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Researchers surprised to discover new lymphatic system in brain

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From ScienceDaily:

University of Queensland scientists discovered a new type of lymphatic brain “scavenger” cell by studying tropical freshwater zebrafish — which share many of the same cell types and organs as humans.

Lead researcher Associate Professor Ben Hogan from UQ’s Institute for Molecular Bioscience said the fundamental discovery would help scientists understand how the brain forms and functions.

“It is rare to discover a cell type in the brain that we didn’t know about previously, and particularly a cell type that we didn’t expect to be there,” he said.

“The brain is the only organ without a known lymphatic system, so the fact that these cells are lymphatic in nature and surround the brain makes this finding quite a surprise.” Paper. (paywall)(paywall) – Neil I Bower, Katarzyna Koltowska, Cathy Pichol-Thievend, Isaac Virshup, Scott Paterson, Anne K Lagendijk, Weili Wang, Benjamin W Lindsey, Stephen J Bent, Sungmin Baek, Maria Rondon-Galeano, Daniel G Hurley, Naoki Mochizuki, Cas Simons, Mathias Francois, Christine A Wells, Jan Kaslin, Benjamin M Hogan. Mural lymphatic endothelial cells regulate meningeal angiogenesis in the zebrafish. Nature Neuroscience, 2017; DOI: 10.1038/nn.4558 More.

Conveniently, zebrafish are “naturally transparent.”

This is a bear market for dogma.

See also: Archaea: Salt-loving methanogen found

5 Replies to “Researchers surprised to discover new lymphatic system in brain

  1. 1
    Dionisio says:

    Look at the fish!

  2. 2
    Dionisio says:

    “The brain is the only organ without a known lymphatic system, so the fact that these cells are lymphatic in nature and surround the brain makes this finding quite a surprise.”

    Is tree any hope that these folks will someday stop getting surprised?


  3. 3
    Dionisio says:

    Error @2:
    Is tree…
    Is there…
    My mistake.

  4. 4
    Latemarch says:

    Found this in search of literature.

    Lymphatics in the brain: novel proof, great hopes and forgotten discoveries

    Éva Mezey, MD, PhD, ASCS, NIDCR, NIH, Bethesda, MD
    Miklós Palkovits, MD, PhD, Semmelweis University, Budapest, Hungary

    The paper in Nature by Louveau and colleagues1 described meningeal lymphatic vessels that were until now missing links in the brain lymphatic system. The authors used an extensive arsenal of modern methods to examine structural features of the components of this system, mainly in animal brains. As elegant as they were, however, the findings were not without precedence.

    During the last two decades a number of workers demonstrated the existence of two separate drainage routes from the brain to the cervical lymph vessels and nodes: 1) subarachnoid cerebrospinal fluid and interstitial fluid and 2) solutes through the perivascular system2-9. It has also been shown that immune cells (T-lymphocytes, microglia, perivascular macrophages, dendritic cells) migrate from the brain into the cervical lymph nodes10,11. The interstitial?perivascular pathway from the brain parenchyma is too delicate to allow passage and traffic of these cells9. The discovery of the lymphatic endothelial cells in meningeal vessels lining the dural sinuses by Louveau et al.1 helps elucidate the transport mechanism for antigen presenting cells. Their findings are an important step in understanding the role of the brain lymphatic system in both healthy and pathological conditions. The importance of lymphatic pathways in clearance of breakdown products from the brain interstitium has already been well documented. The disruption of this pathway has been postulated to be important in the patho-physiology of neuroimmune (sclerosis multiplex) and neurodegenerative (Alzheimer?s) diseases4.

    Since ?regular? lymph vessels do not exist inside the skull and in the brain, the conventional wisdom has been (or still is) that the brain and the lymphatic system are unconnected. Studies in the past two decades, however, weakened this inference. It is worth emphasizing that there has been evidence for a long time that lymphatics do indeed exist within the skull. Unfortunately, this evidence has almost completely been ignored. These studies were damned with faint praise in part because there were no specific markers that could be used to demonstrate convincingly the existence of lymphatic drainage routes from the brain. In addition, the researchers who described central lymphatics may not have realized the clinical significance of their own findings at the time they were made, or they worked too far from the mainstream to be noticed by most of their peers.

