The Brain Drain....from Nervous to Immune system

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jun 1. doi: 10.1038/nature14432. [Epub ahead of print]

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.

In the body there exists a number of systems. We have the blood system, where blood travels from the heart via arteries these get small to become aterioles then the vessels become capillaries and then venules and then veins take blood back to the brain. Some of the blood fluid called plasma can leave the blood vessel and bathes the tissues where it is interstitial fluid then drains via lymphatic vessels into lymph glands and eventually enters the blood again. The skin has lots of lymphatic vessels and so it means that anything entering the skin can be sampled by the local antigen presenting cells and then taken into the lymph gland where it can sensitize the white blood cells, so that next time you encounter this antigen you get a fast immune response to destroy it.

It is the case that some organs are not particularly good at making these sensitizing signals and the brain and testicles are two such organs and they were called immune priviledged sites. Certain sites of the human body have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response. There are many reasons for this immune privilege but one concept was that the brain does not have any lymphatic drainage. This paper indicates that there is indeed some lymphatic drainage and this leads into the lymph glands in the neck. So now you have a lymphatic link. 

Is this how MS starts. Antigens drain from the brain to the glands and hey presto the beginning of MS? This may be the case and is clearly a route of how we can get epitope spread, where immune response to one antigen causes damage and the release of other antigens that sensitize the immune response to cause more damage and so on.  So is "outside-in" the problem where the peripheral immune system enters the brain or is it "inside-out" both possibilities. However the brain has a lot less specialised antigen presenting dendritic cells than say the skin. 

In this study they were seeking to find routes of recirculation of white blood cells. I rather wonder if you really need this recirculation because we can make lots of new cells in lymph glands every day. They can go round the body hunting for a target and so if a cell got into a tissue and didn't find its target, it could die and the lymph gland can make a new one to go elsewhere where if may find it and then it would call other  cells in to deal with the problem and then die. However, it is an age of complication and it is now suggested by some that cells travel round the body and go for a trip in the lungs before heading off to the brain...which seems rather complicated. 

Is there a T cell gateway into the CNS? We had the, may I suggest perhaps mad, idea that the way-in is just via Lumbar 5 spinal, Lumbar 5 was the problem because  this is a weight bearing region and only finding the front leg gateway when the mice were hung upside down by their tail for months..em!. 

Maybe easier just to go through blood vessels expressing the right adhesion molecules and chemokines (movement signalling proteins) responding to inflammation below them. 

Anyway what this study found was that in the meninges  surrounding the brain there were vessels that looked like lymphatic vessels. Indeed they could inject stuff in the brain and it could be picked up in a lymph gland.

This concept is not new and a Doc from Southampton, UK was claiming a lymphatic link between the brain and the cervical lymph gland many,many years ago

Weller RO, Kida S, Zhang ET Pathways of fluid drainage from the brain--morphological aspects and immunological significance in rat and man. Brain Pathol. 1992;2:277-84.

Kida S, Pantazis A, Weller RO CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol. 1993 Dec;19(6):480-8.

However, what this study does do is that it puts extra microanatomy into the mix and suggests that the drainage into the lymph gland in the neck comes direct from the brain and not via the lymphatics in the nose as was previously suggested.

This study shows lymphocytes in the lymphatics and also importantly antigen presenting cells. 

However, we knew that stuff was getting into that lymph gland because when you look in the lymph glands you could see myelin

de Vos AF, van Meurs M, Brok HP, Boven LA, Hintzen RQ, van der Valk P, Ravid R, Rensing S, Boon L, 't Hart BA, Laman JD.Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol. 2002; 169(10):5415-23.

So does this idea in mice occur in humans, is the next question 

As Dr Love and Friends have reported that myelin antigens are found in lymph glands in mice, monkeys and humans then the answer is probably yes. 

So you may be interested in the The glymphatic system (or glymphatic clearance pathway) is a functional waste clearance pathway for the mammalian central nervous system (CNS). The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between the CSF and the ISF is driven by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space. Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of the ISF, facilitated by astrocytic aquaporin 4(AQP4) water channels.

While glymphatic flow was initially believed to be the complete answer to the long standing question of how the sensitive neural tissue of the CNS functions in the perceived absence of a lymphatic drainage pathway for extracellular proteins, excess fluid, and metabolic waste products, The finding reported here  show that the dural sinuses are in fact lined with lymphatic vessels, and that this long-elusive vasculature forms the connecting pathway for the entrance and exit of lymphatic fluid and immune cells from the meningeal compartment to the glymphatic system

Glymphatic system is affected during slow wave sleep and there is clearance of interstitial waste products increases during the resting state. Changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes maybe the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain.