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Missing link found between brain, immune system -- with major disease implications

ebethc

Senior Member
Messages
1,901
not surprising, but great that the medical community is finding evidence. especially interesting to anyone with both sinus issues and alzheimer's genes.

"In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia (UVA) School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis....

...As to how the brain's lymphatic vessels managed to escape notice all this time, Kipnis described them as "very well hidden" and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. "It's so close to the blood vessel, you just miss it," he said. "If you don't know what you're after, you just miss it.

...The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist."

- See more at: http://www.neuroscientistnews.com/r...jor-disease-implications#sthash.7XeJaMOY.dpuf
 
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Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
In theory these findings bolster the possibiliy of being able to detect metabolites of, for example, neuroinflammation (quinolinic acid?) in serum. I'm sure I've already seen some studies but I'd also expect some inconsistencies between srum and CSF measures.

It would be nicely non-invasive though if possible..
 

MEMum

Senior Member
Messages
440
That is already on the cards since we know of autoimmunity to potassium channel complexes and other CNS proteins.

Antibodies to the pyruvate kinase receptors of the basal ganglia found in at least one person with ME.
Hopefully Professor Vincent will find out more in the IiME project with Bharat Harbham (med student) and Dr Bansal.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
The article I read said that the lymph drains into the sinuses. Is this useful information for people here with chronic sinus infections (@heapsreal ) or nasal symptoms? Would lymphatic drainage of the head perhaps be useful to alleviate brain issues?

Exactly so, according to Ray Perrin - see above

I am afraid scarecrow has got me off on a Pythonesque tangent on this. I was reminded of Stanley Unwin's concept of 'trickly-how' as in:

Trickly-how of snowflakers shimmer'n'twinklit under the streel lamp. Joy! Thenfrozzlit pavey, & falollop on the borkus there. Deep Folly!

or

Joseph trickly-how along the roam with Mary all two-square on the botty astrile a donkey, seekit accomodakers. Weary weary all eye-rubbit and...

But seriously, I am beginning to think this study needs the razor sharp analysis of certain PR members who can be relied on to pop up when needed. Firstly, these are dural venous sinuses, not nasal air sinuses - completely different thing. Dural sinuses are basically veins. Now if these lymphatics drain into the sinuses their contents will go straight to the lungs and heart, not the lymph nodes, so I think we need to know which, because to function as lymphatics it would need to be to lymph nodes.

I am also thinking that these channels are in the dura and the dura is a heck of a long way from most parts of the brain. If an immune response were to occur in thalamus I find it hard to see how any dendritic cells could find their way to the region of dural sinuses. So maybe what these people have found is a lymphatic drainage of meninges but not really a lymphatic drainage of deep brain tissue.

I really need to read all the papers but am a bit busy with other things at present.
 

Strawberry

Senior Member
Messages
2,100
Location
Seattle, WA USA
not surprising, but great that the medical community is finding evidence. especially interesting to anyone with both sinus issues and alzheimer's genes.

So should I print this study and have my MRI re read? (If I can even find a doctor willing to care in my area....)
 

anciendaze

Senior Member
Messages
1,841
Just want to remind people that the Latin medical term sinus is a generic one for a cavity, void or channel in some surrounding structure like bone. There are even "sinuses" in the placenta.

I am less concerned, compared to Professor Edwards, with the fact that these new structures are immediately adjacent to the dura and meninges rather than the brain. Healthy meninges play an important role in functioning of the brain, and get far less respect. Vascularization of the brain is very complicated. Simply supplying neurons with oxygen and glucose, and removing ordinary waste products, is a problem, considering various bizarre geometric constraints due to the shape. We now have a third system to include. This reminds me of the comment attributed to Henry the Navigator when Ptolemaic astronomy was explained to him: "Had I been present at the Creation, I would have suggested something simpler."

