Researchers identify first step in allergic reactions, paving the way for preventative strategies

Editors’ notes

Scientists at Duke-NUS Medical School have identified how the first domino falls after a person encounters an allergen, such as peanuts, shellfish, pollen or dust mites. Their discovery, published in the journal Nature Immunology, could herald the development of drugs to prevent these severe reactions.

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

More than 10% of the global population suffers from food allergies, according to the World Health Organization (WHO). As allergy rates continue to climb, so does the incidence of food-triggered anaphylaxis and asthma worldwide. In Singapore, asthma affects one in five children while food allergies are already the leading cause of anaphylactic shock.

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

Professor Soman Abraham, Grace Kerby Distinguished Professor of Pathology at Duke University, who led this research when working in Duke-NUS’ Emerging Infectious Diseases Programme, said, “We discovered that the inflammasome components played a surprisingly crucial role in transporting particulate mast cell granules which are typically packed in the cell center to the cell surface where they are released. This surprising discovery gives us a precise target where we can intervene to prevent the cascade of events initiated in mast cells that leads to anaphylactic shock.”

Prof Abraham and his team’s eureka moment came while observing mice whose mast cells lacked either of the two inflammasome proteins, NLRP3 or ASC. When these animals were exposed to allergens, they failed to experience anaphylactic shock.

However, anaphylactic shock was observed when mast cell NLRP3 and ASC proteins assembled and bound to individual intracellular granules, forming a complex the researchers call granulosum, facilitating the granules’ movement along tracks formed by the cytoskeleton within the mast cell—akin to hooking them onto a set of “rail tracks.”