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                             Veins and Lymphatics 2015; volume 4:5360

[page 58]                                                          [Veins and Lymphatics 2015; 4:5360]

The discovery of the brain 
lymphatic system
Paolo Zamboni
Translational Surgery and Vascular
Diseases Center, University of Ferrara,
Italy

In the latest issue of Nature Antoine
Louveau and a team of collaborators of the
University of Virginia, published a break-
through article for who is interested in lym-
phatics, with a clear and elegant description of
the lymphatic system of the brain.1

Surprisingly, few days later a group of
Helsinki confirmed with other experiments
the existence of a cerebral lymphatics network
connected with cervical nodes.2

Despite the rapid popularity of this article it
does not represent a revolutionary discovery,
but rather an updated systematic description
of connections and function of the lymphatic
system in this particular anatomical district. It
should be, in fact, recognized that a forgotten
literature on Durand Fardel’s periarterial and
perivenous Virchow-Robin’s spaces, recently
turned into glymphatic system,3 exists from
more than a century. However, this article per-
mits to definitely overcome the neurocentric
concept that lymphatic drainage of the central
nervous system is confined to the meningeal

compartment and there is a lack of lymphatic
drainage in the brain parenchyma. The
Authors also better clarify the structure and
the function of the so called glymphatic sys-
tem, till now more supposed than proved.3

The group of the University of Virginia
clearly found the lymphatic system practically
in the wall of the dural veins, and this testifies
the functional and anatomical cross talk
between the two systems, something which
gives the title to our Journal. Moreover, they
demonstrated with elegant images that inter-
connection of the lymphatic collectors are not
just veins, but also the cerebrospinal fluid
(CSF) (Figure 1), and the deep cervical lymph-
nodes and with the internal jugular veins, as
well. What are the potential implications of
this discovery? The main consequence is that
the dogma of the immune privilege of the
brain, as admitted by the Authors themselves,
dramatically falls down. We all studied that the
brain is segregated from the immunitary point
of view.4 The physical reason was just the lack
of lymphatics, which means no T-cell gataway
into and out of the brain. The demonstration of
the central nervous system lymphatics war-
rants an urgent reassessment of the basic
assumption in neuroimmunology. 

In fact, the immune privilege of the brain
means that T-cell and antibodies found in the
brain and/or in the CSF are of brain autochtho-
nous production. Consequently, the presence of
T-cells was considered of autoimmune origin.

The new concept easily paves the way to recon-
sider the autoimmune etiology of a number of
neuroinflammatory and neurodegenerative dis-
eases, including multiple sclerosis, Alzheimer’s
disease, etc. Of course, the interconnection of
the brain lymphatics with both the nasal
mucosa and the deep cervical lymph-nodes, as
well, permits to understand that there is no seg-
regation at all. To the contrary, T-cells but also
viruses may easily circulate. Moreover, the
interconnection with CSF clearly indicates that
what we found in it cannot be more considered
autochthonous. Furthermore, in origin we know
that manual lymphatic drainage is a valid reha-
bilitation method for treating lymphoedema.
The challenge is: may this technique to be use-
ful also for the brain? May the interconnection
of the brain lymphatics with the deep cervical
lymph-nodes, a draining route toward the tho-
racic duct, be improved? Both articles really
open new and stimulating questions, and this
happens only when a discovery is a real scientif-
ic advancement.

References

1. Louveau A, Smirnov I, Keyes TJ, et al.
Structural and functional features of cen-
tral nervous system lymphatic vessels.
Nature 2015 [Epub ahead of print].

2. Aspelund A, Antila S, Proulx ST, et al. A
dural lymphatic vascular system that
drains brain interstitial fluid and macro-
molecules. J Exp Med 2015 [Epub ahead of
print]

3. Yang L, Kress BT, Weber HJ, et al.
Evaluating glymphatic pathway function
utilizing clinically relevant intrathecal
infusion of CSF tracer. J Transl Med
2013;11:107. 

4. Antel J, Birnbaum G, Hartung H-P, eds.
Clinical neuroimmunology. Boston:
Blackwell Science; 1998.

Correspondence: Paolo Zamboni, Translational
Surgery and Vascular Diseases Center, University
of Ferrara, via Aldo Moro 8, 44124 Cona (FE),
Italy.
E-mail: paolozamboni@icloud.com

Received for publication: 10 June 2015.
Accepted for publication: 10 June 2015.

This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).

©Copyright P. Zamboni, 2015
Licensee PAGEPress, Italy
Veins and Lymphatics 2015; 4:5360
doi:10.4081/vl.2015.5360

Figure 1. Schematic representation of the functional histology specimen showed in the
Nature article.1 The lymphatic system lines the venous dural sinuses and is closely inter-
connected with cerebrospinal fluid (CSF) space, as well as with meningeal vessels. Out of
the skull the interconnection was found by the researchers of the Virginia University both
with the internal jugular vein and with the deep cervical lymph-nodes.

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