Central nervous system and brain lymphatics
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.
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
- Old concepts of the brain lymphatics
- New discovery about the brain lymphatics
- Experimental evidence
Peripheral lymphatic system
General and 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.
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.
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.
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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.
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.
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 of the brain lymphatics
Immune privilegeAbout 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.
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.
New discovery about the brain lymphatics
General and 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
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.
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.
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:
ligating the direct communication between the brain lymphatics and
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.