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New Study Suggests Brain Is Connected to the Lymphatic System: What the Discovery Could Mean for Neurology

Shaw, Gina

doi: 10.1097/01.NT.0000469526.77988.9e
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ARTICLE IN BRIEF

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Investigators at the University of Virginia have identified a system of lymphatic vessels in the meninges, upending conventional understanding of anatomy and physiology.

Up until now, diagrams and maps showed the human lymphatic system ending at the base of the skull, with the tonsils, adenoids, and cervical lymph nodes. The brain itself, it has long been thought, has no direct connection to the lymphatic system. But that conventional wisdom has now been challenged by a team of researchers at the University of Virginia, who have identified a system of lymphatic vessels in the meninges.

In a paper published in the June 1 online edition of Nature, Jonathan Kipnis, PhD, a professor of neuroscience and director of the Center for Brain Immunology and Glia, his postdoctoral fellow Antoine Louveau, PhD, and their colleagues described how they identified these vessels.

It all started with an experiment Dr. Louveau was conducting on mouse meninges. After developing a method to mount them on a single slide and examine them as a whole, he noticed vessel-like patterns in the distribution of immune cells on those slides. He tested them for classic markers of lymphatic endothelial cells (LEC) — and there they were. Preliminary experiments suggested that a similar structure exists in humans, long unnoticed because of how closely it tracks the dural sinuses (sagittal and transverse).

“These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes,” they wrote in the paper. “The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.”

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These findings track with other recent work on the immune system and the brain, said Robyn Klein, MD, PhD, a professor of medicine and director of the Center for Neuroimmunology and Neuroinfectious Diseases at Washington University in St. Louis, whose laboratory studies the pathogenesis of neuroinflammatory diseases of the central nervous system (CNS).

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Dr. Klein, who was not involved with the current study, cited the work of Maiken Nedergaard, MD, DMsc, and colleagues at the University of Rochester in New York who identified in 2012 what Dr. Nedergaard called the brain's “glymphatic system,” a network of microscopic channels that clear waste-laden cerebrospinal fluid from the brain.

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“With the publication of that 2012 paper, it made me wonder whether or not there was an additional system that really had not been evaluated,” Dr. Klein told Neurology Today. “For a long time, people have known that lymphocytes enter the brain and perform effector functions, but there has been little investigation regarding whether and how they exit. Now, perhaps we have an anatomical pathway to investigate this process.”

Much of Dr. Klein's work has focused on the trafficking of lymphocytes across the blood-brain barrier. “My laboratory has investigated molecular mechanisms of lymphocytes' entry into the brain in the context of autoimmune diseases such as multiple sclerosis (MS), and also during infections with neurotropic viruses,” she said.

“One huge question in MS has been, how do you drive immunopathologic cells out of the brain? In an autoimmune disorder like MS, where immune cells have continued inappropriate access to the brain parenchyma, we would need to understand the avenues of exit in order to drive these cells out. This suggests such a mechanism and potential additional avenues to identify new treatment targets.”

Dr. Kipnis said the current discovery could have many implications and requires further characterization in humans. “I think that in any neurologic condition where the immune system is involved, these vessels could be playing a role,” he said. “For example, there are immune abnormalities in autism, and we don't understand why. Alzheimer's disease involves immune abnormalities. And there are many others.”

The newly discovered lymphatic system of the brain could play a role in understanding the pathogenesis of MS as well, Dr. Kipnis said. “For example, lymphatic vessels are known in peripheral tumors to affect the state of T-cell activation; maybe it's the same in the brain. There could be abnormal drainage of brain proteins into the lymph nodes; the presence of too many of them might trigger an explosive immune response. Or these vessels could become clogged and not drain cells as they should, triggering an accumulation of cells in the brain. We just need to start exploring. Remember, the current manuscript is not addressing the role of these vessels in any of the neurological disorders, but instead just describes their structure and some function.”

Lawrence Steinman, MD, FAAN, a professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, praised the finding as “very exciting.”

“They have really compelling data from animals and from humans that the brain is drained through a lymphatic system,” he said. “Everyone's always talked about the brain as an immune-privileged site, and I don't see it that way at all. With this discovery, we can treat the brain and brain diseases as we would any other organ when it comes to autoimmune diseases. Histocompatibility proteins and complement proteins play a huge role in neurobiology. Realizing that the brain has its own lymphatic system, we can now swing our thinking back to unexpected roles for these molecules in the brain and more conventional roles for these molecules in brain pathophysiology.”

The next steps, he said, should include mapping the nuances of the heretofore undiscovered lymphatic system of the brain. “There will need to be experiments to determine whether there are new targets and new mechanisms to be discovered within this system, or whether it is, as I suspect, no different than the skin or kidney or any other organ in terms of how the immune system attacks it.”

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After that, Dr. Kipnis said, will come exploration of the newly characterized system's role in disease pathogenesis. “Once we understand what role, if any, these vessels play in the initiation of disease, we could target them and see if it is possible to somehow alter the progression of the disease.”

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EXPERTS: ON THE LINK BETWEEN LYMPHATIC VESSELS AND THE CNS

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LINK UP FOR MORE INFORMATION:

•. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14432.html. Nature 2015: Epub June 1.
    •. Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI http://www.jci.org/articles/view/67677. J Clin Invest 2013;123(3):1299–1309.
      •. Iliff J, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid B http://stm.sciencemag.org/content/4/147/147ra111.long. Sci Transl Med 2012; 4:147ra111
        •. Yang L, Kress BT, Weber HJ, et al. Evaluating glymphatic pathway functional utilizing clinically relevant intrathecal infusion of CSF tracer http://www.translational-medicine.com/content/11/1/107. J Transl Med 2013; 11: 107
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