Researchers identify first stage of allergic reactions, paving the way for preventative strategies

Duke-NUS Medical School scientists have identified how the first domino falls after a person encounters an allergen, such as peanut, shellfish, pollen or dust mites. Their discovery, published in the journal Natural immunology, could herald the development of drugs to prevent these serious reactions.

It is well established that when mast cells, a type of immune cell, mistake a harmless substance, such as peanuts or dust mites, for a threat, they immediately release a first wave of bioactive chemicals against the perceived threat. When mast cells, which reside under the skin, around blood vessels, and in the walls of the airways and gastrointestinal tract, simultaneously release their pre-stored load of bioactive chemicals into the bloodstream, instant systemic shock can result. , which can be fatal. without rapid intervention.

More than 10% of the world's population suffers from food allergies, according to the World Health Organization (WHO). As allergy rates continue to rise, the incidence of food-related anaphylaxis and asthma is also increasing worldwide. In Singapore, asthma affects one in five children while food allergies are already the leading cause of anaphylactic shock.

What the Duke-NUS team has now discovered is that the release of particulate granules from mast cells, which contain these bioactive chemicals, is controlled by two members of an intracellular multiprotein complex called an inflammasome. Until now, it was only known that these inflammatory proteins spontaneously assemble within immune cells to secrete soluble chemicals to alert other parts of the immune system when an infection is detected.

Professor Soman Abraham, Grace Kerby Distinguished Professor of Pathology at Duke University, who led this research while working in the Emerging Infectious Diseases Program at Duke-NUS, said: “We found that the components of The inflammasome played a surprisingly crucial role in the transport of particulate mast cell granules. which are usually packaged in the cell center to the cell surface where they are released. This surprising discovery gives us a precise target on which we can intervene to prevent the cascade of events initiated in mast cells which leads to anaphylactic shock.

Professor Abraham and his team's eureka moment came when they observed mice whose mast cells lacked either of two inflammatory proteins, NLRP3 or ASC. When these animals were exposed to allergens, they did not experience anaphylactic shock.

However, anaphylactic shock was observed when the mast cell proteins NLRP3 and ASC assembled and bound to individual intracellular granules, forming a complex that researchers call granulosum, facilitating the movement of the granules along the tracks formed by the cytoskeleton to inside the mast cell, which amounts to hanging them. a set of “railroad tracks”.

Dr Pradeep Bist, co-first author of the paper and principal investigator of the Emerging Infectious Diseases Program at Duke-NUS, said: “During mast cell activation, we observed rapid movement of granules on tracks dynamics called microtubules to the cell membrane. , where these granules were rapidly released from the cell. However, in mast cells deficient in NLRP3 or ASC proteins, we found no signs of intracellular granule movement and none of these granules were released.

Having demonstrated the trafficking role of NLRP3 and ASC, the team then turned to known inflammasome inhibitors to test whether they could prevent this event from occurring.

Using an inflammasome-blocking drug very similar to those in clinical trials for chronic inflammatory diseases, called CY-09, they administered the treatment to mice before introducing an allergen. They found that in their preclinical model, they were able to effectively prevent anaphylactic shock using this drug.

Dr. Andrea Mencarelli, of the Institute of Immunotherapy, Shanghai Jiao Tong University School of Medicine, Shanghai, China, who first co-authored the paper while working at the Duke-NUS Emerging Infectious Diseases Program, said: “It was remarkable that by employing a drug that specifically blocked the activity of inflammatory proteins, we were able to selectively block the release of pre-stored chemicals from the mast cells without impacting other potentially beneficial activities of mast cells.

While not a cure, it could offer people with severe allergies a new tool to prevent a potentially traumatic reaction from occurring. Currently, emergency treatments are taken immediately after the first symptoms appear. These treatments must be administered within a narrow window of time to be effective, and they also have serious side effects.

“I could see this providing peace of mind to parents of children with severe food allergies when they find themselves in situations where they cannot be sure there is a risk of exposure. Although we “We don't want to disable this part of the immune system for prolonged periods, this could potentially provide short-term protection,” said Professor Abraham, whose team is currently working to optimize the dosage and frequency of use of this medication to achieve the best protective effects against anaphylactic shock.

“After that, we hope to do the same for asthma and allergic skin reactions.”

Professor Patrick Tan, Senior Associate Dean for Research at Duke-NUS, said: “This breakthrough has enormous translational potential and represents a paradigm shift not only for the pursuit of research, but more importantly for the improvement of the quality of life of people at risk of serious allergies. It's a glimmer of hope, especially for parents of young children who live with this constant worry. »