CNS lymph vessels found. Brain is not immune-privileged

[cheerleader]

Brief primer on the lymph system from Kahn Academy...notice lymph vessels go one way, they are kind of like veins, in that they are low pressure, and are lined with endothelial cells. They also have valves, to keep lymph moving. All of our body's lymph drains into the neck veins. We used to think that lymph vessels didn't exist in the brain, that they just stopped in the neck...but now we know that's not true. https://www.khanacademy.org/test-prep/n ... move-fluid

As briefly as I can It's always been known that cerebrospinal fluid cleanses the brain, which then drains into the cervical lymph nodes, but we didn't know how CSF got to the lymph nodes. Now we know that there's a network of lymphatic vessels in the dura mater, that carry immune cells.

Part of the reason researchers thought the brain was immune privileged was that they never saw any lymph vessels, so they developed a special theory on the brain's immune system. For 70 years it was believed that the only reason immune cells would be near the brain was to fight infection, in an inflammatory reaction after a break in the blood brain barrier (like stroke) or due to an "autoimmune" reaction. This theory was developed around the same time as EAE. The Un. of Virginia and Helsinki found the actual lymph vessels, running alongside the dural sinus veins, and this may imply that the brain needs immune cell support in order to function, heal and regenerate. That's certainly been Dr. Michal Schwartz's position for 2 decades ("protective autoimmunity theory.)
I wrote up a blog post explaining the history of the immune privilege theory, for those who have time and or energy to read more...
http://ccsviinms.blogspot.com/2015/06/r ... books.html

how is it that we have oligoclonal bands that are unique to csf? Wouldn't some of the same immune cells drain into the bloodstream and show up on blood tests

I thought OB's could show up in serum? Anyway, I'm following all this quite closely. It must be going to affect a lot of other theories and treatment methods. It's certainly opened my eyes, and I think the implications will be huge.

The banding in the CSF in MS may or may not show up in blood. Bands shows immunoglobulin G (IgG) index and OCBs, which indicate inflammation and a break in the blood brain barrier, and myelin degradation which enters the CSF. Since we now know the lymph and CSF combine in the brain, that won't change anything due to this discovery, because the CSF and lymph combine before they re-enter the blood stream. But CSF bands are not unique to MS. That's why banding is only part of the MS diagnosis (along with lesions in space and time and clinical presentation), because it is not specific.
Here's more on how it's measured. http://www.clinlabnavigator.com/oligocl ... n-csf.html
Make sense? Let me know if not...will try harder
cheer

[Bethr]

Thanks Cheer, I know a bit about the lymphatic system as I have a piece missing, my spleen. Movement is apparently good for your lymphatic system to keep fluid moving. I get quite dirty blood with lots of microparticles and old cells in it and also I have high platelets, so the rest of my lymphatic system and liver are making up for the missing spleen and need all the help they can. I don't seem to get clots, though I do take aspirin every day in case of any stickiness. They do say I have MS now because I had a numb hand last year, so two minor events 7 years apart. I also had a spinal tap last year and all negative so I still have my doubts.

[cheerleader]

Beth-- missing a spleen, wow! I'm sure you're really pretty knowledgable about all of this.
yeah, movement seems like a good idea, since it pulses the lymph through the body, also keeps shear stress going for those endothelial cells.
Hope you are finding other ways to deal with all of this. Every try any proteolytic enzymes (like nattokinese or serrapeptase?) and find them helpful?
cheer

[Anonymoose]

Brief primer on the lymph system from Kahn Academy...notice lymph vessels go one way, they are kind of like veins, in that they are low pressure, and are lined with endothelial cells. They also have valves, to keep lymph moving. All of our body's lymph drains into the neck veins. We used to think that lymph vessels didn't exist in the brain, that they just stopped in the neck...but now we know that's not true. https://www.khanacademy.org/test-prep/n ... move-fluid

As briefly as I can It's always been known that cerebrospinal fluid cleanses the brain, which then drains into the cervical lymph nodes, but we didn't know how CSF got to the lymph nodes. Now we know that there's a network of lymphatic vessels in the dura mater, that carry immune cells.