    Schwalbe12 in 1869 was the first person to use tracers to detect the connection between the subarachnoid space and the cervical lymph nodes. A few years later, Key and Retzius in 187513, then Zwillinger14 in human, in 1912 and Weed15 in 1914 demonstrated fluid flow through the cribriform plate below the olfactory bulb to the nasal mucosa and lymphatic vessels and finally to the cervical lymph nodes. With the exception of the publication of Brierley and Field16 in 1948, these observations were forgotten for almost 100 years. Then, the subarachnoid space/nasal mucosa/cervical lymph node pathway was described again in detail17 and its existence were confirmed by several other groups (refs. 4,5 and 9). It is sad that these pioneers are rarely mentioned in modern texts, and that the publications of two Hungarian groups lead by Földi and Csanda describing the connection of the brain and lymphatic system18-21, and perivascular lymphatics22-24 have also been forgotten. These workers demonstrated that lymph drainage plays an important role in the fluid circulation of the brain. After selective ligation of the cervical lymphatic vessels and nodes, microscopic signs of cerebral edema were seen: half-moon-like gaps in small vessels, among the external sheaths of the adventitia, in large vessels with swollen glial processes, and perivascular end-feet of astrocytes. These hallmarks of ?lymphostatic encephalopathy?, were associated with elevated cerebrospinal fluid pressure18,19. In 1976, Cserr et al.25 pointed out the importance of the perivascular space in the drainage of brain interstitial fluid. This space appears to act in a way that is similar to lymphatic vessels in other organs. After extensive studies Weller and colleagues4-9,17 described the perivascular lymphatic pathway in the brain in detail: interstitial fluid and solutes drain from the brain parenchyma in laminae of basement membranes in the walls of the capillaries and among smooth muscle cells in the tunica media of the small arteries. From there they travel in the adventitia surrounding leptomeningeal arteries towards the carotid artery. The perivascular path appears to end in the jugular foramen. Almost 50 years earlier, Földi and colleagues, based on light and electron microscopic studies, described this pathway in almost exactly the same way21-23. They called it ?prelymphatic-lymphatic? pathway20–perivascular (prelymphatic) until it reaches the jugular foramen, then collected by individual lymph vessels around the internal carotid that terminate in the deep cervical lymph nodes. They described the emergence of lymph vessels intra-cranially within the jugular foramen in layers of the dura mater. Lymph vessels were filled with homogeneous fluid (lymph) and valves appeared in typical lymph vessels21. Csanda and colleagues reported their observation after a focused experimental radiation tissue damage in the brain by Yttrium 90 in dogs, rabbits, cats and rats24. “Most of the breakdown substances of the brain tissue ? originating especially from myelin sheaths ?are phagocytosed by microglial cells and transported to the vessel walls. In the remote vessels the lipid granules the adventitia in half-moon like widenings that are also seen after cervical lymphatic blockade?The migration of these substances tends to be toward the surface of the cortex..”

    Papers published by Csanda?s and Földi?s groups appeared mainly in English journals that were highly regarded at the time (Lancet, for instance18). Consequently, it is hard to imagine why they had so little impact and why they have been ignored. Although some of their findings related to dural lymphatics, none of their publications were mentioned by Louveau and colleagues1.

    Louveau et al. and the people who commented on their work suggested that studies of brain/lymphatic system might lead to better treatments for neurodegenerative diseases. We hope that this is true, but suggest that good ideas may be ?hidden? in plain sight in the literature. It is nice to see this and to acknowledge our predecessors. The methods used 50 to 150 years ago may not have been as sophisticated as the ones that are available today, but scientists were keen observers, thoughtful, and imaginative and their work deserves to be noticed.


