735 . _:b611583004 "2"^^ . _:b611582728 . _:b611582729 . _:b54525957 . _:b611582983 . _:b611582730 . _:b611582731 . _:b611583007 "2"^^ . _:b611582985 . _:b54525958 . _:b611583040 . _:b611583006 "2"^^ . _:b54525959 . _:b611583001 "2"^^ . _:b54525952 . _:b611583000 "2"^^ . _:b54525953 . _:b54526070 "Age-related changes in cerebral arteries impair intramural perivascular drainage of ISF [54], and this may be a trigger for the amyloid cascade, loss of homeostasis and propagation of tau protein in the brain in Alzheimer\u2019s disease [>>139<<]." . _:b611582879 . _:b611583003 "2"^^ . _:b54525954 . _:b611583002 "2"^^ . _:b54525955 . . . _:b54526025 . _:b611583013 "2"^^ . _:b54525957 . _:b54525964 . _:b611583012 "2"^^ . _:b611582894 . _:b54525965 . . _:b611583015 "2"^^ . _:b611582511 . _:b611582574 . . _:b54525966 . . _:b611583014 "2"^^ . _:b54525967 . _:b54525848 "Such intramural perivascular basement membrane pathways are not large enough to allow the traffic of APC to regional lymph nodes and this may be a key factor in inducing immune privilege in the parenchyma of the CNS [>>24<<, 26].Fig." . _:b611583009 "2"^^ . _:b54525960 . _:b611582547 . _:b54525828 "privilege for the CNS arose from experiments by Shirai nearly 100\u00A0years ago in which foreign homologous tissues were grafted to the brain and survived for prolonged periods; the concept was further emphasised by Medawar in 1948 [29, >>86<<]. Nevertheless, immunological reactions do occur within the CNS particularly in association with infections by microorganisms and with diseases, such as multiple sclerosis (MS), that have an autoimmune component." . . _:b611583008 "2"^^ . _:b54525961 . _:b611582972 . _:b611583011 "2"^^ . _:b611582746 . _:b54525962 . _:b611582627 . _:b611583010 "2"^^ . _:b611582857 . _:b54525963 . . _:b611583021 "2"^^ . _:b54525972 . . . _:b611583020 "2"^^ . _:b611582474 . _:b54525973 . . _:b611582660 . _:b611583023 "2"^^ . _:b54525828 . _:b54525974 . _:b611583022 "2"^^ . _:b54525975 . _:b611582837 . _:b611583017 "2"^^ . _:b54525830 . _:b54525968 . _:b611583016 "2"^^ . . _:b54525969 . _:b611583019 "2"^^ . _:b54526015 . _:b54525970 . . _:b611583018 "2"^^ . _:b54525971 . _:b611583048 . . _:b54525841 . _:b611583029 "2"^^ . . _:b611582745 . _:b54525898 "Moreover, myelin and axonal epitopes have been found in deep cervical lymph nodes after axonal injury and (autoimmune) demyelination [36, 40, 79, >>93<<]. Although it can be emphasised that APC may drain with CSF to lymph nodes by various routes, the migration of APC from brain parenchyma with ISF along narrow intramural periarterial pathways is highly unlikely (see section on \u201CIntramural" . _:b54525980 . . _:b54525993 "However, recent studies performed in a Lewis rat model of EAE have shown that the majority of intravenously inoculated encephalitogenic T-cell blasts do not directly cross CNS microvessels, but rather accumulate in the lung [>>43<<, 100]. In the lung and its draining lymph nodes, the T-cell blasts were found to profoundly reprogram their gene expression profile, i.e., they upregulated a migratory program involving adhesion molecules, motility factors, and chemokine" . _:b54525907 . _:b611583028 "2"^^ . _:b611582590 . _:b611582842 . . _:b54525981 . . _:b611583031 "2"^^ . _:b54525982 . _:b54526013 "In healthy individuals, it is mostly central memory T cells and B cells and low numbers of innate immune cells that are detected in the CSF [7, 46, >>71<<, 111]. This further underscores the ability of activated T and B cells to breach the outer brain barriers in the absence of neuroinflammation and perform immunosurveillance of the CNS by entering the CSF spaces." . _:b611582638 . _:b611583030 "2"^^ . _:b54525983 . _:b611583025 "2"^^ . _:b54525976 . _:b611583024 "2"^^ . _:b611582648 . _:b54526047 "Although CD8 T cells contribute to immune surveillance of the CNS [>>22<<] and are key players in neuroinflammation [117], little is known about the cellular and molecular mechanisms involved in the migration of CD8 T cells into the CNS." . _:b54525977 . _:b611583027 "2"^^ . _:b611583108 . _:b611583109 . _:b54525978 . . _:b611583110 . _:b611583111 . _:b611583026 "2"^^ . _:b611583104 . . _:b611583105 . _:b54525979 . _:b611583106 . _:b611583107 . _:b611583037 "2"^^ . _:b611583116 . _:b611583117 . _:b54525988 . _:b611582774 . _:b611583118 . _:b611583119 . _:b611583036 "2"^^ . _:b611583112 . _:b611583113 . _:b54525989 . _:b611583114 . _:b611583090 . _:b611583115 . _:b54526038 "Similar mechanisms for trafficking across the BBB have also been shown for myeloid cells, including DC; this applies especially to the predominant role for \u03B14-integrins [42, >>63<<]. These findings have been translated to clinical use by treating relapsing-remitting MS with the humanized anti-\u03B14-integrin antibody natalizumab [127]." . _:b611583039 "2"^^ . _:b611583092 . _:b611583093 . _:b54525990 . _:b611583101 . _:b611583094 . . _:b611583095 . _:b54526000 . _:b611583038 "2"^^ . _:b611583088 . _:b611583089 . _:b54525991 . _:b611583090 . _:b611583091 . _:b611583033 "2"^^ . _:b611583100 . _:b611583101 . _:b54525984 . _:b611582486 . _:b611583102 . _:b611583103 . _:b611583032 "2"^^ . _:b611583096 . _:b611583080 . _:b611583097 . _:b54525985 . _:b611583098 . . . _:b611583035 "2"^^ . _:b611583099 . _:b611583076 . _:b611583077 . _:b611583078 . _:b54525986 . _:b611583079 . _:b611583034 "2"^^ . _:b611583072 . _:b611583073 . _:b54525987 . _:b611583074 . . _:b611583045 "2"^^ . _:b611583027 . _:b611583075 . _:b611583084 . _:b611583085 . _:b54525996 . _:b611583086 . _:b611583087 . _:b611583044 "2"^^ . _:b611582956 . _:b611583080 . _:b611582945 . _:b611583081 . _:b54525997 . _:b611582788 . _:b611583082 . _:b611583083 . _:b611583047 "2"^^ . _:b611583060 . _:b611583061 . _:b54525998 . _:b611583062 . _:b611583063 . _:b611583046 "2"^^ . _:b611582911 . _:b611583056 . _:b611583057 . _:b54525999 . _:b611583058 . _:b611583059 . _:b611583041 "2"^^ . _:b611583068 . . _:b54525992 . _:b611583069 . _:b611583070 . _:b611583071 . _:b611583040 "2"^^ . _:b611583064 . _:b611583065 . _:b54525993 . _:b611583076 . _:b611583066 . _:b611583067 . _:b54525836 "Expression of MHC class I and II molecules on microglial cells has been shown to be suppressed by the electrical activity of CNS neurons [>>94<<]. Disturbance of this activity during neurological disorders combined with cytokine activation of microglial cells leads to expression of MHC class I and class II molecules on their surfaces and subsequent presentation of antigen to" . _:b611583043 "2"^^ . _:b611583044 . . _:b54525994 . _:b611583045 . _:b611583046 . _:b611583047 . _:b54525988 . _:b611583042 "2"^^ . . _:b611583040 . _:b611583041 . _:b54525995 . _:b611583042 . _:b611583043 . _:b611583053 "2"^^ . _:b611583052 . _:b611583053 . _:b54526004 . _:b611583054 . _:b611583055 . _:b611583052 "2"^^ . _:b611583048 . _:b611583049 . _:b54526005 . _:b611582507 . _:b611583050 . _:b611583051 . _:b611583055 "2"^^ . . _:b611583028 . _:b611583029 . _:b54526006 . _:b611583030 . _:b611583031 . _:b611583054 "2"^^ . _:b611583024 . _:b611583025 . _:b54526007 . _:b611582991 . _:b611583026 . _:b54526074 "that activated T cells can enter the CSF in the leptomeningeal spaces irrespective of their antigen-specificity; this closely resembles the routine immunosurveillance of tissues performed by T cells in organs other than the CNS [>>118<<]. These observations emphasise that, although there is immune privilege in the CNS, such privilege does not extend to the ventricles and leptomeningeal spaces that contain CSF." . _:b611583027 . _:b611583049 "2"^^ . . _:b54525958 . _:b611583036 . _:b611583037 . _:b54526000 . _:b611583038 . . _:b611583048 "2"^^ . _:b611583039 . _:b611583032 . _:b611583033 . _:b54526001 . . _:b611583034 . . _:b611583051 "2"^^ . _:b611583035 . _:b611583012 . _:b611583013 . _:b54526002 . _:b54525866 . _:b611583014 . _:b611583015 . _:b611583050 "2"^^ . _:b611583008 . _:b611583009 . _:b54526003 . _:b611583010 . _:b611582637 . _:b611583061 "2"^^ . _:b611582765 . _:b611583011 . _:b611583020 . . _:b54526012 . _:b611583021 . . _:b611583022 . _:b611583023 . _:b611583060 "2"^^ . _:b611583016 . _:b611583017 . _:b54526013 . _:b611583018 . _:b611583019 . _:b611583063 "2"^^ . _:b611582996 . _:b54525914 "Bulk flow of ISF also occurs along the white matter fibre tracts [>>2<<]. Functionally, the ECS provides a pathway for the diffusion and exchange of ions and molecules between cells; the movement of ISF through the ECS surrounding the cells of nervous system depends on diffusion [96, 130]." . _:b611582556 . _:b54526014 . _:b611582860 . _:b611582997 . _:b611582998 . _:b611582999 . _:b611583062 "2"^^ . _:b611582992 . _:b611582993 . _:b54526015 . _:b611582780 . _:b611582994 . _:b611582995 . _:b611583057 "2"^^ . _:b611583004 . _:b611583005 . _:b54526008 . _:b611583006 . _:b611583007 . _:b611583056 "2"^^ . . _:b611583000 . _:b611583001 . _:b54526009 . _:b611583002 . _:b611583003 . _:b611583059 "2"^^ . _:b611582552 . _:b611582980 . . _:b54526010 . _:b611582981 . _:b611582982 . _:b611582679 . _:b611583058 "2"^^ . _:b611582983 . _:b611582976 . _:b611582977 . _:b54526011 . _:b611582978 . _:b611582979 . _:b611583069 "2"^^ . _:b611582988 . _:b611582989 . _:b54526020 . _:b611582990 . _:b611582878 . _:b611582991 . _:b611583068 "2"^^ . _:b611582984 . _:b611582985 . _:b54526021 . _:b611582986 . _:b611582987 . _:b611583071 "2"^^ . _:b611582904 . _:b611582546 . _:b54526022 . _:b611583115 . _:b611583070 "2"^^ . _:b611583109 . _:b611583088 . _:b54526023 . . _:b54525938 "In the brain, basement membranes have been reported to be secreted by meningeal cells and contribute to the migration and final positioning of neurons and to the differentiation of the laminar cortical pattern during development [>>89<<]. Basement membranes are composed mainly of collagen type IV, laminins, nidogens, fibronectin, and heparan sulphate proteoglycans. The basement membrane is a dynamic complex, capable of remodelling itself. In vitro, type IV collagen," . _:b611583065 "2"^^ . _:b54526016 . . _:b611583064 "2"^^ . _:b611582593 . _:b54526017 . _:b611582461 . . _:b611583067 "2"^^ . _:b611582838 . _:b54526018 . _:b611582444 . . _:b611583066 "2"^^ . _:b611582431 . _:b54526019 . _:b611583077 "2"^^ . _:b611582643 . _:b54526028 . _:b54525921 "Individually, blood vessels in the mouse brain have a similar basic structure to those in the human brain [>>76<<]." . _:b611583076 "2"^^ . _:b611583056 . _:b54526029 . _:b611583079 "2"^^ . _:b54526030 . _:b611583078 "2"^^ . . _:b54526031 . _:b611583073 "2"^^ . _:b54525901 . _:b54526024 . _:b611582786 . . _:b611583072 "2"^^ . _:b611582730 . _:b54526025 . _:b611582797 . _:b611582895 . _:b611583075 "2"^^ . . _:b54526026 . _:b611583074 "2"^^ . _:b54526027 . _:b54525986 _:b54526052 . _:b611583085 "2"^^ . _:b54525986 _:b54526053 . . . _:b54526036 . . _:b54525986 _:b54526048 . _:b611583084 "2"^^ . . _:b54525986 _:b54526049 . _:b54525986 _:b54526050 . _:b54526037 . _:b54525986 _:b54526051 . _:b611583087 "2"^^ . _:b54526038 . . _:b611583086 "2"^^ . _:b611582952 . . _:b54526039 . _:b611582770 . . _:b611583081 "2"^^ . . _:b54526048 "Although CD8 T cells contribute to immune surveillance of the CNS [22] and are key players in neuroinflammation [>>117<<], little is known about the cellular and molecular mechanisms involved in the migration of CD8 T cells into the CNS." . . _:b54526032 . . _:b54525859 "Very recently, in back-to-back studies, the next generation sequencing was used to assess B-cell receptor repertoire in MS in peripheral blood versus CSF [104] and in brain versus cervical lymph nodes [82, >>128<<]. Stern and colleagues [128] found B-cell populations with sequences closely resembling the germline, dubbed founder events, which were highly represented in both the CNS and cervical lymph nodes." . _:b611583080 "2"^^ . _:b611582499 . _:b54526033 . _:b611583026 . _:b54526020 "In the framework of EAE, it has been shown that the recognition of their cognate antigen on these APC is prerequisite for the subsequent migration of CD4+ T cells across the glia limitans into the CNS parenchyma to cause clinical EAE [>>13<<]. Direct evidence for this scenario has been derived from live cell-imaging studies of the spinal cord leptomeningeal spaces." . _:b54525986 _:b54526028 . _:b611583083 "2"^^ . _:b54525986 _:b54526029 . _:b611582496 . _:b54525986 _:b54526030 . _:b54526034 . _:b54525928 "adhesion of the vascular smooth muscle cells to their basement membranes is essential for maintaining the integrity of the arterial wall and for recognizing and integrating the high variety of signals that modulate the cell function [>>126<<]." . _:b54525986 _:b54526031 . _:b54525986 _:b54526024 . _:b611583082 "2"^^ . _:b54525986 _:b54526025 . _:b54525986 _:b54526026 . _:b54526035 . _:b54525986 _:b54526027 . _:b611582865 . _:b54525986 _:b54526020 . _:b611583093 "2"^^ . _:b54525986 _:b54526021 . _:b611582571 . _:b54525986 _:b54526022 . _:b54526044 . _:b54525986 _:b54526023 . _:b611582725 . _:b54525986 _:b54526016 . _:b611583092 "2"^^ . _:b611582673 . _:b54525986 _:b54526017 . . _:b54525986 _:b54526018 . _:b54526049 . _:b54526045 . _:b54525986 _:b54526019 . _:b54525986 _:b54526044 . _:b54526035 "In addition, it has been proposed that the other adhesion molecules, such as ninjurin-1, ALCAM, and MCAM, participate in T-cell migration across the BBB [>>61<<]. A recent in vitro study showed that extensive crawling of encephalitogenic T cells against the blood flow is a unique characteristic when low levels of ICAM-1 are expressed on the BBB allowing the T cells to find sites for paracellular" . _:b611583095 "2"^^ . . _:b54525986 _:b54526045 . _:b54525986 _:b54526046 . _:b54526046 . _:b611582473 . _:b54525986 _:b54526047 . _:b54525986 _:b54526040 . _:b611583094 "2"^^ . _:b54525986 _:b54526041 . _:b54525986 _:b54526042 . _:b54526047 . _:b611582442 . _:b54525986 _:b54526043 . _:b54525986 _:b54526036 . _:b54525899 "the extracellular spaces (ECS) and then rapidly enter the basement membranes of cerebral capillaries and drain directly via basement membranes in the tunica media of arterioles and arteries out of the brain to cervical lymph nodes [>>24<<, 26, 33] (Figs.\u00A01, 2c, 3, 4)." . _:b611583089 "2"^^ . _:b54525986 _:b54526037 . _:b54525986 _:b54526038 . _:b54526040 . _:b54525986 _:b54526039 . . _:b54525986 _:b54526032 . _:b611583088 "2"^^ . _:b54525986 _:b54526033 . _:b611582813 . _:b54525986 _:b54526034 . _:b54526041 . _:b54525986 _:b54526035 . . _:b54525986 _:b54525996 . _:b54525919 . _:b611583091 "2"^^ . _:b54525986 _:b54525997 . _:b54525986 _:b54525998 . _:b54526042 . _:b54525986 _:b54525999 . _:b54525986 _:b54525992 . _:b611583090 "2"^^ . _:b54525986 _:b54525993 . . _:b54525986 _:b54525994 . _:b54526043 . _:b54525986 _:b54525995 . _:b54525986 _:b54525988 . _:b611583101 "2"^^ . . _:b54525986 _:b54525989 . _:b611582581 . _:b54525986 _:b54525990 . _:b54526052 . _:b54525986 _:b54525991 . _:b54526050 . . _:b611583100 "2"^^ . _:b611582592 . _:b54526053 . _:b54525986 _:b54525987 . _:b54525986 _:b54526012 . _:b611583103 "2"^^ . _:b54525986 _:b54526013 . _:b54525986 _:b54526014 . _:b54526054 . _:b54525986 _:b54526015 . _:b54525986 _:b54526008 . _:b611583102 "2"^^ . _:b54525986 _:b54526009 . _:b54525986 _:b54526010 . _:b54526055 . . _:b54525986 _:b54526011 . _:b54525986 _:b54526004 . _:b611583097 "2"^^ . _:b54525986 _:b54526005 . _:b54525986 _:b54526006 . _:b54526048 . _:b54525986 _:b54526007 . _:b611582798 . _:b54525986 _:b54526000 . _:b611583096 "2"^^ . _:b54525986 _:b54526001 . _:b54525986 _:b54526002 . _:b54526049 . . . . _:b54525986 _:b54526003 . _:b611583099 "2"^^ . _:b54525978 "The immunological significance of the convective tracer influx/glymphatic system [>>62<<, 113] is unclear." . _:b54525986 "efferent pathways between lymph nodes and the cns" . . _:b54526050 . _:b611583098 "2"^^ . _:b54525828 . _:b54526051 . _:b611582582 . _:b611583109 "2"^^ . _:b54525829 . _:b54526060 . _:b611583108 "2"^^ . _:b611582912 . _:b54526061 . _:b54525830 . _:b611582731 . _:b611583111 "2"^^ . _:b54525831 . _:b54526062 . . _:b611583110 "2"^^ . . _:b54526063 . _:b611583079 . _:b611583105 "2"^^ . _:b54525831 "of immune privileged sites as those in which: \u201Cgrafts transplanted to them are in some way partially or fully exempted from the normal rigours imposed by their histocompatibility status\u201D is a definition of a state of relative tolerance [>>12<<, 45]. One further point that has been emphasised is that immune privilege does not apply to the meninges and CSF spaces [45]." . _:b54526056 . _:b54526044 "The apposition of inflammatory cells in the CSF and demyelination in the cerebral cortex suggests that the diffusion of soluble agents may either pass from CSF into brain [>>57<<], or agents, such as cytokines, may defuse from the brain into the CSF and attract inflammatory cells to the subarachnoid space [8]." . _:b611583104 "2"^^ . _:b54526057 . _:b54525826 . _:b54525960 . _:b54525862 "Second, work from Lloyd and Dennis Kasper on how polysaccharide A from Bacteroides fragilis protects against EAE demonstrates increased numbers of regulatory T cells in cervical lymph nodes [>>98<<]. These studies underscore the importance of cervical lymph nodes for both T-cell and B-cell responses." . _:b611583025 . _:b54525905 "10\u00A0% contribution to the total volume of ISF, but recently, it has been proposed that a large fraction of ISF is derived from the blood, passing through the capillary endothelium and driven by Na, K ATPase with water following passively [>>2<<]. In addition to water, ISF consists of tissue metabolites and secreted proteins." . _:b611583107 "2"^^ . _:b54525827 . _:b54526058 . . _:b611583106 "2"^^ . _:b54525836 . _:b54526059 . _:b611583117 "2"^^ . _:b54525980 _:b54525981 . _:b54525980 _:b54525982 . _:b54526068 . _:b54525837 . _:b54525980 _:b54525983 . _:b611583116 "2"^^ . . _:b54526069 . _:b54525838 . . _:b611582452 . _:b611583119 "2"^^ . _:b54525839 . _:b54526070 . _:b611582824 . _:b611583118 "2"^^ . _:b54525832 . _:b54526071 . . _:b54525865 "DCs first crawl along the lymphatic endothelium using specific adhesive interactions, e.g., the cytokine CCL21, before they detach and are passively transported to the regional lymph nodes in the larger calibre lymphatic vessels [>>97<<, 115]. Once they have arrived in the lymph node, DCs activate antigen-specific T cells that in turn proliferate and reach the blood stream via the efferent lymphatic vessels. The activation of B cells is mediated by the binding of soluble" . _:b611583113 "2"^^ . _:b54525833 . _:b54526064 . . _:b611582708 . _:b611583112 "2"^^ . _:b611582465 . _:b54526065 . _:b54525834 . _:b611583115 "2"^^ . . . _:b54525835 . _:b54526066 . . _:b611583114 "2"^^ . . _:b611582462 . _:b54526067 . _:b54525844 . _:b611582681 . _:b611582868 . _:b54525845 . _:b611582872 . _:b54525935 "There are regional differences in the structure of arteries within the brain as shown by the enlarged perivascular spaces that develop with age around arteries in the basal ganglia [109] and white matter [>>140<<]; the perivascular spaces are enclosed by two layers of leptomeninges in these regions of the brain [109]." . . _:b54525846 . _:b54525847 . _:b54525847 "contrast to CSF, ISF drains from the brain parenchyma to cervical lymph nodes along very narrow, restricted pathways that comprise 100\u2013150\u00A0nm-thick basement membranes in the walls of cerebral capillaries, arterioles, and arteries [24, >>26<<] (Fig.\u00A01). Such intramural perivascular basement membrane pathways are not large enough to allow the traffic of APC to regional lymph nodes and this may be a key factor in inducing immune privilege in the parenchyma of the CNS [24, 26]." . _:b54525980 _:b54525984 . . . _:b54525980 _:b54525985 . _:b54525840 . . _:b54525841 . _:b54526072 . _:b611582727 . _:b611583117 . _:b611582503 . _:b611582650 . _:b54526073 . _:b54525842 . _:b54525843 . _:b54526074 . . . _:b54525852 . . _:b54525853 . _:b611582910 . _:b611582687 . _:b54525854 . . _:b54525855 . _:b54525848 . _:b611582554 . _:b54525849 . _:b611582670 . . _:b54525850 . . . _:b54525851 . _:b611582977 . _:b54525860 . _:b54526052 "Although \u03B14\u03B21-integrins contribute to B cell and myeloid cell entries into the CNS [>>63<<, 77], the precise entry routes and molecular mechanisms involved in their multi-step recruitment across the brain barriers remain to be explored." . . _:b54525861 . . . _:b54525862 . _:b54525892 "Several studies have also demonstrated efflux of T cells and APC from the CSF into deep cervical lymph nodes [47, 50, >>51<<, 66, 101]." . _:b611582527 . . _:b54525863 . . _:b54525871 "Both CSF and ISF drain to lymph nodes and are involved in immunological reactions within the CNS [>>34<<, 74, 106]." . _:b54525856 . . _:b54525857 . . _:b54525858 . _:b611583045 . _:b54525859 . _:b54526059 "By analogy, similar factors may modulate or reactivate autoimmune inflammation in MS [>>129<<]." . . _:b611582455 . _:b54525868 . _:b611583039 . _:b611582572 . _:b54526054 _:b54526068 . . _:b54526054 _:b54526069 . _:b54526054 _:b54526070 . _:b54525869 . _:b54526054 _:b54526064 . _:b54526054 _:b54526065 . _:b54525835 "If foreign tissue grafted into the brain enters the ventricles, it is rejected [45, >>85<<]." . _:b54526054 _:b54526066 . _:b54525870 . . _:b54526054 _:b54526067 . _:b54526054 _:b54526060 . _:b54526054 _:b54526061 . _:b54526054 _:b54526062 . _:b54525871 . _:b54526054 _:b54526063 . . _:b54526054 _:b54526056 . _:b54526054 _:b54526057 . _:b54526054 _:b54526058 . _:b54525864 . _:b54526054 _:b54526059 . _:b54525865 . _:b54526054 _:b54526055 . _:b54525866 . _:b54525867 . _:b611582929 . . _:b54525876 . _:b54525848 . _:b611582663 . _:b54525877 . _:b54525936 . _:b611583007 . _:b611582625 . _:b54525878 . _:b54526061 . _:b54525879 . _:b611582799 . _:b611583021 . . . _:b54525872 . _:b54525873 . _:b611583112 . _:b54525874 . _:b54526071 _:b54526072 . _:b54526071 _:b54526073 . _:b54526071 _:b54526074 . _:b54525875 . . _:b54526035 . _:b611582887 . _:b54525884 . . . _:b611583097 . _:b54525885 . . . _:b611582427 . . _:b54525886 . _:b54525846 . _:b611582959 . _:b54525887 . . . _:b54525880 . _:b54525881 . . _:b611583010 . _:b54525882 . _:b54526046 . _:b54525883 . _:b54525892 . _:b611583082 . . _:b54525893 . . _:b54525894 . _:b54525895 . . _:b54525888 . _:b54525889 . _:b611583093 . _:b54525890 . _:b54525863 "lymphatic drainage of systemic organs other than the cns" . _:b611582694 . _:b54525891 . _:b54525973 . _:b611582430 . _:b54525856 "Recent studies claim that in experimental stroke, autoimmunity does develop after massive release of CNS antigens, [>>133<<]. This follows up on studies by the same group demonstrating brain antigens in cervical lymph nodes of patients with stroke; there is some correlation between antigen load, type, and clinical outcome [108]." . _:b54525900 . _:b54525979 "The immunological significance of the convective tracer influx/glymphatic system [62, >>113<<] is unclear." . . _:b54525901 . _:b54526053 "Although \u03B14\u03B21-integrins contribute to B cell and myeloid cell entries into the CNS [63, >>77<<], the precise entry routes and molecular mechanisms involved in their multi-step recruitment across the brain barriers remain to be explored." . _:b54525975 . _:b54525902 . _:b54526026 . _:b611582877 . _:b54525903 . _:b54525934 . . _:b54525896 . _:b54525968 . . . _:b611582621 . _:b54525897 . . _:b611582587 . _:b611582607 . _:b54525876 "A further proportion of CSF drains to regional lymph nodes via nasal lymphatics and dural lymphatics and via lymphatic vessels associated with cranial and spinal nerve roots [11, 33, 65, >>69<<, 81] (Fig." . _:b54525898 . . _:b54525899 . _:b611582935 . . _:b54525908 . . _:b54525909 . _:b54525895 "Moreover, myelin and axonal epitopes have been found in deep cervical lymph nodes after axonal injury and (autoimmune) demyelination [>>36<<, 40, 79, 93]." . _:b54525910 . . _:b54525911 . . . _:b54525904 . _:b54526005 "Migration is achieved by engaging constitutively expressed VCAM-1 on the BBB endothelium with activated \u03B14\u03B21-integrins expressed on the surface of the activated CD4+ Th1 cells [107, >>134<<] (Fig.