Part of the reason researchers thought the brain was immune privileged was that they never saw any lymph vessels, so they developed a special theory on the brain's immune system. For 70 years it was believed that the only reason immune cells would be near the brain was to fight infection, in an inflammatory reaction after a break in the blood brain barrier (like stroke) or due to an "autoimmune" reaction. This theory was developed around the same time as EAE. The Un. of Virginia and Helsinki found the actual lymph vessels, running alongside the dural sinus veins, and this may imply that the brain needs immune cell support in order to function, heal and regenerate. That's certainly been Dr. Michal Schwartz's position for 2 decades ("protective autoimmunity theory.)
I wrote up a blog post explaining the history of the immune privilege theory, for those who have time and or energy to read more...
http://ccsviinms.blogspot.com/2015/06/r ... books.html

how is it that we have oligoclonal bands that are unique to csf? Wouldn't some of the same immune cells drain into the bloodstream and show up on blood tests

I thought OB's could show up in serum? Anyway, I'm following all this quite closely. It must be going to affect a lot of other theories and treatment methods. It's certainly opened my eyes, and I think the implications will be huge.

The banding in the CSF in MS may or may not show up in blood. Bands shows immunoglobulin G (IgG) index and OCBs, which indicate inflammation and a break in the blood brain barrier, and myelin degradation which enters the CSF. Since we now know the lymph and CSF combine in the brain, that won't change anything due to this discovery, because the CSF and lymph combine before they re-enter the blood stream. But CSF bands are not unique to MS. That's why banding is only part of the MS diagnosis (along with lesions in space and time and clinical presentation), because it is not specific.
Here's more on how it's measured. http://www.clinlabnavigator.com/oligocl ... n-csf.html
Make sense? Let me know if not...will try harder
cheer

Thanks, Bethr & cheer.

Did I miss something? I thought CSF drained into the dural sinus via the arachnoid villi. Has that whole line of thinking been set aside?

The csf ocbs used in diagnosis are those that don't show up in blood. If they are both places, they don't count. It just seems that the bands should show up in blood too if everything from CNS is winding up in the blood. Maybe those bands unique to csf aren't immunoglobulins afterall. Immunoglobin mimics? Something easily cleansed from blood but not csf? Does the blood flow from the brain run through the kidneys/liver before circulating through the rest of the body? Maybe whatever is making the unique bands is taken out there?

Curiouser and curiouser. I know the new non-privileged status doesn't change test results, but maybe it will change test (and overall disease) interpretation.

[cheerleader]

Here's a great new article from the Canadian Medical Association Journal which explains the discovery---and how this brain drain functions or how non-functioning could cause the damage we see in MS.

Craig Moore, a neuroscience researcher at Memorial University of Newfoundland, agrees that this is "the most convincing evidence that [lymphatic] vessels are present in the mammalian brain." For the past decade, researchers have known that there is some type of "glymphatic" system involving glial cells that drains harmful molecules from the brain, Moore explains. "This paper provides compelling evidence for how this glymphatic system actually works."

Researchers have known that inflammation occurs in the brain, causing cells to respond by releasing cytokines and other soluble proteins that can damage the brain. "So there obviously has to be a mechanism to drain these products so they are eliminated from the brain," says Moore. The question was how.

This question is a critical one in neurodegenerative diseases. Moore says that in MS, for example, researchers have been looking at meningeal inflammation that leads to the demyelination of nerves. "Maybe in MS the glymphatic system is not functioning and these [products of inflammation] are not draining," he explains. He says there is a current debate over whether the harmful molecules that fail to drain are creating "follicle-like structures" thought to affect the brains of patients with MS.

http://www.cmaj.ca/site/earlyreleases/2 ... ases.xhtml

The lymph/CSF exchange I was referencing is the (g)lymphatic drain system/exchange and solute clearance discovered at the U of R, anonymoose. sorry for confusion! I didn't really explain that well. But yes, it is all new. Their research was published in 2013, before this new lymphatic vessel discovery. so it's all in flux. Lots of things we thought we knew are going to be re-evaluated. I don't really know how these discoveries will all play into MS diagnostics, like CSF banding.
But it's probably going to change how MS treatments will be developed.
Here's more on the U of R (g)lymphatics cleansing discovery--

This 'peri-vascular' route for CSF-ISF exchange constitutes a complete anatomical pathway, which we dubbed the glymphatic system due to its dependence on glial cells performing a 'lymphatic' cleansing of the brain interstitial fluid. Further characterization of the involvement of the glymphatic system in a number of neurological diseases and neurodegenerative disorders is underway.

