
New research shows brain is directly connected to the immune system - Phithagoras
https://news.virginia.edu/illimitable/discovery/theyll-have-rewrite-textbooks
======
ComputerGuru
Not really new, research came out 10 months ago, discussed here on HN
previously with 131 comments (but it is incredible):

[https://news.ycombinator.com/item?id=9647253](https://news.ycombinator.com/item?id=9647253)

Full link to the original study:
[https://www.dropbox.com/s/2mmdmty3nxfe5u8/2015-louveau.pdf](https://www.dropbox.com/s/2mmdmty3nxfe5u8/2015-louveau.pdf)

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dnautics
It's worth noting that it's long been known that the brain was connected.
Antibodies in the brain have long been known, as has the inflammatory nature
of some diseases like Alzheimer's.

What has not been known is the mechanism: the dogma was that the blood brain
barrier would prevent immune involvement. With the discovery of this new
system, that dogma remains true as explained by this impressive discovery of a
special access network for the immune system.

~~~
entee
Yeah the brain is a privileged site, a fancy way of saying it's not like
places that have ready bloodflow with very little to separate the organ. The
blood brain barrier is a real problem in drug development, but it's not that
surprising that there is in fact a way around it for the immune system. As the
parent mentions, there's been lots of evidence stretching back years that the
brain isn't totally isolated from the immune system. This paper (quite amazing
and important work btw) just elaborates how that happens. The press release
from the university is a little hyperbolic, but this is good and important
work.

~~~
daveguy
I would say this work is incredibly important. Like you said, the blood-brain
barrier is a significant obstacle in pharmaceutical research. One thing pharma
companies are very good at is producing antibody based drugs and their
derivatives. By conjugation of molecules to the antibodies that are accepted
through this pathway, essentially hitching a ride in the process, the blood-
brain barrier could essentially be eliminated in drug development. Delivery
method is one of the most important and difficult aspects of drug development.
Characterization of this process is definitely a breakthrough.

~~~
entee
Coupling small molecules to antibodies is tricksy :-P.

There have been a lot attempts at doing that (the first I recall is from the
late 90's but possibly even earlier), but not many have made it into actual
clinical practice. Turns out that the linkage is important, the
pharmacokinetics can get complicated and getting the proper concentration in
the bloodstream can be difficult. That said I've heard people are getting this
kind of strategy to work more recently, particularly in oncology.

But of course, better understanding and finding an alternative method around
the blood brain barrier is absolutely critical to drug development. It's a
huge issue for any small molecule treatment for neurological disease, and
regardless of how you conjugate or what you conjugate it to (now that we know
something about it, maybe a full antibody isn't required, you could maybe get
nearly the same effect with a shorter peptide), this is a breakthrough.

~~~
daveguy
I was thinking more of larger protein-antibody conjugates and I agree it
probably doesn't need to be a whole antibody. Still a lot more to learn, but
very exciting for central nervous system pharma development.

~~~
dnautics
If you don't use the whole antibody, the serum half life us capped in the
knees because the body gets rid of serum proteins without glycosylation. In
the case if antibodies, glycosylation is on the heavy chain FC region.

The first protein antibody conjugates were to couple ricin to antibodies in
the late 80s. Ricin's warhead polypeptide chain conveniently has a single
cysteine residue that they tried to conjugate to antibodies using disulfide
exchange. Of course this was not kind to the antibodies, and the structural
disruption is very likely one of the reasons this strategy failed miserably.

In general the challenge for ADC is that attaching your drug to an antibody is
nontrivial, and the titer is tricky. How many of your molecule does it require
to take down a cell? 100? 1,000,000? Can you deliver that number of molecules
to each cell, that start reliably conjugated to a large molecule, after yield
losses as a result of molecular decoupling?

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tosseraccount
Nature publication here :
[http://www.nature.com/nature/journal/v523/n7560/full/nature1...](http://www.nature.com/nature/journal/v523/n7560/full/nature14432.html)
: "Structural and functional features of central nervous system lymphatic
vessels"

Warning: Paywall. (Your tax dollars at work!)

 _" 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."_