What this finding shows is that there is enough steady traffic of leukocytes out of this region to require separate pathways. Since these cells are not created in either the brain or meninges there must be traffic in the opposite direction, even in non-pathological situations. Tapping into this flow at some point where this does not require trepanning should provide a unique view into immune activity in and around the brain which we have not had.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
First we learnt about retrovirology for xmrv; then a beginner's course in medical stats for the PACE trial, and a crash course in study design and good practice for medical trials; then a crash course in autoimmunity for rituximab; then it was the krebs cycle and metabolism for Julia Newton's research; and now it looks like it will have to be an anatomy lesson as well! Oh, and then there's genetics, epigenetics, and immunology. With a little oncology thrown in, and proteomics and metabolomics yet to come. Have I missed anything? I've probably missed quite a bit. At least our illness won't have been a complete waste of time - if we don't all have enough knowledge to get a degree in biology by the time we're cured, then I'll be very surprised! :)

Edit: oh, and expert crowdfunders, bloggers, community support advisers, carers and advocates thrown in to the mix. Not to mention making lots of wonderful friends and meeting quality fellow travellers on the way.

Sorry, slightly off-topic!
 
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lansbergen

Senior Member
Messages
2,512
Firstly, these are dural venous sinuses, not nasal air sinuses - completely different thing. Dural sinuses are basically veins. Now if these lymphatics drain into the sinuses their contents will go straight to the lungs and heart, not the lymph nodes, so I think we need to know which, because to function as lymphatics it would need to be to lymph nodes.

They say connected to the deep cervical lymph nodes.

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.
 

ebethc

Senior Member
Messages
1,901
The article I read said that the lymph drains into the sinuses. Is this useful information for people here with chronic sinus infections (@heapsreal ) or nasal symptoms? Would lymphatic drainage of the head perhaps be useful to alleviate brain issues?

common sense would say "yes" but who knows what your doctor would say :) I have chronic sinus probs AND brain fog, so that's what my own takeaway is from this article. It's something that I have always believed myself, but didn't have the proof. I'll take this to my doctor visit @ OMI in July (Dr Kaufman at the Open Medical Institute)
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Leaving anatomical specifics and Dr Perring aside my own simplistic take on this is that these structures may play a key role in removing waste products (from normal metabolic processes/pathology related damage) from the brain. It seems to me that impaired waste removal might logically lead to prolonged symptoms.

PS doesn't cerebrospinal fluid service/permeate the whole brain?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Leaving anatomical specifics and Dr Perring aside my own simplistic take on this is that these structures may play a key role in removing waste products (from normal metabolic processes/pathology related damage) from the brain. It seems to me that impaired waste removal might logically lead to prolonged symptoms.

PS doesn't cerebrospinal fluid service/permeate the whole brain?

I think maybe we need to get the functional anatomy right before we can make any sense of this. Tissue fluid dynamics is a subject that scientists often get wrong. Rod Levick and I had to completely rewrite the fluid dynamics of synovium in the 1980s because we realised that for synovium influx and outflux occurred in parallel, not in series.

I think we can assume that these lymphatics have nothing particular to do with the dural sinuses; they are just alongside in position. They form an outflux pathway from CSF to lymph node.

So does CSF permeate the brain? The traditional description I think says no. It says that CSF is generated as an ultrafiltrate of plasma through the choroid plexus in the lateral ventricles. And that the fluid so formed moves very gradually through third and fourth ventricles to the subarachnoid space, where it is reabsorbed by arachnoid granulations. Tissue fluid within the brain will be an ultrafiltrate from intracerebral capillaries. In most tissues you need lymphatics to drain off this ultrafiltrate but because the brain is bathed in a pressurised fluid compartment there may be no need to drain fluid volume from brain tissue in the same way. However, if there is excess ultrafitrate in the brain from its capillaries the only other way out is in to CSF so I think the traditional description proposes that a small amount of cerebral interstitial fluid diffuses into the CSF and is then removed via granulations. The discovery of lymphatics does not really have any impact on that since it just changes the last word to lymphatics.

The traditional description of CSF flux has always been odd because it does not seem to achieve anything. There is no organised directional flow, for instance to the spinal cord, which is a blind alley. One cannot expect the flow pathway to get rid of debris. Old cells in the sacral root sheaths would be unlikely to find their way to an arachnoid granulation. Why bother to produce and reabsorb? All that CSF seems to be needed for is a constant volume fluid shock absorber for brain.

