Study Aims to Reveal Novel Drivers of Allergic Disease

Chronic allergic disorders affect millions of individuals worldwide, and their frequency is increasing, especially in children and adults living in the U.S. Often, multiple allergic diseases, such as asthma, food allergies, atopic dermatitis, and some gastrointestinal disorders can occur in a single patient.

Investigators at The Children’s Hospital of Philadelphia are studying the underlying biological features that could be common from one allergic disease to another. In particular, they are interested in how two small adapter proteins, Ndfip1 and Ndfip2, activate enzymes called E3 ubiquitin ligases that could play an important role in preventing allergic disease.

“A small protein, ubiquitin, is the basis for the garbage disposal system of the cell,” explained Paula M. Oliver, PhD, in the Cell Pathology Division of CHOP and an associate professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine. “When ubiquitin is tagged to a protein, one of the outcomes can be degradation of that protein. So it is the cell’s way of removing unneeded proteins. When you don’t get rid of those proteins, you can get allergic disease.”

Dr. Oliver’s study team is using genetically engineered mice to study E3 ubiquitin ligase function. They previously have shown that mice in which a particular ligase — aptly named ITCH — cannot function, develop an allergic dermatitis-like phenotype that causes them to scratch. They also get inflammation of the lungs that is reminiscent of asthma and gastrointestinal disorders that have features similar to food allergies.

In Dr. Oliver’s current work that received funding in July from the National Institute of Allergy and Infectious Diseases, the investigators already have figured out how E3 ubiquitin ligases remain inactive in a closed, “off” position until Ndfip1 and Ndfip2 seem to open them up and turn them “on.”

“We took the next step in thinking that maybe there are some ways of forcing that to happen and turn on these enzymatic pathways in cells to prevent or treat allergic disease,” Dr. Oliver said.

This strategy is an exciting alternative to current treatments for allergic disease that globally shut down immune function, Dr. Oliver said. The new approach they are studying would disarm only the component of the immune system that drives allergic responses, while not affecting its ability to respond to viruses or pathogenic bacterial infections.

Over the next year, the study team will move toward developing therapeutic methods to regulate E3 ubiquitin ligase activation. They will design small penetrating peptides aimed at catalyzing the transfer of ubiquitin to a substrate protein in the cell. They also will work with a local company to create small molecule activators of the ligases, as a second possible approach.

“We are quite sure that there are other mechanisms that might control these things as well, so we’re continuing to understand exactly how this happens,” Dr. Oliver said. “We’re also trying to understand what the substrates are that need to be gotten rid of because that might tell us more about how allergic diseases start or which proteins are important in driving allergic diseases.”

In addition to receiving funding from the NIAID, Dr. Oliver’s work is supported by the American Asthma Foundation.