I haven't read anything related to treating autoimmune diseases with mRNA, that would be quite exciting. Do you happen to have a reference for this?

I have Ulcerative Colitis, which is a form of an autoimmune disease. A vaccine as a cure would be a game changer.

But I thought we don’t really know what causes UC. Fungi? Bacteria? Genetic factors? Something else?

You're correct, doctors/biologists still do not know the root cause of IBD (UC/Chrons). In fact, most autoimmune diseases are quite poorly understood due to the vast dimensional space that can influence the human immune system. If there is evidence that it could be controlled via an mRNA vaccine, it would give me much hope for the future of controlling autoimmune diseases without consistent drug intervention or surgery.

Maybe something like that is relevant: https://science.sciencemag.org/content/371/6525/145. There's also a bit more context here: https://www.nature.com/articles/s41587-021-00880-0.

How would the treating of auto immune work? In my understanding you can trick the immune system into putting yet anther protein on the "kill on sight" list, by forcing the protein's mRNA blueprints into the production pipeline of some cells and... waiting, assuming that the immune system does its thing. So far so good. But isn't an autoimmune problem an entry on the "kill list" that shouldn't be there? I understand how we can append to that list (through a fascinatingly elaborate stack of indirections), but how can we revoke an entry?

Not questioning, just willing to learn.

They target signaling mechanisms that the immune system uses.

I think I don't understand it very well, but it seems one approach is to have the vaccine cause cells involved in an auto immune disorder to put a bunch of 'friend' markers on their surface. So the technology is that they can trigger protein expression and the medical approach is to get cells to express proteins that lessen immune activity against the cell.

I work in a pharma company, and I have been working with the animal model they use for this paper regularly for the past 4 or 5 years. I am not an mRNA therapy expert by any means, so I'll only comment on the results from the MOG35-55 and PLP EAE models.

They have good disease induction in their control groups, their targeted mRNA therapy shows pretty remarkable efficacy, and they show they can diversify a little bit with respect to the target.

These models are a little too "furry test tube" for me for this application. They work by injecting an antigen, either a short version of the myelin oligodendrocyte glycoprotein (MOG) peptide or the myelin proteolipid protein (PLP). The mouse makes antibodies against that antigen, and those antibodies also attack those antigens in their natural environments, leading to demyelination in the CNS. Well their mRNA for the MOG model makes more MOG peptide, giving the antibodies another target so they don't cause demyelination. In the human condition, there are multiple antibodies against multiple targets, so I'm not sure this is as relevant as they're suggesting, unless I'm missing something. I do want to add that this paper has a ton of work in it, and it looks pretty high quality as far as I can tell.

None of this is to say there's no value here, I'm just not sure what target they would make an mRNA for to treat human MS based on this paper or how they'd identify and test that target to get FDA approval to move into trials.

I'm not at all in the field, but that doesn't match what I got from the Nature abstract. I didn't see anything describing the mechanism as "giving the antibodies another target". What I read is that the introduced MOG caused regulatory T cells to retrain the immune system to stop attacking MOG.

They do bring up the multiple target problem. The glint of hope for that involves "bystander suppression", which they found some evidence for happening, but I don't really understand what that is.

Are there any online resources where I could learn more about what mRNA treatments could theoretically cure? Take Hashimoto's disease for example, a disease where your thyroid gland slowly gets destroyed by your immune system. If I understand correctly, mRNA could stop your thyroid gland from getting destroyed in the first place, but it cannot regenerate the thyroid gland if it has already been destroyed. Is that correct?

My mental model is that in the next decade or so mRNA treatments could be effective if a disease can be treated through the expression of a small number of proteins. These proteins could either have a direct function or stimulate an immune response. I think your example works.

What kind of proteins are important when you're looking at the immune system? Is there a protein that can attach to thyroid gland cells and signals to the body that it isn't a threat? Or is there some sort of memory of the immune system with non-threat cells, that mRNA could overwrite? I'm not a biologist, I'd love to read more about these specific inner workings without dissecting a whole undergraduate biology book.

If that's possible, curing type 1 diabetes would be on the horizon as well. There's some evidence that people with t1d have latent beta cells that could be reactivated to restore normal(ish?) insulin response. That would be incredible.

I really really hope so.