Chronic Spontaneous Urticaria: Type 2 Inflammation and Mast Cell Hyperreactivity

Dr Raj Chovatiya explains how type 2 inflammation drives mast cell activation in chronic spontaneous urticaria (CSU), highlighting the roles of IL-4, IL-13, and IgE in both immune and neuroimmune pathways. Learn why CSU itch is primarily histaminergic, how neuropeptides and sensory nerves influence disease activity, and why targeted therapies are essential for patients who fail antihistamines.

Transcript

Hi there. My name is Dr Raj Chovatiya. I'm an associate professor at the Roslyn Franklin University of Medicine and Science, Chicago Medical School and founder and director of the Center for Medical Dermatology and Immunology Research in Chicago, Illinois.

How does type 2 inflammation contribute to mast cell activation in CSU?

Dr Chovatiya: Chronic spontaneous urticaria is a newer, let's say, disease state in the type 2 inflammatory umbrella as it's not one we necessarily thought of with this lens. So there's been a lot of recent research to better understand what are cytokines like IL-4 and IL-13 doing in this disease state that are contributing to mast cell activation that we know drives a lot of the histaminergic itch that we think about in CSU. There's probably a couple different things happening. So we know that IL-4 is a key driver of differentiating naive T lymphocytes to TH2 cells, and so that's probably happening centrally and we know TH2 cells produce a lot of cytokines like IL-4 and -13 that then perpetuate inflammation downstream. IL-4 and -13 promote B-cell activation and class switching, and so that includes IgE production and thus it probably enhances auto-antibody mediated mechanisms as well as trafficking of the immune cells to the site of inflammation. That's probably an important part of this disease too, especially as it relates to where immunoglobulins are involved. At the neuroimmune axis, we know that IL-4 and IL-13 can activate and sensitize nerves to a whole diverse host of pruritogens, and so that's probably also enhancing and helping the itch process here too. And so it's believed that all of these in totality, are probably leading to mast cell hyperactivity and contributing to this continuous cycle of neuroimmune inflammation.

What roles do IL-4 and IL-13 play in IgE-dependent and IgE-independent pathways in CSU?

Dr Chovatiya: IL-4 and IL-13 are two cytokines among others that are able to bind directly to mast cells and influence their activity as well as many of the peripheral and surrounding cells in the mast cell environment in individuals that have CSU. So more than likely what's ending up happening in this disease state rather than IL-4 and IL-13 being singular triggers, they're probably highly influential on the different phenotypes of disease itself, both ones that seem to depend on autoantibodies or antibodies like IgE and perhaps even routes that don't depend on that by altering not only mast cell activity, but also neuronal activity in addition to cellular trafficking as well too.

How does IL-31 contribute to itch in CSU compared with AD and PN?

Dr Chovatiya: IL-31 seems to be important across most of our itchy type 2 and inflammatory diseases, but perhaps it's a little less important in CSU than our other conditions. And this is largely related to the fact that in diseases like atopic dermatitis and prurigo nodularis we're largely thinking about the activation of non-histaminergic itch pathways. In the case of CSU, a disease state where antihistamines are actually appropriate, histamine seems to be a major driver of itch. Thus, histaminergic pathway seem to largely be important here. Now, this doesn't mean that IL-31 doesn't still have a role to some degree, but it is a reason why we've seen therapeutic development for agents that block things like IL-4 and -13 and not so much -31 for CSU, in part because it's believed the predominant mechanism of itch in this disease is going to be mediated by histamine.

Why does itch in CSU fluctuate rather than become chronically fibrotic?

Dr Chovatiya: Rather than having low-level or even medium level continuous activation of immune cells, in the case of chronic spontaneous urticaria, the name sort of implies there's a spontaneous element of the disease itself. Mast cell degranulation is typically going to be driving bouts of hives as well as itch and or angioedema. And mast cell degranulation is not continuously happening all the time. If one were having continuous coordinated mast cell degranulation over the entire body, that would be more something like anaphylaxis. It would be actual compromise of blood pressure and vascular tone across the entire body. In the case of CSU, you're having sort of these random bouts of activation, and so that's the reason why patients can have these unpredictable episodes that occur, but then also go through periods where there isn't anything happening too, which is a little different than atopic dermatitis, which is waxing and waning to a degree, but there's a little more stability of lesions or prurigo nodularis, which we believe to not be as waxing and waning of a disease, but to be rather much more stable.

How do neuropeptides and sensory nerves influence mast cell behavior in CSU?

Dr Chovatiya: We've learned a lot in type 2 inflammatory diseases about what's happening at the neuroimmune access when thinking about peptides that are produced by cutaneous neurons that act back on immune cells. This is completely true in chronic spontaneous urticaria too. So we know that neuroinflammation has an important role here, and there's actually a variety of receptors directly on the mast cell that can bind to the myriad of neuropeptides that are produced by cutaneous afferents in the skin. Thus, nerves actually have a really important role to play as being modulators and dry risk of mast cell activation, which is one reason why you can think about a variety of different loops causing continued itch and inflammation in this disease.

What distinguishes CSU as a type 2 disease despite its transient skin lesions?

Dr Chovatiya: Type 2 inflammation as a process can have so many different manifestations and appearances, and really if one was to show you a clinical image of an individual with chronic spontaneous urticaria, prurigo nodularis in a prototypical eczematous plaque, you might be hard-pressed to find the similarity. But we know that the pattern with which immune cells as well as neurons seem to be involved and activated in these disease states mean that there's a lot of shared pathogenesis, in particular cytokines like IL-4, IL-13, IL-31, and others all seem to play an important organizing and modulatory role that is driving dysregulation across multiple axes. So even though CSU tends to have episodes of clearance and episodes of involvement and a very different appearance in terms of the rash itself, it belongs in the type 2 inflammatory disease family. Much like the other examples I've mentioned.

Are there any tips or insights you would like to share regarding type 2 inflammation and urticaria?

Dr Chovatiya: When it comes to CSU, we've spent a long time thinking that antihistamines are probably sufficient, and if they're not, there must be some other deeper cause or driver of disease that needs to be found. I think the most important point that I can get away with is that, yep, about half of patients are going to probably do okay on antihistamines, but for that other half, largely speaking, that is going to be the population to think about our many targeted therapies in the type 2 inflammatory umbrella and beyond, as there truly is not going to be an easily ascertainable cause as to why the individual has CSU. Searching for the etiology is often going to be fruitless. So again, in this case, if you can diagnose it and you have treatment failure, you can definitely treat your patients and get them on a targeted therapy.