Tolerance isn’t easy

Our immune system needs to be on a hair-trigger. When you breathe in a virus or a bacterium enters a cut on your arm, you don’t want to mess around:

(disclaimer: most of what George Carlin says in the rest of that clip is not supported by the science (though it’s funny as hell))

But all of that heavy immunological artillery is dangerous, and when it’s directed at the wrong target, there can be a lot of collateral damage. Some of the most important parts of the immune system are mechanisms of tolerance – teaching the immune system to ignore the things that aren’t a threat. For the innate immune system, tolerance is hard-wired. The receptors that signal danger have evolved over hundreds of millions of years to only detect conserved pattern that are present on potential pathogens.

For the adaptive immune system, it’s a different story. T-cells and B-cells generate their receptors at random, and have the potential to recognize an effectively infinite number of targets. From birth, these cellular assassins have a single, specific target, and the means to do significant damage to it. But if that target is, say, insulin, you don’t want that assassin making it out onto the street. So, during development, T-cells and B-cells undergo an elaborate education process in which cells that react against any self targets are forced to commit suicide, taking their potentially damaging targeting system with them. But this “central tolerance” mechanism is only half of the story.


As anyone with allergies can tell you, having an immune system that attacks harmless targets can be miserable, or even deadly. Foreign, but benign molecules are not present where T- and B-cells develop, so central tolerance isn’t enough. There is no place where this problem is more apparent than in the gut, which has to deal with trillions of non-harmful bacteria, as well as foreign molecules in the form of food. As a result, there are a plethora of so-called “peripheral tolerance” mechanisms at play in the gut. One of these is a special type of T-cell called a regulatory T-cell (or Treg) that, rather than activating the immune system, actually suppresses it.

The environment of the gut is known to induce Treg‘s, and it was recently discovered that retinoic acid – one of the products of vitamin A metabolism – was partly responsible. To immunologists, this made a lot of conceptual sense. It’s still not exactly clear how T-cells decide what their fate will be, and it made sense that a dietary factor – something that would only be present in one of the places Treg‘s are most needed, would help skew that choice. But before you run out and start and downing VitA supplements to treat your food allergy, consider this:

ResearchBlogging.orgCo-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

IL-15 is a cytokine – a type of molecule that the immune system uses to communicate between cells – and it turns out that when IL-15 is around, retinoic acid actually behaves in precisely the opposite way with respect to T-cells. It decreases the number of Treg‘s, and increases inflammation. This is an observational study – there’s not a lot of information about how IL-15 behavior causes this change. The authors chose to look at this because it’s known that patients with celiac disease (an allergy to dietary gluten) have elevated levels of IL-15, but it’s not even clear if it’s the IL-15 that decreases Treg development so that inflammation gets going, or if the inflammation starts for some other reason and the IL-15 just makes it worse.

The major implication here is that the folks hoping to use VitA to help calm down the gut immune system are probably out of luck – that could make the situation even worse.

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Extras
- It turns out the experiment of therapeutic retinoids increasing inflammation in the gut might have already been tested on accident.
- Bonus conclusion (with no data) – the authors threw this gem into the discussion section:

Conversely, these findings provide an explanation as to why children suffering from vitamin A deficiency in developing countries respond less efficiently to oral vaccines than children from developed countries, and also indicate that engineering mucosal vaccines that induce IL-15 may be beneficial[...]

I’d love to see some follow-up on that.

DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, & Jabri B (2011). Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature, 471 (7337), 220-4 PMID: 21307853

Comments

  1. #1 don donahue
    March 26, 2011

    Kevin,
    I’m interested in learning more about the immune system and stumbled upon you blog (via reddit). I thought you might find what I just did for my allergies/vasomotor rhinitis/chronic sinusitis interesting. It’s call helminthic therapy. There is a wikipedia page and a separate wiki at opensourcehelminthictherapy.org. It is clear that helminths negotiate with ones immune system. I am remarkably better in only 7-8 weeks. Anybody interested in the immune system would find this at least interesting. You can email me if you have any questions.

