The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Structural and functional features of central nervous system lymphatic vessels
Open accessAbstract
One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. 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. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. 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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“In 2015, lymphatic vessels draining from CSF to neck lymph nodes were for the first time detected in walls of dural venous sinuses (51, 52).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [52]
In the citing paper
“two other groups reported that classical lymphatic vessels draining brain interstitial CSF might also be identified in the dura – the fibrous external layer of the meningeal membranes (39, 40).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [39]
In the citing paper
“Yet the glymphatic and meningeal lymphatic systems are clearly connected: CSF tracers can exit the CNS via the meningeal lymphatic vessels, particularly by way of the lymph vessels draining the ventral aspect of the brain draining to the cervical lymph nodes (39, 40, 42).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [39]
In the citing paper
“the recent groundbreaking work by Louveau et al (2015) showing active lymphatic vessels connecting the CNS to the lymphatic system that may possibly act as a conduit for neuroimmunological dysfunction.”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Louveau et al (2015)
In the citing paper
“These results emphasize the importance of initial lymphatics at the dorsal brain meninges in CSF drainage5,12,18.”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [18]
In the citing paper
“The dural compartment of the meninges, closest to the skull, is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, as well as immune cells which are distinct from the CNS.”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Louveau et al., 2015
In the citing paper
“CSF macromolecules are likely reaching the dura by traversing the arachnoid layer underlying the dural sinuses17.”
From Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons (2020) · cites this paper as [17]
In the citing paper
“The extent of enhancing tissue within parasagittal dura does not resemble the previously reported appearance of true dural lymphatic vessels, which are tubular-shaped structures of sub-millimeter cross-sectional diameter near the venous sinus wall3,4,11, and also far from the classical MRI appearance of arachnoid granulations bulging into venous sinuses12.”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [4]
In the citing paper
“true lymphatic vessels were shown to reside within the dura mater3,4”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [4]
In the citing paper
“it seems plausible that molecules within parasagittal dura structures may well reach adjacent lymphatic vessels, and perhaps also vice versa”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [4]
In the citing paper
“Although the CNS parenchyma does not have a conventional lymphatic drainage system (3), lymphatics have been discovered in the dura mater and just outside holes in the skull bone (4-9).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [4]
In the citing paper
“Antigen drainage from the dura mater occurs in a similar fashion by way of lymphatic vessels traversing the dura mater and draining to the deep cervical lymph nodes (4, 5, 64).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [4]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Sleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
The anatomical and cellular basis of immune surveillance in the central nervous system
Ransohoff, R. M., & Engelhardt, B. (2012) · Nature reviews. Immunology · doi:10.1038/nri3265 · Cited by 1,029
Functionally specialized junctions between endothelial cells of lymphatic vessels
Baluk, P., Fuxe, J., Hashizume, H., Romano, T., Lashnits, E., Butz, S., Vestweber, D., Corada, M., Molendini, C., Dejana, E., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062596 · Cited by 1,006
The lymphatic vasculature in disease
Alitalo, K. K. (2011) · Nature Medicine · doi:10.1038/nm.2545 · Cited by 980
Multiplicity of cerebrospinal fluid functions: new challenges in health and disease
Johanson, C. E., Duncan, J. A., Klinge, P. M., Brinker, T., Stopa, E. G., & Silverberg, G. D. (2008) · Cerebrospinal Fluid Research · doi:10.1186/1743-8454-5-10 · Cited by 861
HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes
Girard, J.-P., Moussion, C., & Förster, R. (2012) · Nature Reviews Immunology · doi:10.1038/nri3298 · Cited by 713
The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms
Engelhardt, B., & Ransohoff, R. M. (2005) · Trends in Immunology · doi:10.1016/j.it.2005.07.004 · Cited by 674
Interstitial dendritic cell guidance by haptotactic chemokine gradients
Weber, M., Hauschild, R., Schwarz, J., Moussion, C., de Vries, I., Legler, D. F., Luther, S. A., Bollenbach, T., & Sixt, M. (2013) · Science · doi:10.1126/science.1228456 · Cited by 555
Kida, S., Pantazis, A., & Weller, R. O. (1993) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1993.tb00476.x · Cited by 520
Lymphatic drainage of the brain and the pathophysiology of neurological disease
Weller, R. O., Djuanda, E., Yow, H.-Y., & Carare, R. O. (2009) · Acta Neuropathologica · doi:10.1007/s00401-008-0457-0 · Cited by 488
Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues
Debes, G. F., Arnold, C. N., Young, A. J., Krautwald, S., Lipp, M., Hay, J. B., & Butcher, E. C. (2005) · Nature Immunology · doi:10.1038/ni1238 · Cited by 484
