CCSVI2..Don’t Do it.

C

 

Messing about with suspected blocked blood vessels led to the CCSVI movement, that was discredited by science, 
 
So yesterday we had the media suggesting that you should block a different vessel in the brain to get rid of MS. 
 
One of the readers asked whether this is the beginning of CCSVI2
 
 It was claimed that a “Team identifies brain’s lymphatic vessels as new avenue to treat
multiple sclerosis” in the headline from Medical express…”
What do they actually say?



Louveau A, Herz J, Alme MN, Salvador AF, Dong MQ, Viar KE, Herod SG, Knopp J, Setliff JC, Lupi AL, Da Mesquita S, Frost EL, Gaultier A, Harris TH, Cao R, Hu S, Lukens JR, Smirnov I, Overall CC, Oliver G, Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 2018. doi: 10.1038/s41593-018-0227-9. [Epub ahead of print]


Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here, we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.


 

 

This study, elegantly  shows that there are drainage pathways from the brain to the lymph glands that may
remove stuff in the fluid bathing the brain and spinal cord. 
 
This provides a methods of  waste disposal system for the brain, allowing it to remove stuff it doesn’t want and allows the immune system to sense, what is occuring in the brain.
They also show that cells in the brain leave the brain via this route
and use a chemokine receptor (CCR7) that lymphocytes use to leave lymph
glands.
 
 
We know that cells rapidly disappear from lesions in EAE. This
provides a route.
We know that cells that leave the lymph glands can re-enter the blood
via a place called the thoracic duct.
It is suggested that there is something in the fluid that
calls lymphocytes into the CNS
We know that nerve proteins are broken down and so they will enter the lymph glands this way.
The proteins will be taken up by macrophages/dendritic cells in the lymph glands and
they can stimulate white blood cells. Also the first few cells (which go in to the brain un-noticed becuase of their low number) entering the CNS may signal the recruitment of a major wave of  cells that are noticed as clinical signs develop. 
What is the signal? More research needed, but this could be any of a number of
inflammatory signals and is unlikely to anything new as biology would not need
to make a specific migratory signal.  
 
The lymphocytes enter the
blood system and when they come across markers on the blood vessels (chemokines
and adhesion moleculets etc, triggered by early lesional events) that say “infection near me”, the immune
cells will pour in, do their business and then either die or leave.
 
So this is nice science but what does it mean to you.
 
According to the media, “It’s a new avenue to treatment”.
Indeed in the study they blocked the lymphatic vessels and less severe EAE developed. 

They cut the nasal (i.n.) and menigeal (i.c.m) lymphatics with a molecular knife (visudyne & laser) to see what happens and the number of T cells exiting the brain into the lymph glands were reduced and also the development of EAE was delayed.

However, note this was just delayed by a few days and essentially all animals eventually got disease and one suspects that there would have been very little difference if the experiment had not been stopped at 20 days  when animals are still getting worse disease (as the blue line was still on the way up).

Indeed, this is what you may have suspected as physical removal of the lymph gland does not stop neurological disease either, as shown by DrLove and colleagues in the Netherlands many years ago.

van Zwam M et al. Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. J Pathol. 2009; 217:543

Therefore, this is not a magic answer and sloppy media reporting to suggest this (again, although perhaps fuellted by the researchers in their media quotes) .

The lymphatics are there for a reason, like clearing out the brain-garbage (non-needed, nerve synapses) that accumulates each day and are then forgotten as we sleep. Therefore, we can remember new things the following day.
So if you think about finding some crack-pot doctor who would ever think of
doing something like severing the lymphatic pathways (which is highly unlikely)…Don’t do it…or in Dutch…Schtop 🙂

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MouseDoctor

9 comments

    • ABSTRACT
      Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice.

      THIS REPLICATES THE CURRENT STUDY

      Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice.

      THEREFORE BLOCK THE LYMPHATICS AT OUR PERIL

      Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance.

      Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological disease

      SO OPPOSITE OF BLOCKING VESSLES IN THIS STUDY, JUST AS I SUGGESTED IT WOULD BE BAD NEWS. SO THANKS FOR THAT.

  • It seems like the authors are looking for ways to link their discovery of new lymphatic drainage from the CNS to possible disease pathology. I think that BBB disruption is still the key to understanding neuroinflammation. Maybe infiltration of lymphocytes via meningeal lymphatics precedes BBB disruption and provides seeding for further inflammation is an alternative mechanism.

  • "The lymphocytes enter the blood system and when they come across markers on the blood vessels"

    There is a close relationship between lesion sites and the anatomy of brain venous system. For example, Dawson's fingers, i.e common periventricular lesions uniquely found in MS, form in places where large brain veins drain into the periventricular veins. Therefore, it is the venous system that defines the site of these lesions and not vice versa.

    • Ah the Dawsons fingers…excellent piano playing:-).
      What about lesions outside the ventricles? What about histology?.
      No doubt the neuroanatomy plays a part.

    • "What about lesions outside the ventricles?"

      Why should i have an answer for both periventricular and other lesions when you unable to explain even the first ones?
      Still, i have the answer: Non periventricular lesions form upstream from Dawson's fingers along certain veins, where they bend, branch, or narrow. Again, it's the venous anatomy that defines lesion sites.

      What is your explanation of lesion topology? And what about histology?

    • "well how do they help find a treatment..?"

      Forgive my naivety, but the best way to find an effective treatment is by finding the cause of MS. Dawson's fingers are a distinctive feature of MS and most patients have them. This alone should mean something to you and should be the guiding light of research. Why? Because they prove that MS brain lesions do not appear in random places, therefore they can NOT be the result of some EBV or immune activity.
      MD challenged me about lesions outside ventricles. Well, brain lesions appear where veins bend, branch or narrow. Most of them have a naked-eye visible vein in the middle, but some evolve only from parts of a nearby vein as if BBB has been breached only from one side. These are long known facts and should be explained. EBV or B-memory-cell mythology is unable to provide any answer, therefore don't expect any promising treatments along that path.

      Take a look at my photo. It is an original MRI, not mine, not from web. Notice how delicately do Dawson's fingers radiate from the ventricle surface, their tips pointing outwards. Does this seem random to you?

  • Astrocytes, for example, appear to be very important in decreasing beta-amyloid formations in Alzheimer's.
    In compensation in MS, for some reason not yet understood (and I still think it's a mixed genetic factor with some environmental factor remaining in the brain), astrocytes become "too aggressive."

    So, if the meninges lymphocyte pathway is interrupted, can a person with MS directly also develop Alzheimer's as a consequence?

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