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