its a game of numbers and timing. first off there is a patrol inside that cell that cleans up mRNA that doesnt have a "hall pass" cells that are very damaged or confused will go into a procedural death mode called apoptosis, different from simple cell death as others are imformed of events and can react accordingly.

as soon as the cell expresses S protien the immune system may then tag it and take a sample then produce a great many antibodies for the price of a small number of cells death relative to the large number of antibodies

If you (or others) would humor a newbie question - assuming that host cells start expressing the spike protein, and the immune system learns to react to it, what are the chances that it will also learn to react to other proteins expressed by those cells, which are not related to the virus, and basically learn to attack its own cells?

In other words, is there a worry of MRNA causing auto-immune reaction/disease due to those proteins getting expressed by host's own healthy cells?

there is a self recognition system, the body indexes its components and will end process when the protien is recognized as self. foriegn molecules are not indexed and if large enough [as in protiens, not water or salt] they will trigger immune response a wanted poster and a bunch of antibodies are produced that tag the invader.

the mRNA of concern will not modify your DNA sequence, the expression of the S protien occurs untill the mRNA is destroyed by the cell, or the cell itself is destroyed taken apart and compared to self antigens, the foriegn antigen is expressed by MHC cells and PresenteD in a context of this is a hostile thing [a wanted poster]

this all occurs in a system of interdependent cell types and thier interactions.

your question addresses the crux of immunology, and needs a lot more attention than would be constructive here.

put on your reading cap and check this out:

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

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

Where does the body store this index of components recognized as self?

this is a million dollar question probably nobel prize winning.

keep in mind this is not proven but is a promising angle, CRSPR as made popular is a hijacked mechanism used to edit DNA sequences. normally this mechanism is used in prokaryotic organisms as an immune system. there are tags in the prokaryotes DNA that are used to match with foriegn DNA and signal it for destruction.

this type of arrangement MAY, possibly exist in eukaryotes as well and may be the basis of self/nonself recognition.

i have yet to talk to anyone else in professional context, this is inference on my part but it the best answer i can suggest for now.

you would want to look at antigen presentation and antibody production mechanisms, in deep detail .

This has been an AWESOME thread to follow. Thanks for taking the time to answer through the thread.

Yes. Reading the thread you quickly realize what a natural wonder our immune system is, and how much more there may be left to learn about it.

They are made by https://en.wikipedia.org/wiki/Thymic_epithelial_cell (see the section on Positive and negative selection) as part of the selection process.

It does not. All index entries that correspond to body are filtered out during aging process. If some are missed or close enough to the body proteins past puberty, you would get an autoimmune reaction

look back in the thread and you will see this part is about an autoimmune question. other than that yes you have the concept.

“The body stores this index of components recognized as self in the thymus” / gtp3 gets more specific

There is a guy living in a house inside a tree with huge library. The first responder cells will call him by phone and he will check the library for what to do.

Disclaimer: All I know about this comes from Cells at Work/Hataraku Saibou.

(https://en.m.wikipedia.org/wiki/Cells_at_Work!)

I know just enough to be dangerous :) I actually have an autoimmune disease, so that's the reason for my question, specifically wondering about the chance for an MRNA vaccine triggering or deepening autoimmune disease.

So if I understand you correctly, the self-recognition system is something built-in and doesn't change in response to foreign antigens? Or in other words, it's only the recognition of foreign molecules that will change, but this shouldn't affect the production (or culling) of T-cells that are super-sensitive to host's own self-antigens?

PS. And thank you and thanks to others for answering newbie questions on this thread! :)

Without knowing which auto-immune disease its hard to give more information (which is fine, this is not medical advice).

> So if I understand you correctly, the self-recognition system is something built-in

Yes. before immune cells are released and "primed" they go through a selection process where the receptors they have for (unknown) antigens are tested against a vast array of proteins the body normally produces, if they bind, they are killed off. Sometimes this doesn't work and if they are activated and bind their (self-)antigen when the immune system is activated (i.e. during an infection) they can attack uninfected cells. Which as a one off event is not problematic, the problem comes from the fact that those immune cells stick around when they contact their antigen, and if it is produced by the body this is a lot, and continue to kill healthy cells and cause inflammation.