~~~
throwaway321423
[https://sci-hub.io/10.1038/nature14432](https://sci-
hub.io/10.1038/nature14432)

~~~
striking
Someone who isn't me should write an extension replacing paywalled study links
with sci-hub links.

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nonbel
I've been wondering about this for years now, I wonder if it is related:

"While performing immunohistochemistry on rabbit brain sections, we noticed a
small number of neurons that were stained with only the secondary antibodies
to rabbit IgG. The staining was distinctively localized in the dendrites and
cytoplasm of cell bodies, in a Golgi-like staining, and was obviously
different from a ubiquitous ‘background’ staining."
[http://www.ncbi.nlm.nih.gov/pubmed/12426046](http://www.ncbi.nlm.nih.gov/pubmed/12426046)

AFAIK, that research has gone largely ignored. It could mean a lot of
immunohistological results are inaccurate.

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Kinnard
Was it just me or was there nothing about the structure and function of these
vessels in that article?

~~~
dluan
I really wish HN wouldn't fall for these cookie cutter press release
strategies that catch people on buzzy, sciency vaportalk. eg "They'll have to
rewrite the textbooks", pffft.

If this was VC funding mechanics or technical architecture articles, this kind
of stuff wouldn't fly. So why are these self-promoting research articles the
exception?

~~~
marshray
VC funding mechanics and technical architecture don't have the wide human
interest as medical scientist. Everybody has a body after all.

So a larger proportion of medical topic articles for non-doctors get written
to be consumed by least common denominator readers. My impression is that
there are fewer 'informed enthusiasts' and 'pro-sumers' on medical topics
compared to, say, personal computing or photography.

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heimatau
The gut (many say is ~70% of our immune system) is strongly linked to our
psychological health. So, I don't see this as a surprise. The next question is
what strains of bacteria tend to effect what in certain people? I don't think
this will be answered quickly nor easily. The gut is crazy complicated.

~~~
pygy_
Both anorexia nervosa _and_ bulimia are likely linked to a single _E. coli_
protein and the immune reaction against it.

The clinical presentation depends on whether the antibodies end up acting as
agonists or antagonists of the receptor the bacterial protein targets.

There's experimental (causative) evidence in rodents and correlations in
humans.

[http://www.nature.com/tp/journal/v4/n10/full/tp201498a.html](http://www.nature.com/tp/journal/v4/n10/full/tp201498a.html)

~~~
Kenji
Does that mean anorexia and bulimia could be treated with antibiotics that
would cut back the population of bacteria that excrete this protein?

~~~
pygy_
Maybe a total wipe of the gut flora followed by an appropriate ( _e. coli_
-free) stool transplant could do it.

It's still very early, no clinical data has been published.

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guy_on_internet
Great example of new techniques driving science. Looks promising for
translational research!

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dougk16
Somewhat related:
[https://en.wikipedia.org/wiki/Wim_Hof#Scientific_research](https://en.wikipedia.org/wiki/Wim_Hof#Scientific_research)

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blubb-fish
It's known for thousands of years - but it's nice to see how school medicine
is catching up with the Buddhists and the Shamans :)

~~~
mvanvoorden
Give it another 10, may be 20 years, and there might be enough research
available that people stop downvoting posts that remind people that this
knowledge has already been around for a few thousand years.

------
known
Can we cure cancer/diabetes by stimulating brain?

~~~
Ace17
As long as half people in clinical trials are given placebos, the answer must
be "to some extent".

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robmclarty
For people studying the brain, I would have hoped not to read the article in
the highest contrast my screen can produce with pure white text on a pure
black background. After the first two paragraphs I could see nothing but lines
:(

~~~
xlm1717
The worst part is it looks like they wanted the text to have a nice gray shade
of #666, which is OK to read on a white background, but for some reason
decided that white on black is better.

~~~
robmclarty
Designers need to understand that screen != print. When your design _emits_
light (rather than reflects it) it can make brains feel bad.