Cserr, H. F., Harling‐Berg, C. J., & Knopf, P. M. (1992) · Brain Pathology · doi:10.1111/j.1750-3639.1992.tb00703.x · Cited by 450
Shechter, R., London, A., & Schwartz, M. (2013) · Nature reviews. Immunology · doi:10.1038/nri3391 · Cited by 422
Integrin-α9 Is Required for Fibronectin Matrix Assembly during Lymphatic Valve Morphogenesis
Bazigou, E., Xie, S., Chen, C., Weston, A., Miura, N., Sorokin, L., Adams, R., Muro, A. F., Sheppard, D., & Makinen, T. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.06.017 · Cited by 347
Yang, L., Kress, B. T., Weber, H. J., Thiyagarajan, M., Wang, B., Deane, R., Benveniste, H., Iliff, J. J., & Nedergaard, M. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-107 · Cited by 317
Pro-cognitive properties of T cells
Kipnis, J., Gadani, S., & Derecki, N. C. (2012) · Nature Reviews Immunology · doi:10.1038/nri3280 · Cited by 246
Self-citationT cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa
Goldmann, J., Kwidzinski, E., Brandt, C., Mahlo, J., Richter, D., & Bechmann, I. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.0306176 · Cited by 192
Current views on the function of the lymphatic vasculature in health and diseasePreprint
Wang, Y., & Oliver, G. C. (2010) · Genes & Development · doi:10.1101/gad.1955910 · Cited by 183
Drainage of Cells and Soluble Antigen from the CNS to Regional Lymph Nodes
Laman, J. D., & Weller, R. O. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9470-8 · Cited by 168
Weller, R. O., Galea, I., Carare, R. O., & Minagar, A. (2009) · Pathophysiology · doi:10.1016/j.pathophys.2009.10.007 · Cited by 146
Liu, N.-F., Lü, Q., Jiang, Z., Wang, C., & Zhou, J. (2009) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2008.11.029 · Cited by 143
Immunological update on multiple sclerosis
Hohlfeld, R., & Wekerle, H. (2001) · Current Opinion in Neurology · doi:10.1097/00019052-200106000-00006 · Cited by 111
Immune privilege of the CNS is not the consequence of limited antigen sampling
Harris, M. G., Hulseberg, P. D., Ling, C., Kármán, J., Clarkson, B. D. S., Harding, J. S., Zhang, M., Sandor, A., Christensen, K., Nagy, A., et al. (2014) · Scientific Reports · doi:10.1038/srep04422 · Cited by 95
The lymphatic vasculature revisited
Kerjaschki, D. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74854 · Cited by 90
Migration of monocytes after intracerebral injection at entorhinal cortex lesion site
Kaminski, M., Bechmann, I., Pohland, M., Kiwit, J. C. W., Nitsch, R., & Glumm, J. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0511241 · Cited by 86
In Vivo Imaging of Lymphatic Drainage of Cerebrospinal Fluid in Mouse
Mathieu, E., Gupta, N., Macdonald, R. L., Ai, J., & Yücel, Y. H. (2013) · Fluids and Barriers of the CNS · doi:10.1186/2045-8118-10-35 · Cited by 66
Evidence for Lymphatics in the Developing and Adult Human Choroid
Koina, M. E., Baxter, L., Adamson, S., Arfuso, F., Yu, Y., Madigan, M. C., & Chan‐Ling, T. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15705 · Cited by 65
A New Mouse Model to Study Acquired Lymphedema
Schneider, M., Ny, A., de Almodóvar, C. R., & Carmeliet, P. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030264 · Cited by 32
Generalized lymphedema associated with neurologic signs (GLANS) syndrome: A new entity?
Berton, M., Lorette, G., Baulieu, F., Lagrue, E., Blesson, S., Cambazard, F., Vaillant, L., & Maruani, A. (2014) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2014.10.033 · Cited by 8
Flagged first, then by citations
Cited by
Sorted by citations
The role of inflammation in depression: from evolutionary imperative to modern treatment target
Miller, A. H., & Raison, C. L. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.5 · Cited by 3,942
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.188 · Cited by 3,076
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,312
Immunopathology of multiple sclerosis
Dendrou, C. A., Fugger, L., & Friese, M. A. (2015) · Nature Reviews Immunology · doi:10.1038/nri3871 · Cited by 2,215
The Bidirectional Relationship of Depression and Inflammation: Double Trouble
Beurel, E., Toups, M., & Nemeroff, C. B. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.002 · Cited by 2,136
Metadata
- Authors
- Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., Harris, T. H., & Kipnis, J.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Louveau, Antoine
- Kipnis, Jonathan
- ORCID
- Venue
- Nature
- Published
- 2015-06-01
- Volume
- 523
- Issue
- 7560
- Pages
- 337-341
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4506234
- OpenAlex
- W1588685142
- Cited by
- 4,413
- References
- 30
- Citations by year
- 2026: 391 · 2025: 399 · 2024: 423 · 2023: 417 · 2022: 429 · 2021: 435 · 2020: 365 · 2019: 376 · 2018: 367 · 2017: 338 · 2016: 323 · 2015: 146
- FWCI
- 170.91
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-02-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG034113)
- National Cancer Institute (P30CA044579)
- National Institute of Allergy and Infectious Diseases (T32AI007496)
- National Institute of Neurological Disorders and Stroke (R01NS061973)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- meningeal lymphatic drainage, cerebrospinal fluid, lymphatic endothelial cells, dural venous sinuses, neuroimmunology, neuroinflammation, neurodegenerative diseases, deep cervical lymph nodes
- MeSH terms
- Animals, Central Nervous System, Cranial Sinuses, Female, Humans, Immune Tolerance, Immunologic Surveillance, Male, Meninges, Mice, Inbred C57BL, T-Lymphocytes, Lymphatic Vessels
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
