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A (delayed) history of the brain lymphatic system

Nature Medicine volume 25, pages 538–540 (2019)Cite this article

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It has been only recently that scientists come to realize the existence of a lymphatic system within the central nervous system. However, an Italian anatomist had already found and described the system in fine detail over 200 years ago.

The (re)discovery of the existence of the lymphatic system within the central nervous system (CNS) has been one of the most surprising findings of the last decade1,2 and has led scientists to question a long-lasting dogma that the brain was an ‘immune-privileged' site. The function of meningeal lymphatic vessels in brain physiology has been recently demonstrated: when these vessels were ablated in young mice and cognitive deficits were observed, their role began to be uncovered in mouse models of neurodegenerative pathologies, including Alzheimer’s disease3. Probably the most overlooked role of meningeal lymphatic vessels is the one they play in connecting the CNS to peripheral immunity. It is possible that dysfunction of these vessels or their hyperfunction may lead to initiation of an autoimmune attack. Their ablation results in dysregulated and impaired meningeal immunity4. Interestingly, under conditions of neuroinflammation (such as animal models of multiple sclerosis), ablation of meningeal lymphatic vessels may offer a route to amelioration of brain-associated inflammation5. It is highly plausible that these vessels, which have also been visualized in humans using state-of-the-art imaging techniques6, represent a promising therapeutic target for CNS-associated neuroinflammatory conditions.

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Fig. 1: Portrait of Paolo Mascagni by S. Ricci; stipple engraving by G. Buccinelli after R. Focosi after S. Ricci.
Fig. 2: Figure from the Vasorum Lymphaticorum Corporis Humani Historia et Ichnographia (1787).

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Authors and Affiliations

  1. The Computational, Cognitive & Clinical Neuroimaging Laboratory (C3NL), Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom

    Stefano Sandrone

  2. Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador

    Daniel Moreno-Zambrano

  3. Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA, USA

    Jonathan Kipnis

  4. University of Utrecht, Utrecht, the Netherlands

    Jan van Gijn

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  1. Stefano Sandrone
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  2. Daniel Moreno-Zambrano
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  4. Jan van Gijn
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Correspondence to Stefano Sandrone.

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Competing interests

S.S. receives royalties from Oxford University Press (United States) for Brain Renaissance (2015). J.K. is a scientific co-founder and a scientific board member of Ariya Therapeutics, Inc. (PureTech Health).

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Sandrone, S., Moreno-Zambrano, D., Kipnis, J. et al. A (delayed) history of the brain lymphatic system. Nat Med 25, 538–540 (2019). https://doi.org/10.1038/s41591-019-0417-3

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