    1 Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337-341, doi:10.1038/nature14432 (2015).
    2 Zhang, E. T., Richards, H. K., Kida, S. & Weller, R. O. Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta neuropathologica 83, 233-239 (1992).
    3 Schley, D., Carare-Nnadi, R., Please, C. P., Perry, V. H. & Weller, R. O. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Journal of theoretical biology 238, 962-974, doi:10.1016/j.jtbi.2005.07.005 (2006).
    4 Carare, R. O. et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathology and applied neurobiology 34, 131-144, doi:10.1111/j.1365-2990.2007.00926.x (2008).
    5 Weller, R. O., Djuanda, E., Yow, H. Y. & Carare, R. O. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta neuropathologica 117, 1-14, doi:10.1007/s00401-008-0457-0 (2009).
    6 Weller, R. O., Galea, I., Carare, R. O. & Minagar, A. Pathophysiology of the lymphatic drainage of the central nervous system: Implications for pathogenesis and therapy of multiple sclerosis. Pathophysiology 17, 295-306, doi:10.1016/j.pathophys.2009.10.007 (2010).
    7 Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4, 147ra111, doi:10.1126/scitranslmed.3003748 (2012).
    8 Iliff, J. J. et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123, 1299-1309, doi:10.1172/JCI67677 (2013).
    9 Laman, J. D. & Weller, R. O. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J Neuroimmune Pharmacol 8, 840-856, doi:10.1007/s11481-013-9470-8 (2013).
    10 Engelhardt, B. & Ransohoff, R. M. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26, 485-495, doi:10.1016/ (2005).
    11 Goldmann, J. et al. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80, 797-801, doi:10.1189/jlb.0306176 (2006).
    12 Schwalbe, G. Der Arachnoidealraum, ein Lymphraum und sein Zusammenhang mit dem Perichorioidealraum. Z med Wiss 7, 465- (1869).
    13 Key, A. & Retzius, G. Studien in der Anatomie des Nervensystems und des Bindegewebes. (Samson und Wallin, 1875).
    14 Zwillinger, H. Die Lymphbahnen des oberen Nasalschnittes und deren Beziehungen zu den perimeningealen Lymphraumen. Arch Laryngol und Rhinol 26, 66-78 (1912).
    15 Weed, L. H. Studies on cerebro-spinal fluid. No. II : The theories of drainage of cerebro-spinal fluid with an analysis of the methods of investigation. The Journal of medical research 31, 21-49 (1914).
    16 Brierley, J. B. & Field, E. J. The connexions of the spinal sub-arachnoid space with the lymphatic system. J Anat 82, 153-166 (1948).
    17 Kida, S., Pantazis, A. & Weller, R. O. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathology and applied neurobiology 19, 480-488 (1993).
    18 Csanda, E., Zoltan, O. T. & Foldi, M. Elevation of cerebrospinal fluid pressure in the dog after obstruction of cervical lymphatic channels. Lancet 281, 832 (1963).
    19 Foldi, M. et al. Über Wirkungen der Unterbindung der Lymphgefäße und Lymphknoten des Halses auf das Zentralnervensystem im Tierversuch. Z Gesamte Exp Med 137, 483-510, doi:10.1007/BF02079846 (1963).
    20 Foldi, M. et al. New contributions to the anatomical connections of the brain and the lymphatic system. Acta anatomica 64, 498-505 (1966).
    21 Csanda, E., Foldi, M., Obal, F. & Zoltan, O. T. Cerebral oedema as a consequence of experimental cervical lymphatic blockage. Angiologica 5, 55-63 (1968).
    22 Foldi, M. et al. Lymphogenic haemangiopathy. “Prelymphatic” pathways in the wall of cerebral and cervical blood vessels. Angiologica 5, 250-262 (1968).
    23 Földi, M., Csillik, B. & Zoltán, O. T. Lymphatic drainage of the brain. Experientia 24, 1283-1287 (1968).
    24 Csanda, E., Obál, F. & Obál, F. J. in Lymphangiology (eds M. Földi & J. R. Casley-Smith) 475-508 (Schattauer Verlag, 1983).
    25 Cserr, H. F., Cooper, D. N. & Milhorat, T. H. in Dynamics of Brain Edema (eds H. M. Pappius & W. Feindel) 95-97 (Springer, 1976).

    The above is slightly edited to enhance paragraph breaks where I could detect them.

    My only comment is that blatent errors can persist for decades, or centuries, even in the face of contradictory evidence (See Evolution).

  5. 5
    Dionisio says:

    I think I see your point
    Interesting observation.

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