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Poor clearance of pathogens within macrophages.

Challenging article, but interesting nevertheless (after a few reads! 😉)... It discusses the mechanism whereby macrophages fail to clear pathogens within their walls. This sentence stood out: “LACC1 genetic variants are associated with inflammatory bowel disease (IBD) (Jostins et al., 2012), leprosy (Liu et al., 2015), and juvenile arthritis.” Particularly as Leprosy is a rather close relative to MAP. But what I found most interesting is this sentence: “homozygote MDMs restored NOD2-induced ER-stress, signaling, cytokine secretion, bacterial clearance, and bacterial clearance pathways...”
Particularly as Leprosy is a rather close relative to MAP.

Crohn's susceptibility genes NOD2, ATG16L1 (note that they are ONLY associated with CD, and not UC) overlap with leprosy susceptibility and mycobacterial infection in general, and by extension MAP. They also overlap with innate immunodeficiency diseases.

Of course that doesn't mean MAP is involved, but it does clearly point to pathogens being behind the inflammation due to a genetic factors that hinders the innate immune system from both recognising and clearing bacteria.

Not being able to clear an infection with competence leads to chronic inflammation, crohn's disease.

But the overlap with susceptibility to mycobacterial infection is there in crohn's disease, you can't deny that.

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You can read some interesting books and stories about white fathers in Africa dealing with patients with intestinal TB.

Intestinal TB is a lot like crohn's disease. Not only due to the lesions featuring granuloma that try to wall off the intestine with macrophages, but because the patients with intestinal TB who don't get treated have symptoms that remind you of crohn's disease. Someone who has intestinal TB and doesn't get treatment (which is rare nowadays, which is why you need to read older literature) has chronic relapses of heavy inflammation, scarring, intestinral fibrosis, fistula, features you find in crohn's disease too. Untreated intestinal TB doesn't end well for the patient, but they are interesting stories to read.

Once you read a bit about intestinal TB, look at the susceptibility genes in crohn's disease, it becomes crystal clear that crohn's disease is a chronic infection, the inflammation is coming from macrophages unable to clear the infection.
Kiny, so this is what confuses me about the feasibility of any vaccine: if the problem is from a genetic mutation that deals with the innate immune system, specifically the clearance of pathogens from macrophages how would a vaccine help? Vaccines target different T-cells. These are already stimulated. I saw gobs of red dots representing T-cell activation in Crohn’s patients on a graph when I went to Stanford. (Interestingly, there was another graph of people in remission and they too had activated T-cells in contrast to healthy controls, but a lot fewer than the ones in a flare.) How would stimulating them even more help? It doesn’t make sense to me...
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Most vaccines you have today work through B cell stimulation, the antibodies are able to clear the infection.

This works great against many viruses and extracellular bacteria, it does not work well against intracellular bacteria.

Most pathogens that cause disease in the intestine are intracellular bacteria, like MAP, AIEC, Listeria, Salmonella, and making a vaccine that can clear an intracellular infection that invades macrophages is much harder than eradicating something like smallpox with vaccinations.

That's why there is no ''real'' vaccine against tuberculosis. There are vaccines, but they have a low success rate, especially in adults they aren't successful.

That's why there is no vaccine against pathogenic forms of E Coli.

What you need to kill intracellular bacteria is a cell mediated response, you need protective T cells.

I mentioned there are vaccines against TB, but they don't work well in adults, they're the BCG vaccines. It's the best thing we have against mycobacterial infections, it was actually made from M Bovis, not TB.

It's incredibly hard to make a vaccine against mycobacteria and intracellular pathogens in general.

Intracellular bacteria that are able to bypass innate immune defenses do so by by interferring with phagocytosis steps. Mycobacteria like TB, foodborne bacteria like listeria and salmonella, E Coli, prevent fusion of the lysosome with the phagosome.

They literally punch holes into the phagosome when the macrophage tries to engulf the bacteria and they replicate inside the macrophage.

The last step of the macrophage is the killing of the bacteria after engulfment, when the macrophage never gets to that step, it will keep releasing inflammatory signals in the form of signaling cytokine like TNF-alpha and you get chronic inflammation.

At that point you need a very competent T cell response with some kind of vaccine, but it would take a lot of time and effort to make those.
The reason there are only a few antibiotics out there that can (temporarily) create some kind of remission in crohn's disease and why all the rest doesn't help at all, is because of the intracellular nature of those bacteria.

The bacteria reside inside the phagocytes like macrophages, and only the antibiotics that are able to penetrate the phagocytes change anything. Stuff like cipro is good at penetrating a macrophage. A temporary remissions of a crohn's disease patient after taking oral cipro, means the antimicrobial substance entered an activated macrophage, it managed to kill the pathogen, the macrophage stops signaling, and the pain subsides.

Vaccines for intracellular pathogens are really hard to make, you need a cell mediated response, you need to get a dendritic cell to activate a competent T cell that will then tell the macrophage to kill the ingested pathogen, it is way harder than create a vaccine that just stimulates antibodies.
It's not that crohn's macrophages can't kill MAP or AIEC btw. They surely can, just not in a competent enough matter. The macrophages in crohn's disease don't do it in a timely manner, there are autophagy (xenophagy) defficiencies, not enough neutrophils are recruited, and it results in chronic inflammation, you get tissue damage from oxidative stress, which results in lesions, lesions that then allow regular bacteria from the microbiome to make things worse, etc. It's not that macrophages of crohn's disease are not able to kill bacteria, we'd have much bigger problems if that was the case, they are just not competent enough to overcome the infection.