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Lymphatic Vessels of the Central Nervous System

Contents

Overview

Anatomists have long held fast to the notion that lymphatic vessels can be found anywhere in the body except in the central nervous system. For many years, there was no evidence to support the existence of this accessory circulatory pathway within the brain. Instead, it was believed that intracranial interstitial fluid was reabsorbed into the cerebrospinal fluid compartment and subsequently removed.

Recommended video: Introduction to the lymphatic system
Overview of the anatomy, function and main structures of the lymphatic system.

However, in 2015, scientists found convincing evidence that lymphatic pathways exist within the central nervous system. This article will review the role of the lymphatic pathway, previous dogma associated with central nervous system lymphatic tracts and the new discovery of lymphatic vessels in the brain.

Peripheral Lymphatic System

General & Histological Features

The lymphatic system found peripherally consists of lymphatic capillaries and vessels. In comparison to their vascular counterparts, lymphatic vessels are closed at one end that commence in the interstitial space of organs. They are able to promote unidirectional flow of lymphatic fluid from the lymph nodes to the systemic circulation with the aid of valves.

Lymphatic vessel - histological slide

Lymphatic vessel - histological slide

Histologically, the valves are very prominent when the vessels are cut along their long axis. The thin vessel walls are made of a single layer of non-fenestrated endothelial cells that are often referred to as lymphatic endothelial cells. The cells are tightly packed, lack circumscribing pericytes and have an incomplete basement membrane. Interstitial fluid passively crosses the thin walls of the vessels in order to be returned to the venous circulation. Lymph vessels also have a wider lumen when compared to arteries and veins.

Lymphatic vessel - histological slide

Lymphatic vessel - histological slide

The apposition of the lymphatic endothelial cells is so close that they form overlapping intercellular junctions. When the vessel becomes distended as a result of increased interstitial fluid pressure, the junctions open in order to facilitate the flow of macromolecules and fluid through the lumen. At baseline, the vessels are either partially or fully collapsed and the lymphatic endothelium is anchored to interstitial collagen in the extracellular matrix by elastic filaments. This helps to maintain the communication between the extracellular matrix and the lymphatic vessels.

Lymphangiogenesis

Lymphangiogenesis is the process by which lymph vessels are formed. It is usually preceded by angiogenesis and requires activation of the vascular endothelial growth factor receptor 3 (VEGFR-3) by vascular endothelial growth factor proteins (VEGF-C and VEGF-D). Furthermore, the VEGF signalling proteins are also important for regeneration of lymphatics in adulthood and also for neoplasm associated lymphangiogenesis. It is also believed that the growth of these vessels is guided by semaphorin III signalling protein, which is regulated by the activation of non-kinase receptor neuropilin-2 (NPR2) by VEGF-C.

A third significant signalling protein in the lymphangiogenesis pathway is angiopoietin 2 (Ang2); it is expressed by lymphatic endothelial cells. Absence of or deficiency in any of these three signalling proteins can result in hypoplastic, haphazard lymphatics. Finally, the primero homeobox  1 transcription factor aids in committing endothelial cells to specific lymphatic endothelium. It is expressed only by lymphatic endothelial cells in adults. Its activity depresses blood endothelial cells and promotes lymphatic endothelial cells.

Functions

While the major role of the lymphatic system being discussed is that of accommodating excess interstitial fluid back to the circulation, additional immune functions of the lymphatic system are  important for optimum functionality.

The immune functions of the lymphatic system generally include transportation of lymph cells to and from target sites and also plays a role in neoplastic development and metastasis. Evidence suggests that while neo-lymphangiogenesis related to existing tumors is not a requirement for metastasis, it acts as an alternative mechanism of metastasis; resulting in enhanced tumor spread. Furthermore, ectopic VEGF production also results in an increase in the calibre of the pre-existing lymphatic vessels. Therefore, the risk of metastasis would increase just by increasing the number and size of available pathways.

Lymphocytes - histological slide

Lymphocytes - histological slide

Similarly, chemokines receptors such as CCR7 and its associated ligands (CCL19 and CCL21) play a major role in the mobilization of lymphocytes toward lymph nodes. These ligands are also markedly increased in the presence of metastatic neoplasms such as breast cancer and melanoma. As a result , the possibility exists that not only are there more lymphatic channels to carry the neoplastic cells, but expression of chemotactic agents can also enhance metastasis.

Old Concepts on Brain Lymphatics

Immune Privilege

Blood-Brain Barrier

Blood-Brain Barrier

About two hundred years ago, it was thought that the central nervous system did have lymphatic channels that ran on the surface of the brain. However, that was disputed and the accepted theory regarding movement of immune cells to and from the brain parenchyma was then believed to be facilitated by the cerebrospinal fluid. The concept of immune privilege emerged as researchers believed that the central nervous system is the only region of the body devoid of lymphatics. Instead, the blood – brain, blood – cerebrospinal fluid and blood – nerve barriers provide strict separation of the blood from the central nervous system components.