Although we demonstrate that interstitial solutes are cleared by AQP4-dependent bulk flow along paravenous pathways, these pathways may not necessarily be the terminal route for solute clearance from the cranium. From previous studies, two routes for such terminal clearance appear most likely. First, the movement of solutes along the microvasculature and large draining veins of the brain provide ready access of solutes to specific transport mechanisms at the BBB. A second possibility is that solutes draining along the internal cerebral and caudal rhinal veins to their associated sinuses are cleared to the bloodstream via arachnoid granulations (22–24), providing an exit route for interstitial solutes that do not interact with or have saturated specific transport pathways at the BBB.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551275/
http://ccsviinms.blogspot.com/2015/04/g ... gaard.html

cheer

[Leonard]

specific CD8+ cytotoxic T cells produce IFNγ.

could it be that in the inflammatory stage, this mechanism is used to suppress the virus in the cell by boosting epigenetic mechanisms (herpes, VZV)?

[cheerleader]

specific CD8+ cytotoxic T cells produce IFNγ.

could it be that in the inflammatory stage, this mechanism is used to suppress the virus in the cell by boosting epigenetic mechanisms (herpes, VZV)?

Not sure how the viral mechanisms will become part of this research, Leonard. Nothing published yet, it's all new.

But here's some interesting research published last year which showed how UVB rays released regulatory t cells from the lymph nodes in people with MS, and calmed inflammation and reduced symptoms.
We can see this all in a "new light" today

MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin 21.

http://www.ncbi.nlm.nih.gov/pubmed/24771567

I wrote about this discovery last year on my blog. The endothelium is the interface between the vasculature and the immune system, since endothelial cells line lymph vessels and blood vessels, and both are affected by nitric oxide. And NO attenuates the release of Tregs from lymph nodes, which we now know, are directly connected to the CNS.
http://ccsviinms.blogspot.com/2014/04/m ... mptom.html

cheer

[Leonard]

...which showed how UVB rays released regulatory t cells from the lymph nodes in people with MS, and calmed inflammation and reduced symptoms.
...

yes cheer, you take the right slant on things. I think it is correct to talk about an inflammation calming down i.e. the immune system calming down. The widely held believe of immune suppression is just wrong. The immune system is much smarter than these people who coined the term suppression. What really happens in this microcosm is that conditions change in order that the immune system calms down, get less triggers to act.

on the viral connection, look at this: http://www.bio.davidson.edu/courses/imm ... gamma.html
The very first sentence starts like this: "Interferons (IFN’s) are a group of proteins known primarily for their role in inhibiting viral infections ..."
If it is almost evident and was right under our nose all the time, I ask myself the question, WHY, FOR CHRISTS SAKE WHY has this connection not been researched much stronger? Why?
I would not want to be in the room when the full truth in this dossier comes to light.

on the NO, yes there may be something with the Treg cells. In my concept, NO is an ingredient of a biochemical reaction with the super oxide that is released by the EBV infected B cells (mechanism to prevent recurrent infections). The product is peroxynitrite which jams the cells, causes huge oxidative stress. NO synthase is influenced by sex hormones, higher in women which explains the gender bias in autoimmunity and MS.

Leo

[cheerleader]

Hey Leo-
The published research I've been putting on this thread is regarding the newly discovered link to the peripheral lymphatic system and the CNS via lymphatic vessels and nodes. Hard to know how it's going to impact interferon and viral research in MS, since nothing's been published yet. But I do think interferons have been given a lot of attention in MS research already. http://www.webmd.com/multiple-sclerosis ... -sclerosis

Dr. Michal Schwartz has been publishing on the protective properties of immune cells, for two decades now. She has always contended that ablating or suppressing the immune system was not the right approach in MS, since immune cells are needed for brain plasticity and protection. She has focused on regulatory T cells.
http://www.ncbi.nlm.nih.gov/pubmed/12374425

if anyone wants to learn more about Dr. Schwartz and the Weizmann Institute, I wrote up a blog post on her.
http://ccsviinms.blogspot.com/2015/06/d ... right.html

Dr. Kipnis, one of the publishing authors in the Un. of Virginia paper on the lymphatic CNS vessels is head of the Kipnis Lab. He got his PhD at the Weizmann Institute, where he was part of Dr. Schwarz's revolution. He is also co-author of the paper linked above on T reg cells.