> and doesn't change in response to foreign antigens?

By the time the immune cells bind to foreign agents they have already gone through the selection process.

Necessarily a vaccine will produce an immune response (or otherwise it won't have the intended effect), this could cause an autoimmune response because the atuoresponsive cells, presumably, have their antigen around.

> but this shouldn't affect the production (or culling) of T-cells that are super-sensitive to host's own self-antigens?

new ones, no. In fact if you're not a child, you aren't producing many new (unique) T-cells at all. Old ones however may proliferate if their antigen is present and an immune response is triggered (to the vaccine or the virus).

If you want real advice, don't take it from some random on the internet with only a minor in biomed, talk to your doctor or immunologist.

yes you have the concept.

the molecular level of the mechanism, beyond the cellular level is detail that needs to be elucidated.

> specifically wondering about the chance for an MRNA vaccine triggering or deepening autoimmune disease.

I think the medical guidance has been pretty clear that you should not get the vaccine in this case. There are a lot of people who care more about their own safety than yours who may try to change your mind. Don't listen to them; don't get your medical advice on the internet. Find an expert.

i have a friend that is quite allergic to aluminum, and zinc on contact. these sort of allergies are about hypersensativity, it sounds like you may have problems with any sort of foriegn challenge to your body. A major component of most vaccines is an adjuvent and that is intended to make your immune system extremely ready to recognize foriegn antigens. this means a very good chance you will have a flare up. you want to have sound medical advice from a doctor regarding your own health characteristics. Bare minimum i would want to see direct supervision and observation after a vaccine.

Allergic reactions to adjuvants is an entirely different matter (than autoimmune reactions) and may actually not apply to these vaccines. This just goes to show, don't get your medical advice from HN.

hypersensativity is an autoimmune disorder, and by the way the use of aluminum salts as adjuvent is being phased out, there is great opportunity to formulate the liposomasal delivery vesicle to mimick a pathogenic cell wall.

My understanding is that normal viral infections cause proteins to be expressed by cells in the same way — in fact, uninfected cells also continually display a "status report" of protein fragments. Your immune system monitors this to detect cells that have gone haywire, whether by mutation or infection.

https://en.wikipedia.org/wiki/MHC_class_I#Effect_of_viruses

I don't honestly understand how the immune system decides which protein fragments are okay to develop a response to, but the point is that that is already part of the normal immune response pathway that learns new antigens every day; after the protein fragment shows up on the cell surface, the rest of the process is similar to the response to an attenuated-virus vaccine or a natural infection.

this is a very new and edgey statement however here goes. the self/nonself antigen profile is likely in the DNA and in eukaryotes likely functions in similar fashion to the NORMAL crspr system of prokaryotes [as in not the hijacked gene editing one of current topic]

keep in mind there is no proof yet that this is how it works but it is a promissing direction to look into.

If one gets infected with COVID19, the cells containg the virus will too produce the spike protein among other virus constituents as specified by the virus RNA.

I'm no expert either, but I don't see a difference here between virus infected cells and mRNA "infected" cells. So cells primed with mRNA simply produce less virus parts than those with the real virus?

this is hard to say yes, but i can tell you that the live virus will replicate in the cell and increase copy number of its RNA until the cell dies. the vaccine mRNA will remain until degraded and stop producing valid copies.

the vaccine is not the whole mRNA, its only the part that codes for immunogenic protien [SARS-2 S] that is exported to the cell membrane

> assuming that host cells start expressing the spike protein, and the immune system learns to react to it,

Firstly they only express it as long as the mRNA remains intact. mRNA are degraded naturally so there is a finite time window as the mRNA is not reverse transcribed into DNA and reintegrated into the genome.

> what are the chances that it will also learn to react to other proteins expressed by those cells,

T (and B cells? I can't remember) cells undergo a selection process in the thymus that select against cells with receptors that bind to self proteins, that is proteins made normally by the body. Sometimes this fails and you get autoimmune disorders. Chances are very slim and no more than any other antiviral vaccine.

> as the mRNA is not reverse transcribed into DNA and reintegrated into the genome

Why not? Just because it doesn't match up, or is there a deeper reason?

because thats not what mRNA and normal cellular processes do and there is no mechanism in the body to allow that to happen.