\u00A05a)." . _:b54525905 . _:b54525979 . _:b611583043 . _:b54525906 . . _:b54525907 . . . _:b54525916 . . . _:b54525917 . . _:b611583105 . _:b54525918 . . _:b54525919 . . _:b54525912 . _:b611582922 . . _:b54525913 . _:b611583116 . _:b54525949 "particles in the range of 15\u00A0nm\u20131\u00A0\u03BCm are injected into grey matter in the brain, they do not drain along intramural basement membranes, but track along the outside of arteries and separate the glia limitans from the vessel walls [24, >>147<<]. It was concluded from these studies that it was very unlikely that, due to their size, APC would be able to track along intramural arterial basement membranes from the brain to cervical lymph nodes [24]." . . _:b611582705 . _:b54525914 . _:b54526042 "In humans, the glia limitans on the surface of the CNS is much thicker than in rodents and consists of multiple layers of astrocyte processes [>>5<<]. Although lymphocytes and APC readily penetrate the delicate glia limitans around post-capillary venules in the human brain, the penetration of inflammatory cells through the thicker glia limitans on the surface of the brain and spinal" . _:b611582618 . _:b54525915 . _:b611582684 . _:b611583018 . _:b54525924 . . _:b611582815 . . _:b54525925 . . _:b54525926 . _:b611582445 . _:b611583003 . _:b54525927 . _:b611582668 . _:b54525920 . . . _:b54526014 "In healthy individuals, it is mostly central memory T cells and B cells and low numbers of innate immune cells that are detected in the CSF [7, 46, 71, >>111<<]. This further underscores the ability of activated T and B cells to breach the outer brain barriers in the absence of neuroinflammation and perform immunosurveillance of the CNS by entering the CSF spaces." . _:b54525921 . . _:b611583017 . _:b611582622 . _:b54525922 . _:b611582852 . _:b54525923 . _:b611583041 . _:b611582421 . _:b54525932 . _:b611582674 . _:b611582420 . _:b54525933 . _:b611582423 . _:b54525934 . _:b611582422 . _:b54525935 . _:b54526073 . _:b54525928 . _:b54525970 . _:b54526072 . . _:b54525929 . _:b611582419 . _:b54525930 . . _:b611582738 . . _:b611582855 . _:b611582418 . _:b54525931 . _:b54525913 . . _:b54525909 . _:b611582429 . _:b54525940 . _:b54525839 . _:b611582695 . _:b611582428 . _:b54525941 . . _:b611582950 . _:b611582726 . _:b54525942 . _:b611582853 . _:b611582431 . . _:b611582430 . _:b54525943 . _:b611582551 . _:b54525955 "Quantitative studies of lymphatic drainage from the brain have shown that the speed of drainage is comparable to lymphatic drainage from other organs [>>131<<]. The quantity and volume of fluorescent tracers injected to outline the basement membrane pathways for drainage of ISF from grey matter [24] are too small to be detected in the cervical lymph nodes. However, there is further evidence of" . _:b54525982 "In contrast, the spleens of adjuvant controls and untreated monkeys were almost completely devoid of cells containing myelin basic protein and proteolipid protein [>>36<<]." . _:b611582425 . _:b54525936 . . _:b611582423 . _:b54525954 . _:b611582424 . _:b54525937 . _:b611582464 . _:b611582423 "11"^^ . . _:b611582427 . _:b54525938 . _:b611582419 "22"^^ . _:b611582422 "12"^^ . _:b611582418 "28"^^ . _:b611582426 . _:b54525939 . _:b611582992 . _:b54525945 "4) [90, 137, >>146<<]. The drainage route for ISF and solutes is along pathways within the tunica media of arteries and not along perivascular spaces (Fig." . _:b611582421 "12"^^ . _:b611582437 . _:b54525948 . _:b611583098 . _:b611582420 "12"^^ . _:b611582436 . _:b54525949 . _:b54525897 . _:b611582439 . _:b54525950 . _:b54525930 "of desmosomes and small nexus junctions, are reflected from the surface of the brain and spinal cord to coat arteries and veins in the SAS, thus separating CSF in the subarachnoid space from the CNS and perivascular compartments [95, >>137<<] (Fig.\u00A04). Furthermore, leptomeningeal cells form a perivascular sheath around arteries, as they enter the brain." . _:b611582438 . _:b54525951 . . _:b611582433 . _:b54525944 . . _:b54525961 "constitute the extracellular matrix appear to have a role in the properties of the cerebrovascular basement membranes [83] and may be involved in the impaired drainage of fluid and solutes from the brain associated with hyperlipidaemia [>>53<<]." . _:b54526028 . . _:b611582717 . _:b611582432 . _:b54525945 . _:b54525899 . _:b611582435 . _:b54525946 . _:b611582430 "9"^^ . . _:b611582434 . _:b54525947 . _:b611582431 "9"^^ . _:b611582696 . _:b611582445 . _:b611582428 "9"^^ . . _:b611582444 . _:b611582429 "9"^^ . _:b611582427 "10"^^ . _:b611582447 . _:b611582426 "10"^^ . _:b611582791 . _:b611582545 . _:b54525939 "In vitro, type IV collagen, laminin, and fibronectin are capable of assembly into a protein network resembling basement membranes and are interdependent in the formation of the basement membranes [>>145<<]." . _:b611582446 . _:b611582425 "11"^^ . _:b611582597 . _:b54526043 "For example, plaques of demyelination on the surface of the cerebral cortex in MS may be associated with inflammatory cells in the overlying subarachnoid space [>>57<<]. However, the penetration of such cells across the glia limitans is not seen. The apposition of inflammatory cells in the CSF and demyelination in the cerebral cortex suggests that the diffusion of soluble agents may either pass from CSF" . _:b611582441 . . _:b611582424 "11"^^ . _:b611582440 . . _:b611582438 "7"^^ . _:b611582568 . _:b611582443 . _:b611582821 . _:b611582439 "7"^^ . _:b611582790 . _:b611582442 . _:b611582436 "7"^^ . _:b611582453 . . _:b611582437 "7"^^ . _:b611582766 . _:b611582452 . _:b611582937 . _:b611582434 "8"^^ . _:b611582455 . _:b611583019 . _:b611582435 "7"^^ . _:b611582454 . . _:b611582539 . _:b611582432 "9"^^ . _:b611582449 . _:b54525836 . _:b54525900 "the extracellular spaces (ECS) and then rapidly enter the basement membranes of cerebral capillaries and drain directly via basement membranes in the tunica media of arterioles and arteries out of the brain to cervical lymph nodes [24, >>26<<, 33] (Figs.\u00A01, 2c, 3, 4)." . _:b611582433 "8"^^ . _:b611582448 . _:b611582446 "6"^^ . _:b54525947 . _:b54525884 . _:b611582598 . _:b611582451 . _:b611582447 "6"^^ . _:b54525946 . _:b611582450 . . _:b611582450 . . _:b611582444 "6"^^ . . _:b611582461 . _:b611582445 "6"^^ . _:b611582678 . _:b54526010 "With the ventricular CSF, the CD4+ Th17 cells seem to travel to the leptomeningeal (subarachnoid) spaces, where they accumulate and trigger neuroinflammation [111, >>112<<] (Fig.\u00A05c)." . _:b611582460 . _:b611582442 "6"^^ . _:b611582463 . _:b611582443 "6"^^ . _:b54525950 . _:b54525862 . _:b611582462 . _:b611582440 "6"^^ . _:b611582748 . _:b611582457 . _:b611582441 "6"^^ . _:b54525948 . . _:b611582456 . . _:b611582454 "6"^^ . _:b54525885 "described first by Mascagni in 1787 in his study \u201CDe lymphaticis profundis capitis et colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et al. [121], Andres et al. [9], Cserr and Knopf [>>34<<], Kida et al. [69], and more recently by Aspelund et al. [11] and by Louveau et al. [81]." . . _:b611582459 . _:b611582455 "6"^^ . _:b54525896 . _:b611582458 . _:b611582452 "6"^^ . _:b611582453 "6"^^ . . . _:b611582450 "6"^^ . _:b611582994 . . _:b611582721 . . _:b54525942 . _:b54525918 "Diffusion through the ECS and bulk flow of ISF along perivascular drainage routes changes with age and in Alzheimer\u2019s disease [54, >>87<<]." . _:b611582451 "6"^^ . _:b54525934 "There are regional differences in the structure of arteries within the brain as shown by the enlarged perivascular spaces that develop with age around arteries in the basal ganglia [>>109<<] and white matter [140]; the perivascular spaces are enclosed by two layers of leptomeninges in these regions of the brain [109]." . _:b54525951 "serum albumin as a tracer suggest that once ISF and solutes have left the brain, they drain along the tunica media and the tunica adventitia of the major cerebral arteries, through the base of the skull to deep cervical lymph nodes [>>131<<] (Fig.