As far as the connection of NO and T reg cells, again, here's the published research from my blog.
http://www.sciencedirect.com/science/ar ... 0312000870
http://www.jimmunol.org/content/early/2 ... 0.abstract
http://www.ncbi.nlm.nih.gov/pubmed/23720815
cheer

[Leonard]

hi cheer,

sure, lots of work done on interferon, but most of it focused on the 'suppression' of relapses.
it is the sort of meta type analysis that was most interesting and clearly of commercial interest.

what I mean to say is: we need to investigate vigorously role of interferon (gamma) on intra-cellular mechanisms, the role of T reg cells on 'injecting' interferon gamma to suppress the virus in the cell (is this the recovery mechanism in RR?), on the role of the gut and our diet on interferon gamma production which may skew us towards getting sick.

and on the NO: I am not surprised from the coupling with Th17 CD4 CD25 etc T cells.
I could even accept that the NO is first, that the Th17 ets ... follows.
but what is in between in this microcosm that we haven't seen or considered?
it may be a highly complex non-linear system to the level of DNA fragments that sits in between.

sorry, as engineer I normally want to solve problems, not make them more complicated.
but here I am afraid that here there is no other way.

I just had a new MRI done; the picture is largely the same as 7 years ago, with a few minor exceptions no new white matter lesions.
check. there is no feeling of numbness or relapse for the last so many years.
still, I continue to slide back, slowly but steadily.
as an engineer, my feeling says this is not caused in the brains.
I believe the progression is much more caused in the peripheral nerves, and the connection to the actual muscle cells.
and that the VZV plays are key role here.
if I apply neuro muscular electric stimulation, my worst leg is also least sensitive to external stimulation.

lots to thing about.

Leo

[cheerleader]

Leo,
Here is Dr. Zamboni's editorial, The Discovery of the Brain Lymphatic System, published in the medical journal Veins and Lymphatics--
It explains this discovery quite well, from a researcher who understands the lymphatic system and the connection to venous flow. You can download the pdf at this link:
http://www.pagepressjournals.org/index. ... /view/5360

The main takeaway points I got were:
1. This lymphatic system in the brain is not a revolutionary discovery---researchers have known about the perivenous and periarterial Virchow-Robin's spaces for a century, but this has recently been clarified and renamed the (g)lymphatic system.
2. There is a cross-talk between the veins and lymphatic system
3. The dogma of immune privilege is over. We need to reassess neuroimmunology. There is a very real gateway for t-cells to get in and out of the brain. They are not there due to an "autoimmune" reaction.
4. There is an interconnectedness of brain lymphatics, CSF, nasal mucosa and deep cervical lymph nodes-- in which t cells and viruses can easily circulate.
5. Can we improve lymphatic drainage for the brain, as we do for other parts of the body?

Again, it's almost impossible to know the full implications on viruses and immune reactions without further study. But some takeaways in light of recent discoveries are that the gut-brain connection is real, and the micro biome affects immune reactions and neurotransmitters, t cells need to be re-evaluated, and the role of nitric oxide needs further definition. Since I don't have a lab, I can only link or reference what's published But Jeff gets daily cardiovascular exercise, UV rays, lots of phytonutrients, takes a wonderful probiotic (VSL-#3), meditates, laughs, eats a mediterranean diet--and so far, no MS progression in 8 years, no new lesions, and a reversal of gray matter atrophy on MRI. He's still jogging and composing full days. Glad to hear you are doing pretty well too. Keep on keeping on!
cheer

[1eye]

Definitely don't leave it to be funded by the Dark Side (Big Pharma).