Reverse transcription only happens when a reverse transcriptase (found in retro-viruses, e.g. HIV-1, HIV-2, Hepatitis B Virus etc) does that and the RNA is the direct viral genome or a transcript of the viral DNA (for DNA viruses). They have special marker sequences at either end to facilitate this (search for terminal repeats)

SARS-CoV-2 is not a retrovirus.

an enzyme called reverse transcriptase or its equivalent is required, the HIV virus and a number of other retrovirii do this, and implant thier code into the host DNA.

eukaryotes use splicing mechanisms that copy/delete/replicate DNA from one locus to another, this is more reliable as mRNA are unstable and become damaged quickly. cytoplasmic mRNA is not of fidelity and does not reverse compile into the dna sourcecode, or it would produce massive errors and corrupt the DNA.

If the mRNA is unstable, then what are the chances that at some point it might code for a dangerous protein such as a prion as it degrades?

The CDC and other sources argue the vaccine is safe because it doesn't alter your DNA, but I have a vivid imagination and can think of a thousand other ways something might go wrong. Having my DNA altered was never one of my concerns.

prions are a specific sequence, the danger with a prion is that they stack up on each other like building blocks and produce "plaque" structures, there is such a difference that it is about as close to zero as you can get.

what you would get is some false starts, and segment of protien if that at all.

Pardon my ignorance but is this something that could, in theory, trigger a cell to become cancerous or trigger the body to develop an autoimmune condition (as the spike protein is created by the body's own cells)?

short answer, is no

this is not a constituative expression and the cell expressing the foriegn protien is often destroyed later in the process but not always as the vaccine mRNA is edited out of the cytoplasm not replaced by genetic expression and the novel protien goes into turnover mode.

addendum >>there is a halflife/turnover rate, in tech terms the hardware is updated very frequently, by degradation, and replacement. this is loosely what creates a constituatively expressed proteome. the S protien is not part of the program so is degraded and not replaced. if the protien insertion is too extensive or the activity of the protien is egregious for the cell then, apoptosis

These are great questions. Another one since we are talking about editing the programming “code” of the human body is: what if we got it wrong? What sorts of “bugs” might occur in execution or through unforeseen interactions?

> Another one since we are talking about editing the programming “code” of the human body is

...no? This is not gene therapy. The effects of receiving a mRNA vaccine will, apart from training the immune system (which was the whole point), be next to nothing.

Your body is continually being bombarded with random foreign DNA and RNA. That's just how life on Earth works. Yes, introducing a big pile of it at once is not normal... but it's a difference of degree, not something completely new.

If anything, problems are more likely to derive from the lipid bubbles used (at least by Moderna) to package and transport the mRNA.

> If anything, problems are more likely to derive from the lipid bubbles used (at least by Moderna) to package and transport the mRNA.

Noob here, could you expand on that?

Here is an article on Covid vaccines, and the second link is from its references, and explains lipid nanoparticles used in these vaccines. Both the Pfizer and Moderna vaccines use lipid nanoparticles and are very similar in their designs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583697/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624045/

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edit: Here is more specific information on lipid nanoparticles in RNA vaccines, which explains that RNA vaccines that involve lipid nanoparticles tend to cause a local inflammatory effect, i.e. shoulder soreness.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963972/#sec3-v...

So what is causing the side effects people in the studies are suffering? There seems to be a lot of concern on people not wanting the second dose. I know flu shots will always make the injected arm hurts for days (never have that reaction with other vaccines for some reason). If this is just creating proteins and not an inactivated virus, what's causing the responses that are being reported?

This vaccine is like providing a machine learning model another website to read, after reading millions of websites.

It is absolutely not anything like merging a patch into the master branch.

The mRNA gets translated into the spike protein. And then the cell presents it in the surface for the immune cells to track and learn it. This is called MHC-I pathway. As a consequence of this, the immune system might instruct "infected" cells to self-destruction.

There are also other delivery pathways for mRNA vaccines.

The virus is not functional because the mRNA vaccine only contains one little component of the virus, the spike protein.

You can see a quick comparison chart of the most important vaccine methods in this Nature figure: https://media.springernature.com/lw685/springer-static/image...