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Immune Axes and Their Importance in Eczema

What immune responses are behind atopic dermatitis? Brian S. Kim, MD, MTR, FAAD, discusses the current thoughts on the role of the type 2 response and hypotheses into other implications in the immune system. Dr Kim is an associate professor of dermatology as well as the co-director of the Center for the Study of Itch and Sensory Disorders in the division of dermatology, department of medicine, at Washington University School of Medicine in St Louis, MO.



Dr Kim:  When we think about it, the pathogenesis of atopic dermatitis, essentially there are three different immune axis. One is what we call the type 1 immune system. That's very important for protecting against viruses, and certain forms of bacterial infections. There are certain cytokines associated with that.

It seems that a very ancient form of the immunity against particularly worm parasites is the type 2 immune response, which largely is not that important in modern day, but has become more of a problem through diseases like eczema.

Then, there's a third arm, which some people refer to as type 3, some will refer to as TH17, where you get production of cytokines like IL‑17 and then IL‑22. They're also important to some degree for bacterial infections, but also very important for anti‑fungal infections.

What we know is that all of these different parts of the immune system can also go wrong and cause different diseases, whether it's eczema with type 2, or psoriasis with type 3, or TH17. What the point is that how clean of a type 2 immune disease is eczema? I think, pretty clean. That's why these drugs that block type 2 cytokines are so effective.

It's also a complex disease that evolves. You get infections. You get chronic infections, probably even a lot of environmental pollutants coming through your skin. What happens is that, in addition to the type 2 immune response, you start acquiring other immune responses that are increasingly a pathologic component of the disease. At least, that's what we think. In those patients, blocking some of these other pathways now, because those pathways actually take up a big chunk of the pie of what is their eczema, become now important, potentially, for treating the disease, and by blocking them.

The old adage was that acute eczema is TH2, chronic eczema TH1, but probably is not the case, because chronic eczema responds very well to a lot of type 2 blockade. There's probably some contribution that the practical aspects are going to come down to, how are you going to block TH1 or type 1? The cytokines that promote those pathways, like interferon‑gamma, are very important. There's some practical limitations too. There are arms of our immune system that are very important. You could get around that to some degree through partial blockade. That's probably what drugs like JAK inhibitors do, is that they do block some of those. They're broader, and you get lucky because you end up blocking enough of the various different pathways so you get the composite that's very effective. There are at least some significant contribution of TH22. The immunology of that is not entirely clear.

We know that those cytokines are up and we know that if we block it, it will probably have some amount of therapeutic effect, but we don't know exactly how that's happening because we don't have a good grasp on how 22 is specifically pathologic. There's a lot of good science that still needs to be done. There's a lot more that we have to understand.

We recently identified that there is two very distinct pathways, at least two broadly speaking, that mediate chronic itch vs acute itch, and it's very clear cut. In fact, the immune cells that do it are different, the pathways that do it are different. One is allergen‑mediated, the other is probably not. The neurons that are stimulated are different.

Essentially, what we have to start considering is not just acute and chronic eczema, which is fine, but it's probably that there are all different pathways that are operative. We know that. We know we have patients that have chronic itch, but they also have acute itch. Then they have layers. Some people get staph infections and the itch, some people get staph infections and they hurt, they have pain. Different things are happening in different people.

The point being is that, I don't think eczema is just one rash, and I don't think it's just a one itch. It's probably many rashes and many itches. If we're lucky, you can have one drug that can treat it all. If you're unlucky, you might need one, two, or three drugs to go after different components of the disease.

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