I am upset by what my PSW (personal support worker) told me. I am the only one of her clients with MS (she has had many now living and dead), who is in the shape I am in. Many are younger. But it was she who brought up what she thinks it the reason. I have not talked to her much about this at all. She keeps me too busy with exercise, walks, etc. But, in her experience, none of her MS patients is doing as well as I am. Not my words! I think I would be the last person to think I am doing well. She thinks it must be because of the CCSVI procedure I had 5 years ago.

So if she is right (yes, possibly not -- I am also on biotin), why can't everyone with MS have this procedure? Why isn't all available research money going into this new area of human physiology, which may unlock many mysteries, such as MS, and Alzheimer's? We need to stop running down the idea of animal models. Just because those 20th century bozos got hung up on "EAE" (I would describe it differently), as I have said more than once, doesn't mean we have nothing in common with mice. We are mammals. We have a significant amount of evolution in common. I bet you a million or so dollars we have a common lymphatic system in many respects. Those turkey neurologists who suggested all we have to do is cut the jugulars of a few mice to prove CCSVI doesn't exist should be hung, drawn, and quartered. I know that sounds drastic, but you can't fix stupid. It's a chronic, permanent condition. These people would be better off.

I am also a bit upset that the Rochester research didn't get as much airplay (Nature!) as this vessel discovery. What are these vessels? The Rochester discovery was that the brain's lymphatic system has no vessels at all. Daily, the brain makes extra room for waste clearance, by shrinking, and leaving enough space along the outside of existing blood vessels, so that CSF can flow in the gap without mixing with the blood, as if the rest of the brain were a second set of vessel walls, where the privileged CSF goes. During sleep, these pseudo-vessels are filled with CSF. This is probably a very old mammalian brain arrangement.

Dura forms pseudo-vessels for very large veins. Does it form these vessel walls too, being the only place glymph flows within them? Or is it the same everywhere in the brain... Is it only by this autopsy that we know we are mammals too -- I suppose it is a bandwagon anyone can jump on.

[cheerleader]

Never fear, 1eye, it's going to happen for all. Just taking much longer than expected.
And I'm glad to read your PSW is keeping you busy moving, and that she recognizes your abilities are tied to having venous flow. (!!!)
Dr. Dake admitted to me that neuroimmunologists would never see the connection, unless they established the basic science. SO...neuroimmunologists have to find the lymph vessels that drain into the dural sinus and jugular veins, and then they can work on drugs to improve the vessels and control t cell migration. Meanwhile, the vascular doctors will work on interventional procedures. Just as has been done in carotid arteries for 30 years now, and the debate between drugs vs. angioplasty continues. Sadly, it seems more about protecting turf, rather than helping patients. But there will be good coming from it. Promise. The ISNVD is gaining members all the time, next meeting is in NYC 2015, and Dr. Zamboni will have results from Brave Dreams trial plus the NASA Drain Brain project.

The U of R research did get a lot of attention, won awards, and continues to create waves. Dr. Nedergaard's lab is busy, getting lots of independent funding, and establishing the role of sleep and metabolite clearance in all diseases of neurodegeneration. Dr. Nedergaard's husband, Steve Goldman, is down the hall at the U of R, working on stem cells for MS. They're working together at the University of Copenhagen Center for Basic and Translational Neuroscience, as well. http://ctn.ku.dk/about/ And after our visit, she now knows all about CCSVI, and has a few proposals to study the mechanism in her lab. She's committed to finding answers, no matter where they come from.
http://ccsviinms.blogspot.com/2015/04/g ... gaard.html

cheer

[Leonard]

hi cheer, thank you for all these useful references and your blogs. you are a real specialist. your take away points are great. I would hope the ISNVD makes rapid progress. there is just one other point and that is that I believe the white matter issues and progressive MS are not directly linked. progressive MS has a different underlying mechanism (that is why we have the two peaks in the graph of age of onset), possibly located in a different place than the brain. my MRI stayed largely the same over the last 7 years but I continue and steadily go backwards, no flares, but walking becomes more difficult, less energy (oxidative stress, EBV B cells). I suspect that Varicella Zoster plays a role including - or may be I should say in particular - in the peripheral nerves and that post herpetic neuralgia is not far away.