The answer to that puzzle I think lies in the maintenance of protein level. In a closed pressurised system you can achieve hydrostatic equilibrium so that there is no need for convective water movement - diffusion in equals diffusion out. But over time that will tend to produce protein concentration equilibrium, because there is, even in brain, a slight permeability of capillaries to protein so eventually the tissue fluid and CSF protein would come up to plasma levels. It seems that the blood brain barrier is designed to keep brain and CSF protein very low. The only way to do that is to have a non-disequilibrium state with an outflow that continually drains off protein. With a low permeability of capillaries you then end up with a throughput of water constantly washing out any protein that might accumulate. (Note that the route is from brain interstitial fluid to CSF; CSF itself never gets in to brain.)

So this leaves us with an interesting puzzle. If the system is pressurised then you cannot have an open outflow drain - the pressure would collapse and you would get a lumbar puncture type headache. And lymphatics are open outflow drains. So how are our researchers going to explain that!!! The old idea would have been that arachnoid granulations maybe removed protein by having pinocytic cells on their internal surface 'sucking up' any protein in CSF. I don't know if anyone proved that. It seems that if there really are lymphatics they would have to be of very narrow calibre so that they only drained off fluid at a tiny rate. They might still be an important pathway for antigen presenting cells to escape and I guess that would be the main significance of the findings. And rather than arguing whether protein goes out via granulations or lymphatics I suspect the answer will be both, since so many tissues have belt and braces mechanisms for these functions.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
@Jonathan Edwards

Thanks Jonathan for the comprehensive response. I take your point about an open outflow drain.

I would need to think this through but my initial response is that you're describing an organ that doesn't need to excrete waste or if it does only in miniscule quantities which is quite unlike other organs particularly ones with a very high nutritional/energy requirement. 'Flushing' or a rapid flow through the system seems to be the norm.

'Ultrafiltrate' also suggests that there is some residue from metabolic processes. Is it all broken down into proteins that are then excreted very gradually from the CNS (via granulations/lymphatics)? That sounds quite a static/unresponsive system for an organ that seems very sensitive to 'environmental' conditions and not at all like the 'active' flushing proposed by the glymphatic system (dural sinuses and all) :.

http://en.wikipedia.org/wiki/Glymphatic_system
 

anciendaze

Senior Member
Messages
1,841
I'll definitely agree that previous explanations of CSF pressure and flow leave a great deal to be desired. I respectfully disagree with the relevance of comments about capillary permeability and proteins w.r.t. movement of leukocytes. Movement of cells from capillaries into tissues is quite different, as Prof. Edwards is well aware. In addition there is already work showing a much more sophisticated process behind entry of important classes of immune cells into lymphatic vessels.

This was on my mind some time ago, when we had a disagreement over possible explanations of immune operations involving dendritic cells. Research on these cells was "trendy" many years ago because our understanding of their functioning was so incomplete as to be termed fragmentary. This meant "real knowledge", as in the example proffered, was either likely to be based on old knowledge of humoral immune response and direct action by autoantibodies, or to be considered highly speculative. At the time I was too upset over medical matters extraneous to that discussion, which cost me a family member, to explain.

I'm afraid I've seen far too much medical literature with the underlying assumption that "old is good; new is dangerous", completely ignoring the often appalling results of contemporary ignorance. In the practice of immunology, one could write an entire book about professional misuse of steroids alone, quite separate from abuse by athletes. (See iatrogenic Cushing's syndrome.) These were synthesized in the 1930s, with a Nobel Prize in 1939. Problems associated with professional misuse for alleged therapeutic purposes, rather than deliberate misuse for "performance enhancement", still persist.

Just thinking back to people I have known, (though fortunately not talking about medical disasters of which I was a victim,) I can recall people who were treated for TB by deliberate pneumothorax, some of whom died during the procedure. (I didn't know these, I was told by survivors of the process.) I've known people who were functionally blind due to retrolental fibroplasia because "everyone knew" oxygen was good for premature infants. I've known diabetics who suffered amputations due to inadequate monitoring of blood glucose, and recall a battle over allowing patients to test their own blood sugar. I've also mentioned knowing people who underwent vagotomy based on the conventional medical wisdom that peptic ulcers were caused by bad thinking habits in the brain upsetting the stomach.

I'm thoroughly baffled by the extent to which conventional medical ignorance is treated with professional respect.