\u00A02c)." . _:b611582482 . _:b611582699 . _:b611582448 "6"^^ . _:b54525941 . _:b611582973 . _:b611582449 "6"^^ . _:b54525940 . _:b611582920 . _:b611582418 . _:b54525958 . . . _:b611582714 . _:b54525998 . _:b611582461 "5"^^ . . . _:b611582460 "6"^^ . . . _:b611582463 "5"^^ . . _:b611582451 . . _:b611582462 "5"^^ . . _:b611582458 "6"^^ . _:b611582707 . _:b54525827 "immune privilege for the CNS arose from experiments by Shirai nearly 100\u00A0years ago in which foreign homologous tissues were grafted to the brain and survived for prolonged periods; the concept was further emphasised by Medawar in 1948 [>>29<<, 86]. Nevertheless, immunological reactions do occur within the CNS particularly in association with infections by microorganisms and with diseases, such as multiple sclerosis (MS), that have an autoimmune component." . . _:b611582459 "6"^^ . . _:b611582456 "6"^^ . _:b611582690 . _:b611583103 . _:b611582538 . _:b611582457 "6"^^ . . . . _:b611582903 . _:b611582873 . . . . . _:b611582666 . _:b611582441 . _:b54525868 "lymphatic drainage of the cns" . . . . _:b611582469 . _:b54525965 . . _:b54525964 . _:b611582981 . _:b54526039 "These findings have been translated to clinical use by treating relapsing-remitting MS with the humanized anti-\u03B14-integrin antibody natalizumab [>>127<<]." . . _:b54525914 . . _:b54526001 "Live cell-imaging studies have provided evidence for the migration of encephalitogenic CD4+ Th 1 cells across leptomeningeal vessels associated with the spinal cord and the brain [>>13<<, 107, 134]. Migration is achieved by engaging constitutively expressed VCAM-1 on the BBB endothelium with activated \u03B14\u03B21-integrins expressed on the surface of the activated CD4+ Th1 cells [107, 134] (Fig." . _:b611582932 . _:b611582533 . . . _:b54525835 . . _:b54525933 . _:b54525911 . _:b611582505 . . _:b54525905 . . _:b611582544 . _:b54525974 "4) and appears to be driven by arterial pulsations [>>62<<, 113]. Mixing of CSF with ISF is dependent upon the presence of astrocytic aquaporin 4 [62]." . _:b54525906 . . _:b611583077 . _:b611582775 . . . _:b54525851 "contributions of cervical lymph nodes to detrimental immunity in multiple sclerosis (MS) and EAE may seem rather obvious, it is important to point out that the cervical lymph nodes clearly can also mediate the induction of tolerance [>>88<<, 143]. For example, the injection of myelin basic protein into the CSF induces tolerance and prevents the subsequent induction of EAE [49]." . _:b54526028 "[118], but also for the consecutive expression of pro-inflammatory cytokine by the effector T cells that constitutes a crucial signal for the initiation of the parenchymal invasion of immune cells and the clinical autoimmune process [>>67<<]. The local T-cell activation triggers inflammatory events that lead to the upregulation of additional adhesion molecules and chemokines on endothelium at the BBB and epithelium at the blood\u2013CSF barrier, thus, allowing the recruitment of" . _:b611582892 . _:b54525866 "DCs first crawl along the lymphatic endothelium using specific adhesive interactions, e.g., the cytokine CCL21, before they detach and are passively transported to the regional lymph nodes in the larger calibre lymphatic vessels [97, >>115<<]. Once they have arrived in the lymph node, DCs activate antigen-specific T cells that in turn proliferate and reach the blood stream via the efferent lymphatic vessels." . _:b611582914 . _:b611583085 . . _:b611582543 . _:b611582623 . . _:b611582478 . _:b611582712 . . . . . _:b54525952 "The high levels of radioactive tracer and A\u03B2 in the walls of intracranial arteries and the very low levels of tracer and A\u03B2 in the walls of the carotid artery in the neck [>>123<<, 131] together with the presence of lymph nodes within the carotid sheath just below the base of the skull in humans strongly suggest that ISF and solutes leave artery walls in the neck to drain to adjacent cervical lymph nodes [30]." . _:b54526014 . _:b611582579 . _:b54525935 . "PMC0" . . . _:b54526009 . _:b54526073 "However, if grafts extended into the ventricles and thus the CSF, they were rejected [>>86<<]. It has also been shown by several groups and more recently directly by live cell imaging that activated T cells can enter the CSF in the leptomeningeal spaces irrespective of their antigen-specificity; this closely resembles the routine" . . _:b54526055 "This finding suggests that specific responses to CNS antigens are initiated within lymph nodes that drain the CNS [>>135<<]. Further evidence comes from the cryolesion-enhanced form of cerebral EAE in which the removal of deep cervical lymph nodes during the incubation period of EAE and at the same time as the cerebral cryolesion significantly reduces the" . _:b611583071 . _:b611582966 . . _:b611582947 . _:b611582534 . . _:b611582631 . _:b611583047 . _:b611582506 . _:b611583067 . _:b611582803 . . . . _:b54525952 . _:b54525941 "that tracers were co-localized with laminin in the basement membranes of capillaries and in the basement membranes in the tunica media of arteries at time intervals of 5\u201315\u00A0min after intracerebral injections into the caudate putamen [>>24<<] (Fig.\u00A03)." . . _:b611582602 . _:b611582968 . _:b611583011 . _:b611582882 . _:b54525879 "This pathway was demonstrated in humans in 1912 [148] and has more recently been confirmed in more detail in rats and other mammals, including humans [65, >>69<<]. CSF from the spinal subarachnoid space drains to lumbar lymph nodes [69]." . _:b54525863 . . . _:b54525868 . _:b611583075 . . . . . . _:b611583034 . . _:b54526017 "While the perivascular spaces around post-capillary venules harbour rare DCs [>>48<<], large numbers of macrophages are found in the subarachnoid spaces [13]." . _:b611582979 . _:b611582751 . _:b611582909 . _:b611582570 . . . _:b611582702 . _:b611583087 . _:b54525826 . . _:b54525922 "3) [91, >>110<<]. While the junctions between adjacent endothelial cells form unique zonulae occludentes that inhibit paracellular diffusion of solutes, the high number of pericytes embedded in brain capillary basement membranes inhibits transcellular" . . . . _:b611582942 . . _:b611582805 . . _:b54526047 . _:b611582810 . _:b611583060 . _:b611582713 . _:b54525882 "Two recent articles elegantly demonstrated functional lymphatic vessels in the dura mater of the mouse situated bilaterally along the superior sagittal sinus and draining through the cribriform plate into the nasal mucosa [11, >>81<<]. Lymph vessels of the dura mater were probably described first by Mascagni in 1787 in his study \u201CDe lymphaticis profundis capitis et colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et al." . _:b54525850 . _:b611582856 . _:b611582834 . . . . _:b611582806 . _:b54526069 "Age-related changes in cerebral arteries impair intramural perivascular drainage of ISF [>>54<<], and this may be a trigger for the amyloid cascade, loss of homeostasis and propagation of tau protein in the brain in Alzheimer\u2019s disease [139]." . _:b54526004 "Migration is achieved by engaging constitutively expressed VCAM-1 on the BBB endothelium with activated \u03B14\u03B21-integrins expressed on the surface of the activated CD4+ Th1 cells [>>107<<, 134] (Fig." . _:b54525879 . _:b611582812 . . _:b611582493 . _:b54525997 . _:b611582958 . . . _:b611582971 . _:b54525876 . . . _:b611582818 . . . _:b54525881 "Two recent articles elegantly demonstrated functional lymphatic vessels in the dura mater of the mouse situated bilaterally along the superior sagittal sinus and draining through the cribriform plate into the nasal mucosa [>>11<<, 81]. Lymph vessels of the dura mater were probably described first by Mascagni in 1787 in his study \u201CDe lymphaticis profundis capitis et colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et" . . _:b611582528 . _:b611582750 . _:b611582939 . _:b54525880 . . _:b54525886 . . . _:b611583029 . _:b54525908 "Tracer experiments and mathematical models show that ISF is eliminated from the brain by bulk flow along white matter fibre tracts and along perivascular pathways [32, >>119<<]." . . _:b611582896 . _:b54525958 "Impairment is associated with age-related changes in the artery walls and biochemical changes in vascular basement membranes [>>52<<\u201355]. It is also possible to block the perivascular drainage pathways along arterial basement membranes acutely as demonstrated by the impairment of drainage when Immune complexes lodge in arterial basement membranes [27]. Epigenetic" . _:b611582989 . _:b611582443 . _:b611582484 . . _:b611582828 . . _:b611583046 . _:b611582987 . . _:b611583032 . _:b54526021 "T cells having crossed the blood\u2013leptomeningeal barrier will encounter numerous macrophages distributed within the leptomeningeal 3D milieu. These cells actively scan their environment with their cell processes [>>13<<]. Effector T cells migrating within the leptomeningeal environment are in regular contact with these cells that constitutively express MHC class II molecules on their membrane surfaces and thus are able to present myelin antigens to the" . _:b54525887 . _:b54525924 "Fibrous astrocytes form end feet that completely surround the capillary surface: 40\u2013100\u00A0nm separate the astrocyte end feet from the endothelium and this space is occupied by basement membrane [>>38<<]. The layer of basement membrane produced by endothelial cells is distinct in its molecular structure from the basement membrane of the glia limitans produced by astrocytes, but the two basement membranes are fused. The capillary basement" . _:b611582845 . _:b611582515 . _:b611582706 . . _:b54525881 . . _:b611583054 . . . . _:b611582566 . _:b54526066 . . . _:b611582446 . _:b611582743 . . . _:b611582611 . . . _:b54526068 . _:b54525872 "Both CSF and ISF drain to lymph nodes and are involved in immunological reactions within the CNS [34, >>74<<, 106]." . _:b611582569 . _:b611582785 . _:b611583083 . . . . . _:b54525944 . _:b54525892 . . _:b54525842 . _:b54525874 . . _:b611582688 . _:b611582697 . _:b611582953 . . _:b611582619 . _:b611583000 . . . . _:b611582862 . . _:b54525886 "by Mascagni in 1787 in his study \u201CDe lymphaticis profundis capitis et colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et al. [121], Andres et al. [9], Cserr and Knopf [34], Kida et al. [>>69<<], and more recently by Aspelund et al. [11] and by Louveau et al. [81]." . _:b611582567 . . . . . . _:b611583118 . _:b611582711 . _:b54525873 . _:b54525987 "The deep cervical and lumbar lymph nodes have been shown to a function as lymph nodes that drain the CNS [>>34<<]. Thus, effector T and B cells specifically targeting CNS antigens could well be activated in cervical and lumbar lymph nodes and might be imprinted there with CNS-specific-trafficking programs similar to those described above for lymph" . _:b54525930 . _:b54525992 . . _:b54525869 "Of the two extracellular tissue fluids associated with the CNS, CSF is mainly located in the ventricles and subarachnoid spaces and has a total volume in humans of 140\u00A0mL [>>19<<]. The other fluid is ISF in the extracellular spaces of the brain and spinal cord parenchyma and amounts to 280\u00A0mL in humans [19]." . _:b611582752 . . _:b611582897 . _:b611583086 . _:b54526016 . _:b54526005 . . . _:b54525890 "Several studies have also demonstrated efflux of T cells and APC from the CSF into deep cervical lymph nodes [>>47<<, 50, 51, 66, 101]." . . . . _:b611582657 . _:b54525877 . _:b54525832 . _:b611582576 . _:b54526003 . . _:b54525833 . _:b611583073 . _:b54525834 . _:b54525837 "activity during neurological disorders combined with cytokine activation of microglial cells leads to expression of MHC class I and class II molecules on their surfaces and subsequent presentation of antigen to receptive T lymphocytes [>>13<<, 70, 80]. The adaptive response depends upon the presentation of antigen to lymphocytes by antigen-presenting cells (APC)." . _:b54526056 "form of cerebral EAE in which the removal of deep cervical lymph nodes during the incubation period of EAE and at the same time as the cerebral cryolesion significantly reduces the burden of EAE in the cerebral hemispheres [>>106<<]. Transfer of lymphocytes from animals with cryolesion-EAE resulted in EAE lesions that were predominantly in the cerebral hemispheres [73]." . _:b54526022 . _:b54525840 . _:b54526021 . _:b54526020 . _:b611582477 . _:b54525882 . _:b611582836 . _:b54526018 . . _:b611582521 . . _:b611582613 . _:b54525855 "As reviewed by Card et al. [>>28<<], lymphatic endothelium can play active roles in regulating host immunity." . . _:b54525889 "The capacity of the lymphatic drainage pathways for the CSF is reflected in experiments using particulate matter, such as Indian ink and Microfil [65, >>69<<]. Several studies have also demonstrated efflux of T cells and APC from the CSF into deep cervical lymph nodes [47, 50, 51, 66, 101]." . _:b611582530 . _:b611583092 . _:b54526053 . . _:b611582933 . _:b611582943 . _:b611582874 . _:b54525857 . . . _:b611582472 . . _:b611582763 . _:b54526057 "Transfer of lymphocytes from animals with cryolesion-EAE resulted in EAE lesions that were predominantly in the cerebral hemispheres [>>73<<]. These results suggest that lymphocytes from donors with cryolesion-EAE target the brain in recipient animals in preference to the spinal cord. This might be due to tissue-specific cues influencing the function of DC in the draining" . . . _:b611582829 . _:b611582767 . _:b54526034 . _:b611582997 . _:b54526033 . . _:b54525927 . . . . _:b611582463 . . _:b611583038 . _:b611582861 . _:b54525843 . _:b611582787 . _:b611582656 . _:b611582846 . . _:b54525845 . _:b611582990 . _:b54526018 "While the perivascular spaces around post-capillary venules harbour rare DCs [48], large numbers of macrophages are found in the subarachnoid spaces [>>13<<]. In addition, cells that express MHC class II (Kolmer or epiplexus cells) adhere as APC to the apical aspect of the choroid plexus epithelial cells that form the blood\u2013CSF barrier [78]. In the framework of EAE, it has been shown that the" . _:b611582871 . . . . . . _:b611582665 . . _:b611582578 . _:b54526029 . _:b54525884 "dura mater were probably described first by Mascagni in 1787 in his study \u201CDe lymphaticis profundis capitis et colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et al. [121], Andres et al. [>>9<<], Cserr and Knopf [34], Kida et al. [69], and more recently by Aspelund et al. [11] and by Louveau et al. [81]." . _:b611582497 . . . . _:b611582609 . . _:b54525929 . _:b611582651 . . . _:b611582927 . . _:b54526058 "a focal cortical cryolesion injury initially involve chemokines, such as the macrophage chemoattractants CCL2 (MCP-1) and CCL12 (MCP-5), and the activities of afferent and efferent neuronal connections with the site of damage [>>129<<]. By analogy, similar factors may modulate or reactivate autoimmune inflammation in MS [129]." . _:b54525942 "walls was very specific, as tracer was only in the basement membranes between the smooth muscle cells in the tunica media and not in the endothelial basement membranes or in the outer basement membrane encompassing the artery wall [>>24<<]. This defined the drainage route for ISF as an intramural perivascular pathway." . . _:b611582826 . . _:b611582620 . . _:b611582886 . _:b54525982 . . _:b611582954 . _:b611582924 . _:b54526045 . _:b54525889 . . _:b611582804 . . . _:b54525937 "Arteries in the cortex, on the other hand, have only one layer of encompassing leptomeningeal cells and do not have perivascular space [>>146<<] (Fig.