hi 1eye, I like your posts, and just like you I want to get my 6 figure job back. The Rochester research is interesting where I don't exclude at all that in the end this research and the discovery of the brain lymphatic system will come together in some beautiful way, as beautiful many things from our 2 Billion years of evolution.

as regards the short term treatment side, as I continue to slide back (mobility and energy), I am thinking about taking chemo, that is Methotrexate in combination with Rituximab. but I am running here into the big fat wall of our medical system. perverse drivers in the system (including from the Dark Side) have led to a massive systemic failure. that is the challenge we are up to.

if there is any one who reads here and knows about possibilities for treatment with Methotrexate and / or Rituximab in the US or Canada, or anywhere in Europe, please let me know.

[cheerleader]

Leo-
Progressive MS is the real MS. And it starts at the very beginning, with gray matter atrophy. As Dr. Peter Stys says, we should be studying progressive MS exclusively--and not simply focusing on white matter lesions in RRMS, which are inflammatory and can be treated ($). The gray matter atrophy and cytodegeneration is what continues during the entire MS process, and age matters. And a certain point, the brain can no longer reroute around damage, and disabilities become more advanced.

Dr. Peter Stys, neurologist and stroke researcher at the University of Calgary and recipient of a $3.8 million grant from the MS Society in Canada to research the degenerative aspect of MS, has recently published a review of the literature defining MS as a disease of primary neurodegeneration with secondary inflammation, or what he calls an “inside-out mechanism.”

Stys compares MS to other diseases of neurodegeneration, including Alzheimer’s and Parkinson’s disease. Stys considers these diseases within the spectrum of “cytodegeneration”--or cellular death. He posits that the difference between these diseases may be age of onset, since MS begins earlier in life, and “immune responsiveness” is more acute in younger individuals. Included below is a section from a recent review by Dr. Stys, entitled “Will the real multiple sclerosis please stand up?” [6]

One might reasonably ask why other common neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, do not also result in relapsing–remitting neuroinflammation. In fact, both diseases do exhibit inflammation in pathologically vulnerable regions 83,84. Indeed, in these research fields there is also an ongoing debate about whether inflammation is a reaction to, or cause of, ongoing degeneration.

Because diseases such as Alzheimer’s and Parkinson’s have a much more prominent degenerative rather than inflammatory phenotype, the initial assumption was that a degenerative mechanism (or mechanisms) was primarily responsible, with inflammation perhaps a secondary, but possibly important, consequence of the degeneration.

In MS, the situation is reversed: inflammation occurs early and is very prominent in many patients, so it was naturally assumed that autoimmunity might be causal; but, as we argue throughout this Perspective, such an assumption may be incorrect.

If MS is primarily a degenerative disorder in line with an inside-out mechanism, why would this disease be unique in engendering such prominent and cyclic inflammation? The differences may be related to age: Alzheimer’s disease and Parkinson’s disease present decades later than MS, and immune responsiveness wanes with age through a process of ‘immune senescence’ (REFS 21,87). Indeed, the responsiveness of T cells, which are known to be centrally involved in the immunopathogenesis of MS88, appears to be particularly altered with age87. Moreover, it is conceivable that the putative cytodegeneration involving the myelinating unit (oligodendroglia, their processes and myelin) in MS releases debris that is more antigenic35,36,66 than the debris that is shed from the mainly synaptic and neuronal degeneration in Alzheimer’s disease and other traditional neurodegenerative disorders.

http://ccsvi.org/index.php/the-basics/c ... l-diseases

With the newly discovered lymphatics in the brain, and the gateway for t cell entry, Stys' theory that MS is not autoimmune appears to be correct---this mechanism will be further explored, as we learn how impaired (g)lymphatic drainage might leave behind proteins, metabolites and debris in the brain. Not sure how chemo will help with gray matter atrophy, but wish you well in finding treatments that help! If you can get the MRI techs to look at your gray matter (specifically thalamus, brain stem and third ventricle) that might give you a better idea of your brain health. That's how techs saw the reversal of Jeff's gray matter atrophy-by comparing his MRIs and looking at those specific areas. hope they can do that for you! I've written a bunch about research on gray matter health, won't link here, but let me know if you want to read more.
best, cheer