Second Study Shows Lymphatic System in The Brain

[Never Give Up]

The Journal of Experimental Medicine just published this! Note the submission and publication dates at the end.

http://jem.rupress.org/content/early/2015/06/09/jem.20142290.short

A Dural Lymphatic Vascular System that Drains Brain Interstitial Fluid and Macromolecules

Aleksanteri Aspelund,1,2 Salli Antila,1,2 Steven T. Proulx,3 Tine Veronica Karlsen,4 Sinem Karaman,3 Michael Detmar,3 Helge Wiig,4 and Kari Alitalo1,2

ABSTRACT

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.

Submitted: 8 December 2014
Accepted: 4 June 2015

 

[Jonathan Edwards]

Thanks for flagging tht. It seems to clarify some of the queries we discussed on the other thread.

It looks as if immunological drainage from brain may not be through the main reservoir of CSF as such, which may mean that measuring CSF levels of cytokines etc may not be telling us about events in the brain very reliably. It may indicate events in subarachnoid space. The maintenance of a positive hydrostatic pressure despite the presence of exit routes could be explained by 'raspberry valves' - these are exits that have no rigidity so collapse down under the pressure that should be feeding them thereby blocking themselves off. A small exit flow might be maintained by arterial pulsation briefly sucking the exit open and then shutting it again so that individual shots of fluid are expelled - i.e. the system you have in an optic measure on a whiskey bottle. You have to keep reversing the pressure and fluid only comes out in small shots.

 

[Bob]

It looks as if immunological drainage from brain may not be through the main reservoir of CSF as such, which may mean that measuring CSF levels of cytokines etc may not be telling us about events in the brain very reliably.

That's an interesting observation. From reading research literature, I think it's often taken for granted that the CSF is linked to the brain in some way. I'm not sure why. Perhaps people assume there's at least an indirect link, because the fluids are similar? Or perhaps similar infections are often found on the brain and in the CSF?

Shouldn't it be quite easy to find out exactly where brain fluids and CSF fluids drain off to, at least in a mouse model? I would have thought that they could simply inject the brain and CSF with separate (i.e. radioactive) markers and then place the subject in a scanner.

If they can discover exactly where the brain fluids drain to, then the next step would be to see if it's easy to extract the drainage fluids for examination in research studies, thus obtaining brain fluids while avoiding invasive brain procedures.

(Apologies if this has all been discussed before.)

 

[Never Give Up]

Here's a write up from the University of Helsinki:

http://www.med.helsinki.fi/english/news/2015/20150615_aivoimut.html

Unraveling the link between brain and lymphatic system
Researchers at the University of Helsinki and Wihuri Research Institute report an exceptionally surprising finding that argues against all previous anatomy and histology textbook knowledge – lymphatic vessels exist in the central nervous system.

The authors’ original image shows two dura mater lymphatic vessels (red) running along meningeal blood vessels (green).

Researcher Aleksanteri Aspelund and colleagues discovered a lymphatic vessel network in the mouse meningeal linings and that these vessels have a direct connection to the body’s systemic lymphatic network.

Lymphatic circulation forms a network that covers almost the whole body and is especially important to the tissue clearance of excess fluid and macromolecules as well as to the immune defense mechanisms. Until now, the central nervous system has been considered an immune-privileged organ not connected to the lymphatic system....

– However, we didn’t expect to find such an extensive network directly connected to the brain. This incredible finding completely changes our understanding of the brain anatomy and gives a chance to look at brain diseases from a completely new angle, he continues.

Read full article here.

 

[Jonathan Edwards]

That's an interesting observation. From reading research literature, I think it's often taken for granted that the CSF is linked to the brain in some way. I'm not sure why. Perhaps people assume there's at least an indirect link, because the fluids are similar? Or perhaps similar infections are often found on the brain and in the CSF?

Shouldn't it be quite easy to find out exactly where brain fluids and CSF fluids drain off to, at least in a mouse model? I would have thought that they could simply inject the brain and CSF with separate (i.e. radioactive) markers and then place the subject in a scanner.

If they can discover exactly where the brain fluids drain to, then the next step would be to see if it's easy to extract the drainage fluids for examination in research studies, thus obtaining brain fluids while avoiding invasive brain procedures.

(Apologies if this has all been discussed before.)

Studying fluid dynamic physiology is far from straightforward because there are different components of diffusion and convection involved at all different molecular and cellular levels. It should certainly be possible to follow tracers injected into branches of cerebral arteries at least in large mammals. Mice might be tricky and of course the relation of diffusion to convection will be different in mice and humans because of size factors. You also have to distinguish convective flow across boundaries from convective flow within chambers or compartments. Physiologists routinely get the analysis wrong for fluid dynamics - which is where Rod Levick and I had to do work to sort out what really goes on inside joints.

So far my impression is that the most likely message from this new stuff is that antigen presenting immune cells would be able to traffic back to lymph nodes from brain tissue without getting lost washing about in the free CSF compartment - which makes a lot of sense. I am a bit doubtful that ideas on protein clearnace would change much.

 

[Jeckylberry]

Reviving this thread with another article...

https://news.virginia.edu/illimitable/discovery/theyll-have-rewrite-textbooks

Note the bit where the professor of neuroscience says “I really did not believe there were structures in the body that we were not aware of. I thought the body was mapped,” Says everything!! Prannet.

 

[Little Bluestem]

Those unknown unknowns surprise people.

 

[Jeckylberry]

Those unknown unknowns surprise people.

Don't they! They used to believe they had mapped the body when they thought that the heart was fuelled by fire and that the babies grew entirely from the sperm, that bad air was the cause of cholera and that you blow smoke up the backside to revive a drowned person. Every generation has been guilty of this self same arrogance. When will they learn to approach it with the mind of a scientist and not a doctor?