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Comment by peterlk | Hacker News Reader

I just finished up an introductory biology lecture series, and this suddenly makes less sense to me than it did before. What is it about the foreign cells that is identified as foreign by the host cells? The cells ought to be remarkably similar. They're human, with the same function/pluripotency using the same protein interactions. So why attack it?

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Because it's part of the arms race with pathogens that has been going on for a billion years since multi-cellular life first appeared. Pathogens do lots of very clever things to hide from the immune system, so the immune system is tuned to detect very subtle changes. The body largely operates on zero-trust network models, except for a few locations where the benefit of a too-active immune system has serious consequences to the fitness of the organism. The eyes and the testicles are good examples of that in humans.

To add to this: if the immune system would just check that the cell is human then every invader would just evolve to pass that check. The only viable way to defend is to mark the cells as belonging to this specific human. That way even if some bacteria evolves to trick my immune system it's unlikely to also trick yours, and the infection can't spread.

Additionally, if the immune system would just check that the cell is human, then humans would be vulnerable to contagious cancer, such as the facial tumor disease suffered by Tasmanian Devils

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

Humans almost certainly are vulnerable to contagious cancer (there are a few known in other species: https://en.wikipedia.org/wiki/Clonally_transmissible_cancer) . We just haven't acquired/discovered any yet.

HTLV, EBV, HPV

you better believe we have! It’s just rare (thank goodness).

Those are cancers caused by viruses, and it's the viruses getting transmitted.

On the other hand, clonal transmission refers to the cancer cells themselves leaving sick individual A, entering healthy individual B, and continuing to reproduce there.

You could use transmissible preleukemia (eg CHIP in allo transplants) as an example if you wished.

Direct unassisted clonal transmission in humans seems likely but, as you noted, it hasn’t been documented to the extent that Tasmanian Devil facial tumors have.

Warts are a corner case. I’m not sure whether it’s been determined if some hosts end up increasing the fitness of the shed cells. If so, that’s quickly heading towards a globally transmitted precursor lesion.

This weirdly reminds me of public private key authentication

> except for a few locations where the benefit of a too-active immune system has serious consequences

For anyone else curious about this, https://en.wikipedia.org/wiki/Immune_privilege

I guess auto-immune disease is an example of where it also goes the wrong way for somebody. Probably most of us know somebody with IBD, lupus, or any of the others. It's very common for the body to reject something benign, or ourselves.

Type 1 diabetes is a good example of this, where the body detects its own insulin producing cells as threats and eliminates them. Lots of the research in type 1 treatments isn't just about producing insulin, but figuring out how to prevent the body from destroying it again without all of the risks of immunosupressant drugs.

Adding to some of the other comments: Leukocytes (immune cells) such as B and T cells will undergo "education" when they are developing. For example, B cells, before being released, will go through something called central tolerance in the bone marrow. If the B cell receptors bind a "self" antigen (markers that are associated with our own cells) while developing, it will go through negative selection and be destroyed. Of course, some B cells that bind self antigens do make it through in rare cases and this is what manifests as an autoimmune disease.

Thanks for this. I'm perpetually amazed at how mind-bogglingly complex the human body is.

> while developing, it will go through negative selection and be destroyed

Can you share more about how this process works? Even just a link would do. Thank you!

I think Khan Academy does a good job of explaining it: https://www.youtube.com/watch?v=EsQyCHs4IBY

https://en.wikipedia.org/wiki/V(D)J_recombination

There's a lot more to immune response than "does this look like a human cell?"

See, for example, blood types, where giving an A type person B type blood will cause serious issues.

Each human has a largely unique signature of HLAs (https://en.wikipedia.org/wiki/Human_leukocyte_antigen).

The whole point of this, evolutionarily, is so that a parasite that thrived in one human body won't necessarily thrive in another.

This is also why many species reproduce by sex.

This seems to answer it https://www.sciencealert.com/this-protein-could-explain-why-...

Dendritic cells 'teach' lymphocytes what a foreign invader is, right most of us know that from high school, but here's where it goes beyond me:

>They found that differences between the mice donor's and recipient's SIRPα gene correlated with the recipient's immune responses.

SIRPα isn't an unknown protein, already understood to bind to another protein called CD47 that triggers a range of immune responses in different white blood cells.

>Joining the dots, the researchers believe CD47 on monocytes – the white blood cells that grow into dendritic cells – interact with SIRPα receptors on foreign tissues, setting off the entire ID check process.

>"Once these cells are activated, then they turn around and activate the rest of the immune system, and that leads to the full-blown rejection of the organ," lead researcher Fadi Lakkis from the University of Pittsburgh told Liz Reid at 90.5 WESA.

Here's the paper https://immunology.sciencemag.org/content/2/12/eaam6202

This seems to be the relevant bit

>Using an elegant positional cloning approach, Dai et al. have identified polymorphisms in the mouse gene encoding signal regulatory protein α (SIRPα) to be key in this innate self-nonself recognition. They show that SIRPα receptor CD47 binds SIRPα variants with distinct affinities and propose this affinity sensing to be the mechanism that triggers dendritic cell maturation, the first step in the initiation of the alloimmune response. Given that the SIRPα gene is also polymorphic in humans, it remains to be seen whether human SIRPα variations influence transplantation success.

Proteins on the surface of cells identify them as “self” or “not self”. MHC (major histocompatability complex) plays a large role.

It's no one thing, but a combination of factors that allow the immune system to identify and attack foreign cells that have entered the system. Think of it like one of those incredibly stupid algorithms that pass for AI today. Except this algorithm is "trained" over millions of years by the host organism dying when it fails to properly classify hostile foreign biomass. Over that long a time it gets to be pretty good, but not 100% flawless: autoimmune disorders like multiple sclerosis result when the immune system incorrectly attacks the body's own tissues, and allergies result when the immune system overreacts to foreign material, such as food or pollen, entering the body.