  2. #2 Kevin
    March 26, 2011

    Hi Don, I’ve mentioned that sort of thing before, and it’s a really exciting area of research. As I scientist though, I’m extremely hesitant about recommending this sort of natural remedy, even though I think the concept has tremendous promise.

    Helminths can be pathogens, and have historically caused a lot of disease and death. I’m happy to hear that the treatment worked for you, and the link you posted isn’t working, so I can’t comment on the details of it, but I’m not sure it’s responsible to willingly infect yourself with a transmisible pathogen.

    That said, living in the developed world, the same things that have reduced the rate of helminth infection (mainly hygiene) probably means that you won’t actually transmit it. And thankfully, there’s a lot of research going on right to put treatments based on this idea to make treatments for allergies, as well as many types of auto-immunity, safe and effective.

  3. #3 Herbert Smith
    March 27, 2011

    The correct link that Don mentioned is opensourcehelminththerapy.org
    Under the “studies and papers” link on the top left it lists at least 3 studies that performed safety trials establishing that Necator Americanus helminth is safe in small numbers. It also doesn’t reproduce inside humans, so it’s not a dangerous pathogen. Additionally, I was able to put my Crohn’s in remission after suffering for 16 years.

  4. #4 Brooke N
    March 28, 2011

    Hey Kevin – I know a little about this topic (because of immunology class & I have been diagnosed with celiac for 24 years), but I’m wondering is this upregulation of IL-15 found in celiac patients that are consuming gluten, or generally in all celiac patients?

  5. #5 Kevin
    March 28, 2011

    @Herbert: The study I linked to in my previous post uses Trichuris suis, a pig pathogen that also can’t establish chronic infections in humans. Again, I’m not saying that these treatments are definitely unsafe, and i actually think they hold tremendous promise. But we have multiple levels of regulation and clinical trials for a reason, and I know of far too many good ideas gone bad to say we should ignore that. I am absolutely happy for you and don (no sarcasm there, I mean it), but individual anecdotes do not constitute proof of efficacy or safety. I don’t fault you for using a non-FDA approved method, but until I see a lot more data, I won’t endorse it.

    Also note: I’m not a doctor, so you shouldn’t pay attention to any medical advice I would give anyway.

    @Brooke – That’s a great question, I went and looked at the Gastroenterology paper that these authors cited (Jean-Jaques Mention et al, 2003 if you’re interested in taking a look), and they look at both patients with active celiac disease and those that have been on a strict gluten-free diet and (mostly) don’t show any of the tissue pathology. It looks like the later have less IL-15 than the patients with active celiac disease, but it’s definitely elevated above the control “normal” patients (and interestingly, folks with crohn’s disease don’t have elevated IL-15, so it’s not just any old gut inflammation that causes it).

    I didn’t read through the whole paper in detail, but it looks like they did a number of tests comparing folks on a GFD with active celiac patients, and in most cases (again, my look was a bit cursory), it looks as though the people avoiding gluten still have higher levels than non-celiac patients, but lower than people with active disease.

  6. #6 Elizabeth Munroz
    April 4, 2011

    What do you know about this new cat allergy vaccine? Will this also be useful for other allergies, do you think?
    http://www.sciencedaily.com/releases/2011/03/110331163534.htm

  7. #7 Doctor Smart
    April 15, 2011

    I bet Kevin never heard of colloidal silver.

  8. #8 kevin
    April 15, 2011

    Isn’t that what they used in the 3rd Blade movie?

  9. #9 Doctor Smart
    April 16, 2011

    No. it what they use when conventional medicine does not work on bacterial and viral infections. Colloidal Silver is known to kill over 600 various viruses and bacteria. Of course they may have used it in the 3rd blade movie. You know left wing Hollywood.

    Don’t worry about the medical mafia banning it anytime soon. Most people know how to make their own at home. A simple transformer, a few other items, and a silver coin is needed. Simple, effective, cost efficient, and completely untraceable when paid for in cash. Avoiding Big Brother is getting harder every day.

  10. #10 Kevin
    April 16, 2011

    Oh, now I remember where I heard about that before.

  11. #11 rafael matias
    August 2, 2011

    LOL

    Illustrate what i think about our amazing immune system !

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