RESEARCH HIGHLIGHTS Nature Reviews Neurology 11, 367 (2015); published online 23 June 2015; doi:10.1038/nrneurol.2015.105

NEUROIMMUNOLOGY Uncovering the secrets of the ‘brain drain’ —the CNS lymphatic system is finally revealed he traditional concept of the brain human dural tissue, although this finding as an immune privileged site is awaits further confirmation. Tgradually being eroded, and has Next, the authors used fluorescent been dealt a further blow by the recent tracers to explore the drainage capabilities demonstration of lymphatic vessels in of the perisinusal vessels. In anaesthetized the CNS. In a study published in Nature, mice, fluorescein was injected Antoine Louveau, Jonathan Kipnis and intravenously, while QDot655 was injected their colleagues at the University of into the cerebral ventricles. QDot655—but Virginia identified functional lymphatic not fluorescein—could subsequently be vasculature in the meninges. In addition detected in Lyve-1-expressing vessels in to providing new insights into the the meninges. From these results, the team anatomy of the brain, the findings concluded that the meningeal lymphatic could have important implications vessels provide a drainage route from the for understanding the mechanisms cerebrospinal fluid (CSF). underlying neurodegenerative and Intracerebroventricular injection of neuroinflammatory disease. Evans blue dye revealed drainage of fluid “We have been interested in the role from the CSF to deep cervical lymph of the immune system in brain function nodes via the meningeal lymphatic vessels. for some time,” comments Kipnis. “We “We knew that the brain drains to deep showed that mice deficient in T cells are cervical lymph nodes, but we did not tovovan/iStock/Thinkstock cognitively impaired, and that meningeal know how, and we had no control over T cells play an important part in brain the process,” explains Kipnis. “Now we an immunological point of view.” Moreover, function, but we did not know what were know that lymphatic vessels exist in the she advocates further research into the the gateways for immune cells to get into brain, and that they drain immune cells relationship between the glymphatic system and out of the meninges.” and macromolecules from the CSF to the and the meningeal lymphatic vessels. Louveau established a whole-mount draining lymph nodes.” Kipnis believes that the discovery immunohistochemical technique to A team led by Maiken Nedergaard of lymphatic vessels in the CNS could examine the expression of various cell- at the University of Rochester Medical provide the impetus for new experimental specific markers in mouse meningeal Center previously identified a perivascular approaches to probe the mechanisms of tissue. Using this technique, the pathway known as the glymphatic system, neurological disease. “We can control researchers identified T lymphocytes which uses the CSF to clear waste products these vessels—for example, expand them aligned along endothelial structures that from the interstitial compartments of the or ablate them—and we can then ask how ran parallel to the dural sinuses (vessels CNS. The word ‘glymphatic’ derives from manipulation of these vessels affects various that drain blood from the brain into the the system’s reliance on glial cells, and its neurological conditions,” he explains. internal jugular veins). functional resemblance to the lymphatic “We are particularly interested in the roles “We realized that these structures were system. On the basis of their new findings, these vessels are playing in initiation and not blood vessels, so we explored the Kipnis and colleagues propose a model in progression of multiple sclerosis, meningitis unlikely possibility that they are lymphatic which the meningeal lymphatic vessels are and Alzheimer disease.” vessels,” explains Kipnis. “We were amazed connected to the glymphatic system via Heather Wood with our findings.” the CSF. The researchers showed that the Commenting on the new paper, Original article Louveau, A. et al. Structural and functional newly discovered perisinusal vessels Nedergaard says “the most significant features of central nervous system lymphatic vessels. expressed various lymphatic endothelial observation in my mind is that the authors Nature doi:10.10.1038/nature14432 cell markers, including Lyve-1, thereby showed that the meningeal lymphatic Further reading Iliff, J. J. et al. Brain-wide pathway for waste confirming their identity as lymphatic vessels act as a reservoir for leukocytes; it is clearance captured by contrast-enhanced MRI. J. Clin. vessels. Intriguingly, preliminary not entirely novel that the meninges have Invest. 123, 1299–1309 (2013) | Jessen, N. A. et al. The investigations indicated the presence of lymphatic vessels, but prior papers on the glymphatic system: a beginner’s guide. Neurochem. Res. doi:10.1007/s11064-015-1581-6 similar Lyve-1-expressing structures in subject had not studied these vessels from

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