Thursday, 4 June 2015

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.

30 comments:

  1. What does this mean for MS/treatment?

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    1. The presence of lymphatics I suspect very little. I hope some nutter doesn't start trying to sell the idea of lymph gland removal.....they are there for a reason.

      As for the glymphatics an interesting bit of biology that is surely part of brain health

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    2. It means that the little drawing in the advertisement leaflet they give for lemtrada or tysabri (maybe in both) is wrong, false and misguiding. An MS relapse is not due to the crossing the blood/brain barrier (BBB) by immune cells simply because they are always free to come and go in the brain as they like. Is it right?

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    3. A relapse is due to immune cells crossing the blood/brain barrier (in large numbers). The normal traffic of immune cells into the CNS is very low (I used to work in this area many years ago). Thing is you do need some immune cell traffic into the brain to detect possible pathogens, which is why stopping all immune cells enering the brain can cause problems such as PML.

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    4. You just restated what the field thought, no? This article (BTW this not the one making the discovery, it appeared in a much less sexy journal but before: see http://jem.rupress.org/content/212/7/991.abstract) so, this article seems to reshuffle the cards quite heavily about this theory.

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  2. Would this support the stress related theory ?
    Also what implications does this have for trrarment, would it give weight to any of the existing cause theories or would it present a possible new cause of Ms?
    Reading the articles the authors and scientists involved seem to state this is a huge breakthrough for treatment of ms

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    1. Support stress theory........no idea
      Treatment see above....
      Cause theories......no different as the ideas of antigens draining into lymph glands was already known, this just shows a pathway, which was already known
      Reading the article.....yep I agree about claims of break through Just look at the abstract but this is the comic Nature and so it helps if you 'big-up' the story.....However just like to say congrats to Johnathan and the team, it certainly made a splash

      Yep it has changed my neuroimmunology as it gives a drain for T cells to leave the brain, I didn't think much of this concept until yesterday but it is clear that once inflammatory processes are halted they soon get emptied out of the CNS, this should be easy to show if this is the case using fluorescent cells and microscopy. Do cervical lymph nodes fill up with cells from the brain, it would be even better if they only started to glow once they have reached the CNS.

      When you get a primary immune response in the draining lymph node you get blast cells (Large pyroninophilic cells) the ear skin drains into the auricular lymph glands and then also downstream into the cervical glands where this can be seen with a skin sensitizer.
      So if epitope spread occurs in a sequential fashion as claimed by some, due to this route, then one would expect to see T cell expansion in the para cortex during CNS inflammation....however I bet this doesn't happen, maybe it does has anyone looked?.

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  3. There is no new thing under the sun. Dawsons central observation and subsequent thesis of MS cause was the involvement of the lymphatic system of the CNS, and that famous and celebrated publication is 100 years old in 2016! By the way, Wellers papers were some time after
    MM Esiri and D Gay. Immunological and neuropathological significance of the Virchow-Robin space. J neuro Sci 100,1990,3-8. You should read it and learn. See also, Gay F. Activated Microglia in Primary MS Lesions: Defenders or Aggressors. Int MS J. 14,2007,78-83....and learn even more.

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    1. Thanks Derek
      Maybe i have read and learned.
      Yes the virchow.....very important do we want a post on that peeps.

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    2. What is the relevance of these in relation to Ms treatment, I know they support the lymphatic discovery but do they give any new options for treatment?
      From reading the article released they say it could be looked at mechanistically, can this be explained, how can there be a mechanistic approach to what is a viral or immured mediated issue?

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  4. To a non-medical eye, the most immediate possible applications could be in searching for MS biomarkers in places other than CSF, avoiding lumber punctures. I have no idea whether sampling the lymph glands in the neck is any easier, but I suspect it may be.

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    1. interesting but not so sure. Analysing fluids is easier than analysing solid tissue. Also i wonder how you would guide needle in the neck. Removing a lymph gland can cause swelling

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    2. interesting but not so sure. Analysing fluids is easier than analysing solid tissue. Also i wonder how you would guide needle in the neck. Removing a lymph gland can cause swelling

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  5. Assuming that this new information is correct, does it improve or reduce the likelihood of success of anything being studied or used in the MS community now? (getting at it another way, if we know about this now, what will we want to have done looking back 10 years from now - abandon XX approach or drug; study YY in more detail; or it explains why ZZ only works for 50% of people. . .)

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    1. nothing changed at all I would suspect. So all the altmetrics for what.....intersting bit of science for us and not much therapeutic output i suspect

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    2. nothing changed at all I would suspect. So all the altmetrics for what.....intersting bit of science for us and not much therapeutic output i suspect

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  6. Does this discovery minimize the importance of the blood brain barrier integrity in neuro-degeneration? During periods of inflammation the BBB would become a pathway for lymphocyte movement into the CNS. Are reactive t-cells coming from leaky blood vessels or from the lymphatic vessels? And does it really matter how they get into the CNS as long as they are present and causing damage?

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  7. From your comment: "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."
    Is this the same aquaporing 4 which is implicated in NMO?

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    1. Yep so I wonder what this means for their brain flushing.....an obvious study to do if you are interested in NMO.....Based on profGs question about whether anyone with NMO reads this blog...I think we got no positive responses so the only releveant of those posts are for docs reading the blog.

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  8. Does this implicate and or support the ccsvi theory and explain why many have seen success from this treatment

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    1. Absolutely not and the "success" of this treatment is highly dubious as recent clinical data has confirmed.

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    2. perhaps rather a lot of textbooks need to be rewritten - then perhaps patients will come to understand CCSVI in the context of the underlying venous pathology of MS

      http://ccsviinms.blogspot.co.uk/2015/06/rewrite-textbooks.html?showComment=1435436197474

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    3. The discovery of were brain lymphatics will require updates in text books but I really doubt
      that this will be seen in the CCSVI debacle, as the two are in my opinion unrelated one phenonomon appears no to exist the other appears no to.

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  9. I know this won't be posted but I'll write it anyway--This study confirms how important mechanical drainage of the brain is, supporting the importance of venous angioplasty for CCSVI--so of course the loudest naysayers feel the need to dismiss it! I'm just glad there are some researchers with real scientific curiosity out there--the MouseDoctor can't shut them all up by deleting them!

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    1. Wrong on both counts...comment posted and does nothing to support importance of CCSVI, and if you actually read why the American group did the study, it was because they are interested in immunology....something the CCSVIers would have us believe is a waste of time...so yes it is good that researchers are curious but it is misguide to think that we have any influence on their thought process or their ability to do such work

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  10. If the CSF is removing waste to the lymph system that has been 'found' does that mean that the flow of CSF is crucial to neurological health?
    If for instance there is slow blood flow and a decrease in oxygen that is symptomatic, if there is slow CSF flow is that symptomatic?
    If the arterial flow 'powers' the CSF pulsations then aren't the CCSVI decreased flow findings also directly linked to the lymph system's ability to clear the brain, you can't have good CSF and poor blood flows?
    Your comment that CCSVI is not related to the lymph system findings doesn't appear to be at all correct, or even could be biased against CCSVI being a factor in MS.
    Regards Nigel

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  11. Thanks for the reading, i've been following the developments about lymphatic drainage of CNS by a few months. Glymphatic system has been known for some years, but papers goes back to 1992 was something new for me. i am so pleased to find out your comments and i will be following your blog.

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  12. Thanks for this - does it mean that manual lymphatic drainage could be a helpful treatment for MS?

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    1. I wouldn't think so and it certainly does not support the CCSVI theory.

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