Initial Stage of Allergic Reactions: New Preventative Strategies

Scientists have pinpointed the initial step in the allergic reaction process, a breakthrough that may lead to the development of medications to avert severe allergic responses. Researchers at Duke-NUS Medical School have identified the mechanism that initiates allergic reactions when individuals encounter allergens like peanuts, shellfish, pollen, or dust mites. This discovery, detailed in the April issue of Nature Immunology, holds promise for the future development of drugs aimed at preventing these extreme reactions.

Mast cells, a type of immune cell located under the skin, around blood vessels, and in the linings of airways and the gastrointestinal tract, have long been known to release bioactive chemicals when they erroneously identify harmless substances as threats. This release can result in immediate and potentially fatal systemic shock if not promptly treated.

According to the World Health Organization (WHO), over 10% of the global population suffers from food allergies, and this rate is climbing, leading to an increase in food-triggered anaphylaxis and asthma cases worldwide. In Singapore, one in five children suffer from asthma, and food allergies are the leading cause of anaphylactic reactions.

The Duke-NUS team discovered that the release of mast cell granules containing these bioactive chemicals is regulated by two proteins in the inflammasome complex: NLRP3 and ASC. These proteins were previously known only for their role in immune cell signaling during infection detection. Prof. Soman Abraham, the lead researcher, explained that these proteins play a crucial role in transporting granules from the center of the mast cell to its surface for release.

The research team observed that mice lacking either NLRP3 or ASC proteins did not experience anaphylactic shock when exposed to allergens. The formation of a complex called the granulosome, which involves these proteins binding to intracellular granules, facilitates their movement along the cell's cytoskeleton tracks to the cell surface.

Dr. Pradeep Bist, co-first author and principal research scientist at Duke-NUS, noted that upon activation, mast cell granules move rapidly along microtubules to the cell membrane for release. However, this movement was absent in cells deficient in NLRP3 or ASC proteins.

The research team then tested known inflammasome inhibitors to see if they could prevent the release of these granules. Using a drug similar to those in clinical trials for chronic inflammatory diseases, they successfully prevented anaphylactic shock in mice pre-treated with the drug before allergen exposure.

Dr. Andrea Mencarelli, a co-first author of the paper, highlighted that the drug specifically blocked inflammasome protein activity, selectively preventing the release of mast cells' bioactive chemicals without affecting other beneficial mast cell activities.

While not a cure, this discovery could provide a new means of preventing severe allergic reactions. Current emergency treatments must be administered immediately after symptoms appear and often come with significant side effects. This new approach could offer short-term protection, bringing peace of mind to those living with severe allergies, especially parents of children with food allergies.

Prof. Abraham emphasized the potential benefits of this research, noting that it could allow for short-term protection in high-risk situations. The team is now focused on optimizing the drug’s dosage and usage frequency to maximize its protective effects against anaphylactic shock, with hopes to extend this approach to asthma and allergic skin reactions.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, praised the discovery for its potential to significantly improve the quality of life for individuals at risk of severe allergic reactions, representing a paradigm shift in both research and practical applications.

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