New Allergen Pathway Discovery Could Yield New Meds

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Researchers have uncovered the mechanism by which the innate immune system is triggered by allergens, such as insects, mites, and fungi.

In Nature Immunology, researchers revealed new details about how the body’s “type 2 innate immune response” system works, which could yield a new medication for allergy control.

“Disrupting this allergen sensing pathway could provide a unique opportunity to counteract type 2 immunity and alleviate allergic inflammation,” said senior author Marc Rothenberg, MD, PhD, Director, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center

In addition to Rothenberg, the research team included , 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.

Multiple allergens had been shown to induce a similar IL-33 response upon breaching the epithelial layer of mucosal membranes, a process which the researchers pinned down.

“This breakthrough was made possible by new insights into the role of ripoptosome signaling and caspases in allergic inflammation,” said Michael Brusilovsky, MMedSc, PhD, who was the first author of the study.

Specifically, the allergens trigger activity among an interlocked set of cell death-inducing signals called the ripoptosome. This signaling “platform” includes numerous components, but for allergic inflammatory reactions, the key player appears to be a molecular switch called caspase 8. The investigators named the pathway, “RipIL-33” as IL-33 is processed (ripped) by the ripoptosome.

How allergens are sensed has remained a mystery.

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

In mice, inhibiting caspase 8 reduced the IL-33 response to allergens and limited bronchial inflammation in the lungs. Analysis revealed a similar process in humans/ 
“In the human allergic disease eosinophilic esophagitis (EoE), we found that ripoptosome activation markers and mature IL-33 levels dynamically correlated with the degree of esophageal eosinophilia and disease activity,” the study states.

The next steps include studying the RipIL-33 pathway in human allergic reaction and determining whether existing or new drugs could disrupt it.

Source: News-Medical.Net

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