Discovery of a biological response platform could offer the opportunity to relieve allergic inflammation

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New findings on an integrated rapid reaction system that triggers inflammatory responses when people are exposed to allergens, such as insects, mites and fungi, could also be the key to helping more people manage their allergies in the world. coming years.

A study by scientists at Cincinnati Children’s, published on September 16, 2021 in Natural immunology reveals new details about how the body’s “innate immune response type 2” system works. By identifying a common biological response platform, the results suggest that any new drug that can control the response could benefit people with a wide range of allergies.

Disruption of this allergen detection pathway could provide a unique opportunity to thwart type 2 immunity and relieve allergic inflammation. “

Marc Rothenberg, MD, PhD, study lead author and Director, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center

In addition to Rothenberg, the research team included Michael Brusilovsky, MMedSc, PhD, Mark Rochman, PhD, Yrina Rochman, PhD, Julie Caldwell, PhD. Lydia Mack, MS, Jennifer Felton, PhD, Jeff Habel, PhD, Aleksey Porollo, PhD and Chandrashekhar Pasare, DVM, PhD.

Previous research had established that several allergens can induce a similar IL-33 response upon rupture of the epithelial layer of mucous membranes. The Cincinnati Children team identified the mechanisms at work in the process.

Allergen detection system

“This breakthrough was made possible by new knowledge about the role of ripoptosome and caspase signaling in allergic inflammation,” said Brusilovsky, who was the study’s first author.

Specifically, allergens trigger activity among a nested set of signals inducing cell death called the ripoptosome. This signaling “platform” includes many components, but for allergic inflammatory reactions the key player appears to be a molecular switch called caspase 8. Researchers named the pathway “RipIL-33” because IL- 33 is processed (torn off) by the ripoptosome.

Over the past two decades, immunologists have discovered the mechanisms by which bacteria and viruses are detected by the innate immune system, but how allergens are detected has remained a mystery.

“The discovery of this surprising mechanism is the most important breakthrough in understanding how the innate immune system detects allergens to initiate a type 2 response and subsequent allergic inflammation,” says Pasare, one of the study’s lead authors. .

In mice, inhibition of caspase 8 activity reduced the response of IL-33 to allergen exposure and limited bronchial inflammation in the lungs. Further analyzes have indicated that a similar process occurs in humans.

“In eosinophilic esophagitis (EoE), a human allergic disease, we found that markers of ripoptosome activation and levels of mature IL-33 were dynamically correlated with the degree of esophageal eosinophilia and activity. disease, ”the study said.

Editors at Natural immunology chose this paper to appear on the cover of its September print edition.

The next steps are to look for further confirmation of the RipIL-33 pathway in the human allergic reaction and to determine whether existing drugs or a new compound can safely disrupt the inflammation cycle.

Source:

Cincinnati Children’s Hospital Medical Center

Journal reference:

Brusilovsky, M., et al. (2021) Environmental allergens trigger type 2 inflammation via the activation of ripoptosomes. Natural immunology. doi.org/10.1038/s41590-021-01011-2.


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