---
Here's quite a different insight concerning this new work showing a lymphatic system which drains into deep cervical lymph nodes, has anyone commented that the key clinical sign in differential diagnosis of acute bacterial meningitis has long been a stiff neck? Why wasn't there an investigation of such a connection working back from those lymph nodes?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards

Thanks Jonathan for the comprehensive response. I take your point about an open outflow drain.

I would need to think this through but my initial response is that you're describing an organ that doesn't need to excrete waste or if it does only in miniscule quantities which is quite unlike other organs particularly ones with a very high nutritional/energy requirement. 'Flushing' or a rapid flow through the system seems to be the norm.

'Ultrafiltrate' also suggests that there is some residue from metabolic processes. Is it all broken down into proteins that are then excreted very gradually from the CNS (via granulations/lymphatics)? That sounds quite a static/unresponsive system for an organ that seems very sensitive to 'environmental' conditions and not at all like the 'active' flushing proposed by the glymphatic system (dural sinuses and all) :.

http://en.wikipedia.org/wiki/Glymphatic_system

I was not aware of the glymphatic hypothesis - which Wikipedia says may now be out of date! I think a mouse brain may not be quite the same as a human brain here. I find it hard to envisage very major back and forth convective fluid flow in big lumps of deep brain like internal capsule and thalamus but it sounds as if there is at least some convetive exchange to be expected. That will speed up the diffusional model I was working with but probably does not alter the overall structure of the dynamics.

Ultrafiltration occurs at capillary and venular walls where fluid is entering tissues. Water gets through quite easily, and so do small molecules like glucose and its metabolites, but protein moves through much less easily. So where there is net flux out of the vessel the water comes in to the tissue without much protein and as long as water keeps wafting through the protein never builds up. If there is no net convective inwafting of water then protein can gradually equilibrate across the wall so you would have neat plasma in the tissue. There are no tissues where that happens, I think. Bone marrow and spleen have neat plasma in the tissue because their capillaries are effectively open to the tissue.

This field really is very complicated and the next thing to say is that almost all the exchange of water and metabolite molecules into and out of tissue occurs by molecular diffusion across capillary and venular walls and this is much faster than any of the convective movements we have discussed so far. So none of this about lymphatics i very relevant to molecular exchange in respiration. In the time it takes for a net flux of x water molecules to enter tissue from capillary those same water molecules may have diffused back and forth across the same wall a hundred times. For water that is invisible because the net is zero. For glucose, oxygen and lactate it is the main form of exchange.

The real issue is proteins, which are not going to diffuse back out of the tissue into capillaries and venules much once out in the tissue. In most tissues they end up exiting via a lymphatic. In brain it might have seemed there was no way out. People talk about this being relevant to amyloid accumulation but since this is a crystallisation process I am a bit doubtful that this is realistic (as is Wikipedia).

Clearly you were right to say that CSF gets into all brain tissues if the glymphatic story in mice applies equally to humans. And there may be further orders of complexity I am not aware of. It would be interesting to know just what these lymphatics are like and do in humans. It may not be like mice. Within the bird world (Aves) quite closely related species often differ by major things like how many carotid arteries they have. Maybe human dural lymphatics are vestigial after all?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I'll definitely agree that previous explanations of CSF pressure and flow leave a great deal to be desired. I respectfully disagree with the relevance of comments about capillary permeability and proteins w.r.t. movement of leukocytes. Movement of cells from capillaries into tissues is quite different, as Prof. Edwards is well aware. In addition there is already work showing a much more sophisticated process behind entry of important classes of immune cells into lymphatic vessels.

I am not quite sure what point you are wanting to make anciendaze. We all agree that movement of cells across vessels is quite different from fluid and solute flux. I was not suggesting that there was any relevance of one to the other. And clearly intravasation has a different mechanism from extravasation, as I thought I had implied. So lymphatic endothelium has different properties and surface molecules from blood vessels. I think we are still left with the question of how a dendritic cell in the thalamus might find its way to a dural lymphatic a few inches away and if it does do that in what way that makes things different from finding an arachnoid granulation to creep out of and into tissue lymphatics that way. I am not sure what the point of disagreement was to be honest!!