My understanding is that most cells in the human body regenerate. What I don't understand is how cells that are part of the transplant regenerate. Do they use the host or the transplanted DNA to regenerate?

Cells (re)generate by splitting, there's no other way. For non-mobile tissue, the tissue regenerates itself from whatever DNA the cells in that tissue have locally. There are some types of cells that are "manufactured" in one place and "shipped" throughout the body (e.g. blood cells in bone marrow) but for the transplanted tissue any new cells would still have the donor DNA forever.

Also, that applies for chimeric humans that happen to have two different DNA sets from two different fertilized eggs; some parts of their body will forever have different DNA than other parts.

> Also, that applies for hymeric humans

Seems like this: https://en.wikipedia.org/wiki/Chimera_(genetics)

Yep, that's the correct term, English isn't my main language.

Now makes more sense. Thanks for the explaination

> I just finished up an introductory biology lecture series, and this suddenly makes less sense to me than it did before.

The immune system is one of the most complicated and wonderful pieces of biology. It's also scary in the ways that it can malfunction and the challenges it presents to modern medicine.

> What is it about the foreign cells that is identified as foreign by the host cells?

The MHC system is a major determinant of histocompatibility.

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

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

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

MHC is an adaptive immune function used to detect foreign antigen that was evolved as a means to combat intracellular pathogens. This cell-surface machinery collects and presents foreign antigens from inside the cell at the cell surface for discovery by immune cells that come into contact. If something "foreign" is found on the MHC, the immune system targets the cell for deletion and upregulates the immune system for further attack.

The genes that code the MHC proteins vary widely between individuals. This can be beneficial as viruses struggle to evolve in a way that evades all MHCs in a population.

Unfortunately, the MHC proteins are themselves a highly reactive antigen that triggers the immune system. Luckily, the body learns during a process called "negative selection" to cull any immune cell receptors that recognize your own MHCs:

https://en.wikipedia.org/wiki/Thymus (search "negative selection").

If any of your own T-cells match your own MHC, they're killed. Unfortunately, your body doesn't know the shape of MHC proteins from donor tissue and can't learn to kill any TCRs that match. And these proteins are incredibly, incredibly polymorphic:

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

Search "variability", then multiply the numbers -- you're not going to find an exact match for you anywhere, unless you have an identical twin. This is why donor databases exist. If you can find a match for one of the variants, it reduces the product of these multiples.

It's very hard to find a tissue match.

When you transplant foreign tissue, it's an antigen.

Fun fact: did you know your immune system genes aren't at rest and are actually evolving right now? Your immune cells run stochastic hill climbing. It's wild. Check out somatic recombination:

https://en.wikipedia.org/wiki/V(D)J_recombination

The immune system is incredibly complicated.

You post made me wonder about a lot

> Unfortunately, the MHC proteins are themselves a highly reactive antigen thahttps://www.airships.net/hindenburg/interiors/t triggers the immune system. Luckily, the body learns during a process called "negative selection" to cull any immune cell receptors that recognize your own MHCs:

This is very interesting that this process is split into two separate domains / privilege levels. That way you can't have a fork bomb that would overwhelm the MHC production process.

> Unfortunately, your body doesn't know the shape of MHC proteins from donor tissue and can't learn to kill any TCRs that match.

Maybe we'll combat this in the future by finding a way to donate or genetically engineer a whole bone from the organ donor, thus having bone marrow matching the donated organ. If we could get localized immune suppression on only those parts, that would be cool. I guess those leukocytes would be attacked immediately.

> https://en.wikipedia.org/wiki/V(D)J_recombination

Wow.

Probably has some sort of MAC address identifier that can detect whether something if different than the host DNA, but I have no idea nor experience in biology.

I’d say it’s probably more like some kind of checksum against the DNA. If the body detects something has been changed from what was there before it dispatches the white blood cells to kill it off. Immunosuppressants are a way to bypass the checksum, but only for some limited time. Maybe we need a way to change the checksum values altogether, but then the whole body could be rendered rejected and cease to function (death).

I love tech analogies to biological functions.

It amazes me how much 'tech' is always running on a cellular/molecular level.

Thank you!

Indeed. I had read about it before but viewing these visualizations blew my mind:

https://www.youtube.com/watch?v=SMtWvDbfHLo (DNA transcription)

https://www.youtube.com/watch?v=TfYf_rPWUdY (mRNA translation)

https://www.youtube.com/watch?v=I9ArIJWYZHI (DNA replication)

We always reach for the analogies that match our experience most closely. If this were 200 years ago, we'd say that the immune system was like a lock-and-key mechanism, or perhaps we'd say it was like a bank checking for correct signatures.

Indeed, I remember a kid's cartoon about our bodies when I was growing up that showed germs that had evolved the correct antigens as being spies passing through passport control with forged passports.

This is actually an issue in graft-vs-host rejection for bone marrow transplants.

So why attack it?

There is more in your body than just your cells. We are in the infancy of understanding stuff like this, but my WAG is that donor tissue can be rejected because it contains hostile microorganisms that didn't make the radar of the medical staff for whatever reason.

> donor tissue can be rejected because it contains hostile microorganisms

Citation? That sounds both convenient and implausible (medical science has a long way to go in many areas, but microscopy/microorganism detection is pretty far along).

Humans Carry More Bacterial Cells than Human Ones

https://www.scientificamerican.com/article/strange-but-true-...

FYI: WAG stands for Wild Ass Guess. They usually don't involve citations.

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