New research shows brain is directly connected to the immune system | Hacker News Reader

New research shows brain is directly connected to the immune system

news.virginia.edu

199 pointsPhithagoras35 comments

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

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

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.

In the Lancet[0] there is also a persuasive case made for a connection between coeliac (autoimmune) and a host of neurological symptoms. The more these mechanisms are understood the better.

[0] http://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(...

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.

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.

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.

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.

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?

I wonder if the converse is also true: drugs that are attached to antibodies that don't need to (and are not supposed to) enter the brain, could in fact enter the brain.

Also, why haven't such bbb-crossings been seen before?

Nature publication here : http://www.nature.com/nature/journal/v523/n7560/full/nature1... : "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."

https://sci-hub.io/10.1038/nature14432

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

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

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

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

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?

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.

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.

There is another explanation that is simpler. The gut is also lined up with nerve cells. They form the enteric nervous system, containing more neurons than the spinal cord. It's also called the second brain. Its function is to assist digestion by analyzing the food we eat and triggering reflexes. More than 90% of the body's serotonin lies in the gut, as well as about 50% of the body's dopamine.

So, that is why there is a strong link between the brain and the gut, and it explains why we feel so strongly our emotions in the gut.

https://en.wikipedia.org/wiki/Enteric_nervous_system

Nerve cells? Sure. But...probiotics play a major role in anxiety/depression and other psych issues. There isn't a ton of research but it's fairly clear that the bacteria in the gut contribute to a person's psych well-being.

Various sources: https://www.google.com/#q=probiotics+psychological+effects+s...

Article doesnt mention the gut or bacteria.

With 70% of your immune system being the gut...it's implied.

Decent source: https://skeptics.stackexchange.com/questions/17811/is-70-of-...

Yes but the article is talking about the immune system within the brain.

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

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

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.

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

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 :)

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.

Can we cure cancer/diabetes by stimulating brain?

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

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 :(

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.

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

re: downvotes: i'm sorry, but is the legibility of the OP's article not relevant to the discussion of said article?

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