\u00A04)." . . . _:b54525885 . _:b611583113 . _:b54526036 . . . _:b611582531 . . _:b611582734 . _:b54526032 . . _:b54526030 "Lack of T-cell activation by leptomeningeal macrophages will lead to T-cell detachment and their release into the CSF which flows largely driven by respiration rather than the cardiac cycle [37, >>118<<] in this space." . _:b611582848 . . . . _:b611582559 . _:b611582981 . . . _:b611582980 . . _:b611582823 . _:b611582946 . _:b611582983 . . _:b611582605 . . _:b611582982 . _:b611583069 . . _:b611582977 . . _:b611582858 . _:b611582976 . _:b611582979 . _:b54525888 . _:b611582595 . _:b611583028 . _:b611582978 . . _:b611582989 . . _:b54525871 . _:b611582988 . _:b54525868 _:b54525972 . _:b611583053 . _:b611582658 . _:b54525868 _:b54525973 . _:b54525868 _:b54525974 . _:b611582991 . _:b611582563 . _:b54525868 _:b54525975 . . _:b54525868 _:b54525968 . _:b54525868 _:b54525969 . _:b54525868 _:b54525970 . _:b611582990 . _:b54525868 _:b54525971 . _:b54525890 . _:b611582537 . _:b611582749 . _:b611582985 . . _:b54525868 _:b54525976 . _:b611582601 . _:b54525868 _:b54525977 . . _:b54525868 _:b54525978 . _:b611582984 . . _:b54525868 _:b54525979 . . _:b54525868 _:b54525956 . _:b54525883 . . _:b54525868 _:b54525957 . _:b611582469 "5"^^ . _:b611582987 . _:b54525868 _:b54525958 . _:b54525868 _:b54525959 . _:b54525868 _:b54525952 . . _:b54525868 _:b54525953 . _:b611582468 "5"^^ . _:b611582986 . _:b54525868 _:b54525954 . _:b54525868 _:b54525955 . _:b54525850 "tolerance" . _:b54525868 _:b54525964 . _:b54525868 _:b54525965 . _:b611582471 "5"^^ . _:b611582997 . _:b54525868 _:b54525966 . . _:b611583110 . _:b54525868 _:b54525967 . _:b611582716 . _:b54525868 _:b54525960 . _:b54525868 _:b54525961 . _:b611582470 "5"^^ . _:b611582996 . _:b54525868 _:b54525962 . _:b54525868 _:b54525963 . _:b54525898 . _:b611582465 "5"^^ . _:b611582999 . _:b611583033 . _:b611582464 "5"^^ . _:b611582998 . _:b611582753 . _:b611582467 "5"^^ . _:b611582993 . . _:b611582466 "5"^^ . _:b611582992 . _:b611582477 "5"^^ . _:b611582995 . . _:b611582476 "5"^^ . _:b611582994 . _:b54526051 . . _:b54525996 . _:b611582479 "4"^^ . _:b611583005 . _:b611582900 . _:b611582478 "4"^^ . _:b611583004 . _:b611582473 "5"^^ . _:b611583007 . . . . _:b611582683 . _:b611582472 "5"^^ . _:b611583006 . _:b611583050 . . _:b611582475 "5"^^ . _:b611583001 . _:b54526024 "leptomeningeal environment are in regular contact with these cells that constitutively express MHC class II molecules on their membrane surfaces and thus are able to present myelin antigens to the pathogenic effector T cells [13, 70, >>99<<]. In fact, live cell-imaging studies with activation-driven biosensors are able to demonstrate that T cells recognize their cognate antigen on these APC [80, 92] (the cognate antigen is the antigen that the T cell first encountered and" . _:b611582474 "5"^^ . _:b611583000 . . _:b611582940 . . _:b611582485 "4"^^ . _:b611583003 . . . _:b611582484 "4"^^ . _:b611583002 . _:b611582487 "4"^^ . _:b611582565 . _:b611583013 . _:b611582733 . _:b611582486 "4"^^ . _:b611583012 . . _:b611582481 "4"^^ . _:b611583015 . _:b54525984 . _:b611582480 "4"^^ . . . _:b611583014 . . _:b611582483 "4"^^ . _:b54525853 "For example, the injection of myelin basic protein into the CSF induces tolerance and prevents the subsequent induction of EAE [>>49<<]. Intranasal administration of antigen also drives tolerance through superficial cervical and internal jugular lymph nodes [143]." . _:b611583009 . _:b54526031 "expression of ICAM-1, VCAM-1, and de-novo expression of P-selectin and other adhesion molecules) is mediated by a multi-step cascade starting with P-selectin glycoprotein-1 (PSGL-1)-mediated T cell rolling on endothelial P-selectin [>>116<<] (Fig.\u00A06)." . _:b611582482 "4"^^ . _:b611583008 . . _:b611582493 "4"^^ . _:b611583011 . . _:b611582778 . . _:b54526019 "In addition, cells that express MHC class II (Kolmer or epiplexus cells) adhere as APC to the apical aspect of the choroid plexus epithelial cells that form the blood\u2013CSF barrier [>>78<<]. In the framework of EAE, it has been shown that the recognition of their cognate antigen on these APC is prerequisite for the subsequent migration of CD4+ T cells across the glia limitans into the CNS parenchyma to cause clinical EAE" . _:b611582492 "4"^^ . _:b611582772 . _:b611583010 . _:b611582495 "4"^^ . . _:b611583021 . _:b611582819 . . _:b54526071 "immune privilege" . _:b611582494 "4"^^ . . . _:b611583020 . . . _:b611582875 . _:b611582489 "4"^^ . . . _:b611583023 . _:b54525996 "These newly-gained migratory properties enabled that these T cells to efficiently cross the BBB [>>13<<, 68]. Interestingly, encephalitogenic T cells were also shown to persist as long-lived memory cells within the lung tissue, where they could be stimulated to gain the competence to enter the CNS and trigger autoimmune disease within the" . . _:b611582729 . _:b611582488 "4"^^ . _:b611583022 . _:b611582491 "4"^^ . . _:b611583017 . _:b611582490 "4"^^ . . . _:b611583016 . _:b611582908 . . _:b54526006 . _:b611582501 "4"^^ . . _:b611583019 . _:b611582500 "4"^^ . _:b611583018 . . . _:b611582503 "4"^^ . _:b611582921 . _:b611583029 . _:b611583044 . _:b54525843 "CSF drains from the subarachnoid space into lymphatic vessels in the nasal mucosa, in the dura mater, and into lymphatics associated with the sheaths of cranial and spinal nerve roots [11, 33, 69, >>81<<]. The nasal and dural routes appear to allow the traffic of APC to lymph nodes [66, 81]; CSF compartments, (the ventricles and subarachnoid space), do not exhibit the same immune privilege as the parenchyma of the CNS. In contrast to CSF," . _:b611582502 "4"^^ . . _:b611583028 . . _:b611582497 "4"^^ . _:b611582851 . _:b611583031 . _:b54526001 . _:b611582496 "4"^^ . _:b611583030 . _:b611582483 . _:b611582499 "4"^^ . _:b611583025 . _:b611582456 . _:b54525985 "Furtado et al. [44] had similar results upon extirpation of deep and superficial cervical lymph nodes in a transgenic spontaneous EAE model, as did Phillips et al. [>>106<<] in a cryolesion-enhanced model of cerebral EAE." . . _:b611582498 "4"^^ . . _:b611583024 . _:b611582509 "4"^^ . _:b611583027 . _:b611582508 "4"^^ . _:b611583026 . _:b611582511 "4"^^ . . _:b611583037 . _:b611582510 "4"^^ . _:b611583036 . _:b54526051 "CD4 T-cell migration across an in vitro model of the BBB further substantiated that molecular mechanisms mediating the multistep extravasation of CD8+ T cells across the BBB are distinguishable from those involved for CD4+ T cells [>>114<<] and thus need further investigation." . _:b611582505 "4"^^ . _:b54525953 "The high levels of radioactive tracer and A\u03B2 in the walls of intracranial arteries and the very low levels of tracer and A\u03B2 in the walls of the carotid artery in the neck [123, >>131<<] together with the presence of lymph nodes within the carotid sheath just below the base of the skull in humans strongly suggest that ISF and solutes leave artery walls in the neck to drain to adjacent cervical lymph nodes [30]." . . _:b611583039 . _:b611582504 "4"^^ . _:b611583038 . _:b611583064 . . _:b611582507 "4"^^ . . _:b611583033 . . _:b611582506 "4"^^ . _:b611583032 . _:b611582517 "4"^^ . . _:b611583035 . _:b611582516 "4"^^ . _:b611583034 . _:b611582951 . _:b611582519 "4"^^ . _:b54525947 "the route taken by the tracers on their passage out of the brain was outlined by perivascular macrophages containing tracer and situated adjacent to intracerebral arteries and around leptomeningeal arteries on the surface of the brain [>>24<<]." . _:b611582653 . _:b611583045 . _:b54525923 "zonulae occludentes that inhibit paracellular diffusion of solutes, the high number of pericytes embedded in brain capillary basement membranes inhibits transcellular vesicular activity and thus transcellular diffusion of solutes [>>17<<]. Fibrous astrocytes form end feet that completely surround the capillary surface:" . _:b611582516 . _:b611582518 "4"^^ . _:b611583044 . _:b611582513 "4"^^ . _:b611583002 . _:b611582439 . _:b611583047 . . _:b611582512 "4"^^ . _:b611582928 . _:b611583046 . . _:b611582515 "4"^^ . _:b611583041 . . _:b611582514 "4"^^ . _:b611582424 . _:b611583024 . _:b611583040 . _:b611582525 "3"^^ . _:b54525853 . . _:b611583043 . _:b611582524 "3"^^ . _:b611583042 . _:b611582557 . _:b611582527 "3"^^ . _:b54525956 "The quantity and volume of fluorescent tracers injected to outline the basement membrane pathways for drainage of ISF from grey matter [>>24<<] are too small to be detected in the cervical lymph nodes." . _:b611583053 . _:b611582526 "3"^^ . _:b611583052 . . _:b611582521 "4"^^ . _:b611583055 . _:b54525855 . . . _:b611582520 "4"^^ . _:b611583054 . _:b611582523 "3"^^ . _:b611583049 . _:b611582522 "3"^^ . . _:b611583048 . _:b611582533 "3"^^ . _:b611583102 . . _:b611583051 . _:b611582532 "3"^^ . _:b611582548 . _:b611583050 . _:b54525946 "By 30\u00A0min after injection, the tracers had disappeared from the ECS of the brain and from the basement membranes in the walls of capillaries and arteries, but tracers remained in the perivascular macrophages [>>24<<]. By 24\u00A0h after injection, the route taken by the tracers on their passage out of the brain was outlined by perivascular macrophages containing tracer and situated adjacent to intracerebral arteries and around leptomeningeal arteries on" . _:b611582535 "3"^^ . _:b611583061 . _:b611582534 "3"^^ . _:b54525910 . _:b611583060 . _:b611582529 "3"^^ . . _:b611583063 . _:b54526063 . _:b611582528 "3"^^ . _:b611583062 . _:b54526062 . _:b611582531 "3"^^ . _:b54525906 "The rate of bulk flow of ISF is estimated to be 0.1\u20130.3\u00A0\u00B5L\u00A0min\u22121\u00A0g\u22121 in the rat brain [>>2<<]. Tracer experiments and mathematical models show that ISF is eliminated from the brain by bulk flow along white matter fibre tracts and along perivascular pathways [32, 119]." . . _:b611583057 . _:b611582530 "3"^^ . . _:b611583056 . . _:b611582541 "3"^^ . _:b611582487 . _:b611583059 . _:b611582988 . _:b611582540 "3"^^ . _:b611583058 . _:b611582454 . _:b611582543 "3"^^ . _:b611583069 . _:b611582542 "3"^^ . _:b611582540 . _:b611583068 . . _:b611582537 "3"^^ . _:b54526065 . . _:b611583071 . _:b611582536 "3"^^ . . _:b611583070 . _:b611582539 "3"^^ . _:b611583065 . _:b611582538 "3"^^ . _:b611582960 . _:b611583064 . . _:b611582549 "3"^^ . _:b611582859 . . _:b611582931 . _:b611583067 . _:b611582548 "3"^^ . _:b611582809 . _:b611583066 . _:b611582551 "3"^^ . . _:b611583077 . _:b611582550 "3"^^ . . . _:b611583076 . _:b611582545 "3"^^ . . _:b611583079 . . . _:b611582544 "3"^^ . _:b611583078 . _:b611582547 "3"^^ . . _:b611583073 . _:b611582546 "3"^^ . . _:b611583072 . . _:b611582557 "3"^^ . . _:b611583075 . _:b611582556 "3"^^ . _:b611582594 . _:b611583074 . _:b611582664 . _:b611583057 . _:b611582559 "3"^^ . . _:b611583085 . _:b611582558 "3"^^ . . _:b611583084 . _:b611582936 . _:b611582995 . _:b611582553 "3"^^ . _:b611583087 . _:b611583107 . _:b54526022 "within the leptomeningeal environment are in regular contact with these cells that constitutively express MHC class II molecules on their membrane surfaces and thus are able to present myelin antigens to the pathogenic effector T cells [>>13<<, 70, 99]. In fact, live cell-imaging studies with activation-driven biosensors are able to demonstrate that T cells recognize their cognate antigen on these APC [80, 92] (the cognate antigen is the antigen that the T cell first" . _:b611582552 "3"^^ . . _:b54525917 . _:b611583086 . _:b611582555 "3"^^ . _:b611583081 . _:b611582554 "3"^^ . _:b611583080 . _:b611582565 "3"^^ . . _:b611583083 . . _:b611582564 "3"^^ . . _:b611583082 . _:b611582573 . _:b54525854 "Intranasal administration of antigen also drives tolerance through superficial cervical and internal jugular lymph nodes [>>143<<]." . _:b611582567 "3"^^ . _:b611583093 . _:b611582566 "3"^^ . _:b54525909 "Electron microscopy has shown that very narrow gaps separate the cells of the CNS, particularly in the grey matter [>>58<<, 91]. The gaps are interconnected and are filled with ISF; they represent the extracellular spaces (ECS) and are in direct continuity with the basement membranes of capillaries [89]." . _:b611583092 . _:b611582561 "3"^^ . _:b54525949 . _:b611583095 . _:b611582560 "3"^^ . _:b611583094 . _:b611582563 "3"^^ . . _:b611583089 . . _:b611582562 "3"^^ . _:b54525938 . _:b611583088 . _:b611582549 . _:b611582573 "3"^^ . _:b611582736 . _:b611583091 . _:b611582572 "3"^^ . . . . _:b611583090 . . _:b54525867 "cues from food (e.g., vitamin A) and sunlight (UV induced vitamin D3) are metabolized by DCs which allows them to imprint tissue-specific homing patterns in activated effector lymphocytes during the process of antigen presentation [>>125<<]. Effector T cells produced in lymph nodes that drain the skin express the chemokine receptors CCR4 and CCR10 and the cutaneous lymphocyte antigen, while effector T cells produced in lymph nodes that drain the gut express CCR9 and \u03B14\u03B27" . _:b611582575 "3"^^ . . _:b611583101 . _:b611582574 "3"^^ . _:b611583100 . . _:b611583100 . _:b611582569 "3"^^ . . _:b611583103 . _:b611582568 "3"^^ . . _:b611583102 . . _:b611582571 "3"^^ . _:b611583097 . _:b611582570 "3"^^ . _:b611582630 . _:b611583096 . _:b611582581 "3"^^ . _:b611582811 . . _:b54526050 "Although \u03B14\u03B21-integrin is essential for CD8 T-cell entry into the CNS in vivo, the vascular ligand engaged was identified as junctional adhesion molecule-B (JAM-B) rather then VCAM-1 used by CD4+ T cells [>>84<<]. A recent side by side comparison of CD8 versus CD4 T-cell migration across an in vitro model of the BBB further substantiated that molecular mechanisms mediating the multistep extravasation of CD8+ T cells across the BBB are" . _:b611583099 . _:b54525962 "One of the factors involved in the aetiology of WMH appears to be impaired drainage of fluid along intramural perivascular pathways in cerebral arteries affected by cerebral amyloid angiopathy [>>140<<]. Similarly, the occurrence of amyloid-related imaging abnormalities (ARIA) in the white matter of patients treated with A\u03B2 immunotherapy for Alzheimer\u2019s disease may be due to the increase in accumulation of A\u03B2 in intramural perivascular" . _:b611582580 "3"^^ . _:b611582420 . _:b611583098 . _:b611582583 "3"^^ . . _:b611583109 . _:b611582582 "3"^^ . _:b54525829 "As a sequel to the grafting experiments, it was shown that if the same allografts were subsequently grafted on to the skin, allografts in the brain were rapidly rejected [>>29<<, 86]. It appears, therefore, that immunization in peripheral tissues precipitates immunological rejection of foreign tissue in the CNS. The description of immune privileged sites as those in which: \u201Cgrafts transplanted to them are in some" . _:b611583108 . _:b611582577 "3"^^ . . _:b611582710 . _:b611583111 . _:b611582867 . _:b611582576 "3"^^ . . _:b611583110 . _:b611583013 . _:b611582606 . _:b54525851 . _:b611582579 "3"^^ . _:b611583105 . _:b611582801 . _:b611582578 "3"^^ . _:b611583104 . _:b54525887 "profundis capitis et colli\u201D [21], and since then, functional drainage by this route has been demonstrated by Schwalbe et al. [121], Andres et al. [9], Cserr and Knopf [34], Kida et al. [69], and more recently by Aspelund et al. [>>11<<] and by Louveau et al. [81]." . _:b611582764 . _:b611582589 "3"^^ . _:b611582615 . _:b611583107 . _:b611582588 "3"^^ . . _:b54525893 "Several studies have also demonstrated efflux of T cells and APC from the CSF into deep cervical lymph nodes [47, 50, 51, >>66<<, 101]. Moreover, myelin and axonal epitopes have been found in deep cervical lymph nodes after axonal injury and (autoimmune) demyelination [36, 40, 79, 93]. Although it can be emphasised that APC may drain with CSF to lymph nodes by" . _:b611583106 . _:b611582916 . _:b611582591 "3"^^ . _:b611583117 . _:b611582590 "3"^^ . _:b54525986 . _:b54525971 . _:b611583116 . . _:b611582585 "3"^^ . _:b611583119 . _:b611582923 . _:b611582584 "3"^^ . _:b611583014 . _:b611583118 . _:b611582755 . _:b611582587 "3"^^ . _:b611582948 . _:b611583113 . . _:b611582586 "3"^^ . _:b611583112 . _:b611582597 "3"^^ . _:b611582676 . _:b54526013 . _:b611583115 . _:b611582596 "3"^^ . _:b611583114 . _:b611582599 "3"^^ . _:b611582598 "3"^^ . _:b611582593 "3"^^ . _:b611582592 "3"^^ .