The first stage of allergic reactions has been discovered, which opens up new opportunities for prevention

Scientists from Duke-NUS Medical School have identified how a chain of events begins after a person comes into contact with an allergen such as peanuts, seafood, pollen or dust mites. Their discovery, published in the journal Nature Immunology, could lead to the development of drugs to prevent severe allergic reactions.

Mast cells, a type of immune cell, are known to mistake a harmless substance, such as peanuts or dust mites, for a threat and release the first wave of bioactive chemicals against that perceived threat. When mast cells, which are found under the skin, around blood vessels and in the mucous membranes of the respiratory and gastrointestinal tracts, simultaneously release their pre-stored bioactive substances into the blood, an immediate and systemic shock can occur, which can be fatal without prompt intervention.

According to the World Health Organization (WHO), more than 10% of the world's population suffers from food allergies. As the number of allergies increases, so does the incidence of anaphylaxis and asthma caused by food. In Singapore, asthma affects one in five children, and food allergies are already the leading cause of anaphylactic shock.

The Duke-NUS team has discovered that the release of mast cell granules containing bioactive chemicals is controlled by two components of an intracellular multiprotein complex called the inflammasome. Until now, these inflammasome proteins were known only to spontaneously assemble in immune cells to secrete soluble chemicals that alert other parts of the immune system when an infection is detected.

Professor Soman Abraham, Emeritus Professor of Pathology at Duke University, who led the study while working in the Duke-NUS Emerging Infectious Diseases Programme, said: “We found that components of the inflammasome played a surprisingly important role in transporting mast cell granules that are usually packaged at the center of the cell, towards the cell surface, where they are released. This unexpected discovery gives us a precise target for intervention to prevent the chain of events initiated by mast cells leading to anaphylactic shock.

Professor Abraham and his team looked at mice that lacked one of two inflammasome proteins, NLRP3 or ASC. When these animals were exposed to allergens, they did not experience anaphylactic shock.

However, anaphylactic shock was observed when the NLRP3 and ASC proteins in mast cells assembled and associated with individual intracellular granules, forming a complex that the researchers called a granulosome, which promoted the movement of granules along paths formed by the cytoskeleton inside the mast cell, similar to how they "attached to the rail tracks."

Dr Pradeep Bist, first co-author of the paper and principal investigator of the Duke-NUS Emerging Infectious Diseases Programme, said: “When mast cells are activated, we observed the rapid movement of granules along dynamic pathways known as microtubules to the cell membrane, where these granules were immediately released from the cell. However, in mast cells lacking NLRP3 or ASC proteins, we found no evidence of intracellular granule movement and none of these granules were released."

After demonstrating the role of NLRP3 and ASC in granule transport, the team turned to known inflammasome inhibitors to see if they could prevent this event.

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

Dr Andrea Mencarelli, from the Institute of Immune Therapeutics at Shanghai Jiao Tong University School of Medicine, who was the first co-author of the paper while working at the Duke-NUS Emerging Infectious Diseases Program, said: "It is remarkable that using a drug that specifically blocked the activity of inflammasome proteins "We were able to selectively block the release of pre-stored mast cell chemicals without affecting other potentially beneficial mast cell functions."

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

"I can see how this could bring peace of mind to parents of children with severe food allergies when they are faced with situations where it is impossible to be sure there is no risk of exposure. While we don't want to deactivate this part of the immune system for long periods, it could potentially provide short-term protection," said Professor Abraham, whose team is now working to optimize the dosage and frequency of use of this drug to achieve the best protective effects against anaphylactic shock.

"After this, 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 further research but also for improving the quality of life of those at risk of severe allergic reactions. It is a ray of hope, especially for parents of young children who live with constant anxiety."