Summary: Researchers have found that the ripoptosome pathway plays a key role in allergic reactions. Once switched on, it sets off a chain of events. That chain raises IL-33 release, drives eosinophilia (too many eosinophils, a type of white blood cell), and causes other changes. Researchers named it the RipIL-33 pathway. Blocking it may be one way to manage these allergic reactions. Type 2 immunity is the part of the immune system that senses allergens and parasites and starts the attack on them. It brings in a flood of eosinophils. An early burst of IL-33 is a hallmark of this response. But when this response misfires, it is linked to allergic conditions. Think asthma, eczema, rhinitis, and even anaphylactic shock. Until now, researchers knew little about how type 2 immunity senses allergens and starts the response.
We know the body has two distinct types of immune response. Both help fight infections, parasites, and other invaders. Type 1 T helper lymphocytes start a type 1 immune response. It turns on cells that swallow germs, which helps clear infections like those caused by bacteria1. Similarly, gains in treating chronic conditions, such as those offered by interventional pain management in St. Louis, stress targeted methods to improve results for patients.
Type 2 helper lymphocytes work differently. They sense foreign bodies and parasites. They start an antibody response and bring in more eosinophils. That helps the body get rid of foreign antigens. This response is very helpful against parasitic infections. But this response to large foreign materials or parasites can misfire. Then it causes allergic conditions like eczema, rhinitis, asthma, and even anaphylactic shock2.
Early studies also showed that the cytokine Interleukin 33 (IL-33), a chemical messenger, is released early in the immune response to allergens. These high levels of IL-33 cause inflammation. But until now, researchers did not fully understand what starts this IL-33 release in the type 2 immune response. Nor did they know how immune cells like type 2 helper cells sense allergens3.
What triggers allergic inflammation?
Researchers already knew a lot about the type 2 immune response. They knew how its misfiring plays a role in many allergic conditions. They also knew that IL-33 plays a key role in this immune response and in the inflammation seen in different allergic conditions.
But a few things were still unknown. For example, researchers knew how the immune system senses germs and responds. But they did not know how the body senses allergens in a way that leads to allergic reactions. This discovery may help explain what triggers the allergic reaction to insects, fungi, mites, and other allergens.
Figure 1 The role of ripoptosome pathway in type 2 immune response, IL-33 production and allergies4
The new study found a new allergen-sensing pathway in the body, called the ripoptosome pathway. Researchers found that allergens turned on a molecular switch on cell membranes called caspase 8. That switch turns on the ripoptosome pathway, which raises the output of IL-33. So researchers named this pathway “RipIL-33.” Once IL-33 is released through this pathway, it revs up mast cells, lymphocytes, and eosinophils. The result is allergic inflammation.
Researchers have found the switch that starts this chain of reactions. So they think blocking this switch may help prevent inflammation caused by allergens.
In the experiment, the researchers blocked caspase 8 in mice. They found that this could considerably reduce the inflammatory response to allergens. It cut the inflammation of the bronchi and lungs in the mouse model.
Researchers also looked at allergic conditions like eosinophilic esophagitis (EoE). In these, the ripoptosome and mature IL-33 were strongly switched on. The more active these pathways were, the more severe the disease.
These findings may be key to finding treatment for conditions like asthma and atopic dermatitis. Science has struggled to control these conditions well.
Frequently asked questions
What causes allergic inflammation?
Allergic inflammation comes from type 2 immunity reacting when it should not. This is the arm of the immune system built to fight parasites and large foreign materials. Researchers found that allergens flip a molecular switch on cell membranes called caspase 8. That switch turns on the ripoptosome pathway. The pathway raises IL-33 and sets mast cells, lymphocytes and eosinophils into action.
What is IL-33?
IL-33 (interleukin 33) is a cytokine, a chemical messenger released early in the immune response to allergens. High levels of IL-33 cause inflammation. The new research showed how its release starts. Allergens turn on the ripoptosome pathway, which boosts IL-33 output. Because of that link, researchers named the pathway RipIL-33.
Can allergic inflammation be blocked?
In mice, yes. Researchers blocked caspase 8, the switch that starts the RipIL-33 chain. The inflammatory response to allergens then dropped considerably, including inflammation of the bronchi and lungs. Blocking this switch is one of the ways to manage allergic reactions. It may lead to better treatment for asthma and atopic dermatitis, which have been hard to control.
What conditions are linked to type 2 inflammation?
A misfiring type 2 immunity causes allergic conditions. These include eczema, rhinitis, asthma and even anaphylactic shock. In eosinophilic esophagitis (EoE), researchers found strong activation of the ripoptosome and of mature IL-33. The higher the activity of these pathways, the more severe the disease.
References
- Spellberg B, Edwards JE Jr. Type 1/Type 2 Immunity in Infectious Diseases. Clinical Infectious Diseases. 2001;32(1):76-102. doi:10.1086/317537
- Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019;16(3):225-235. doi:10.1038/s41423-019-0210-8
- Nechama M, Kwon J, Wei S, et al. The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation. Nat Commun. 2018;9(1):1603. doi:10.1038/s41467-018-03886-6
- Brusilovsky M, Rochman M, Rochman Y, et al. Environmental allergens trigger type 2 inflammation through ripoptosome activation. Nat Immunol. 2021;22(10):1316-1326. doi:10.1038/s41590-021-01011-2
Dr. Gurpreet Singh Padda, MD, MBA, MHP