Glymphatic System

A recently proposed theory was that waste material is able to gain access to the cerebrospinal fluid via the glymphatic system. Cerebrospinal fluid would be forced into the dense brain parenchyma, thus displacing the interstitial fluid. This fluid would then enter the paravascular pathways adjacent to the penetrating arteries and veins that support the entrance of cerebrospinal fluid into the brain parenchyma and return to the venous system, respectively. Researchers also theorized that the drainage pathway of the brain’s interstitial fluid would pass through the cribriform plate, enter the nasal mucosa, and then drain to the deep cervical lymph nodes.

Deep cervical lymph nodes - ventral view

Deep cervical lymph nodes - ventral view

New Discovery on Brain Lymphatics

General & Histological Features

In 2015, Louveau et. al. elucidated the presence of lymphatic tissue within the central nervous system. These vessels express the lymphatic vessel endothelial hyaluronan (Lyve-1) as well as the VEGFR3 receptors which are characteristic of the lymphatic endothelial circulation. The vessels were elucidated in whole-mount specimen with the meninges still in place. They maintain similar histological features to their peripheral counterparts; i.e.:

  • they are lined by a discontinuous basement membrane
  • they lack pericytes
  • they have non-fenestrated endothelial cells surrounded by elastic anchoring filament

Location

There are approximately two or three vessels that run parallel to the superior sagittal and transverse sinuses within the dural sinus. They extend from the eyes, travelling superior to the olfactory bulb towards their course alongside the sinuses. While the calibre of the cerebral lymphatic vessels is larger than that of the peripheral lymphatic vessels, the para-sagittal lymphatic vessels are slightly smaller than those that follow the transverse sinus.

Superior sagittal sinus - cranial view

Superior sagittal sinus - cranial view

The disparity between the central and peripheral lymphatic vessels could be a result of pressure differences within the cranium (i.e. high pressure cerebrospinal fluid) compared to the low pressures of the interstitial fluid. The brain lymph vessels assume a more complex arrangement at the base of the skull and are noted to have valves at this level. They leave the cranial vault alongside cranial nerves where they go on to drain directly to the deep group of cervical lymph nodes.

Experimental Evidence

By injecting dye into the cerebrospinal fluid and brain parenchyma of anaesthetised lab models, researchers confirmed that the brain lymphatics not only drain fluid from the cerebrospinal fluid, but also from the brain parenchyma. This drainage pathway was further confirmed by two experiments:

  1. ligating the direct communication between the brain lymphatics and

  2. removing the deep cervical lymph nodes

In the first scenario, it was noted that the lymphatic channels were dilated following ligation and there was no dye present in the deep group of cervical lymph nodes. Secondly, after removing the deep cervical group of nodes, there was a notable increase in the number of lymphocytes within the brain's cerebrospinal fluid when compared to lab models that had the deep cervical nodes in place.

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Show references

References:

  • Dissing-Olesen, Lasse, Soyon Hong, and Beth Stevens. "New Brain Lymphatic Vessels Drain Old Concepts". EBioMedicine 2.8 (2015): 776-777. Accessed 30 May 2017.
  • Gray, Henry, and Susan Standring. Gray's Anatomy. 40th ed. [Edinburgh u.a.]: Churchill Livingstone Elsevier, 2009.
  • Iliff, J. J. et al. "A Paravascular Pathway Facilitates CSF Flow Through The Brain Parenchyma And The Clearance Of Interstitial Solutes, Including Amyloid". Science Translational Medicine 4.147 (2012): 147ra111-147ra111. Accessed 30 May 2017.
  • Jessen, Nadia Aalling et al. "The Glymphatic System: A Beginner’S Guide". Neurochemical Research 40.12 (2015): 2583-2599. Accessed 30 May 2017.
  • Louveau, Antoine et al. "Structural And Functional Features Of Central Nervous System Lymphatic Vessels". Nature 523.7560 (2015): 337-341. Accessed 30 May 2017.
  • Louveau, Antoine, Tajie H. Harris, and Jonathan Kipnis. "Revisiting The Mechanisms Of CNS Immune Privilege". Trends in Immunology 36.10 (2015): 569-577. Accessed 30 May 2017.
  • Pepper, Michael S., and Mihaela Skobe. "Lymphatic Endothelium: Figure 1.". The Journal of Cell Biology 163.2 (2003): 209-213. Accessed 30 May 2017.

Article, Review and Layout:

  • Lorenzo Crumbie
  • Francesca Salvador
  • Adrian Rad

Illustrators:

  • Lymphatic vessel (1) - histological slide - Smart In Media
  • Lymphatic vessel (2) - histological slide - Smart In Media
  • Lymphocytes - histological slide - Smart In Media
  • Blood-Brain Barrier - Photo credit: ssshadowcopy via VisualHunt / CC BY (changes were made)
  • Deep cervical lymph nodes - ventral view - Begoña Rodriguez
  • Superior sagittal sinus - cranial view - Paul Kim
© Unless stated otherwise, all content, including illustrations are exclusive property of Kenhub GmbH, and are protected by German and international copyright laws. All rights reserved.

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