Allergies 101: Part the Third

I know this post has been a long time coming. In the first part of this series, I told you that allergies are the result of an immune response against an external, but normally not harmful substance. In part 2, I told you that allergies are the result of a specific type of immune response called "Th2," which leads to the production of IgE antibodies, and that this immune response is thought to have evolved to combat infections caused by worms. But what makes your immune system think it's supposed to be battling a worm?

The short answer to the questions is: we don't know. For other types of immune responses, the past 15 years has given us a great deal of insight into the ways that the immune system recognizes the infections. Toll-like receptors (which I study) and other so-called "pattern recognition receptors" are able to recognize molecules that are unique to bacteria, or unique to viruses and respond accordingly. If there is such a molecular pattern for worms, we don't know what it is, and we don't know what receptor (if any) can recognize it.

But there might be a clue in the nature of the proteins that tend to become allergens. Dust mites, cat dander, birch tree pollen and papayas may not seem to share much in common, either with each other or with the worms the immune system thinks it's fighting, but rather than sharing a particular molecular shape, perhaps they share a particular chemical activity. It turns out, many allergens are proteases - enzymes that cut up proteins.

Normally, cells see their exterior environment through receptors, proteins on the surface of cells that bind onto a specific molecule called its ligand. When the ligand binds to a specific groove in the receptor, it activates a series of events inside the cell that lead to a change in behavior.

Receptor-ligand 2.png

In the case of most pattern recognition receptors, the ligand is some microbial product - for instance, many bacteria (gram negative) have a molecule called lipopolysaccharide (LPS) in their cell wall, and we have a receptor (TLR4) that recognizes LPS. But the sensors of worms (and allergens) may behave a bit differently. Worms are much more closely related to us than bacteria and viruses, and finding differences are essential for this system to work (you wouldn't want your macrophages freaking out over your own cells). Since there might not be a molecular shape that works, what about an enzymatic activity?

Many worms secrete cysteine proteases - enzymes that cleave proteins at cysteine residues and have cysteines in their active site- during their life cycle in the gut, and it may be possible for the immune system to detect this and know to start a Th2 response. In fact, one of the best models for this sort of an immune response is papain, a cysteine protease from papaya and a potent allergen. Knocking out all of the known pathogen sensors has absolutely no effect on papain's ability to activate the immune system, so there's something going on that we don't quite understand.

There are a couple of ways this could work. Their might be a substrate for cysteine proteases that, when cleaved, becomes a ligand for a receptor.

Ligand cleavage model.png

Another possibility is that the receptor itself is cut, and this cut is required for the signaling activity to occur.

Receptor cleavage model.png

There are other known examples of these sorts of mechanisms, but as yet, no one has been able to find a receptor that is responsible for this activity in the immune system, so the jury is still out. In addition, there are many allergens that are not thought to be cysteine proteases, so there may be multiple pathways, or this idea might be completely wrong. But considering allergies are on the rise, and considering how little we know about this aspect of immunity, it might be a good thing for us to figure out.


Allergies 101: Part 1 Allergies 101: Part 2