Researchers identify the first stage of allergic reactionsResearchers identify the first stage of allergic reactions :: LabOnline

Duke-NUS Medical School scientists have identified how the first domino falls after a person encounters an allergen, signaling a new strategy for the prevention of life-threatening allergic reactions. Their discovery was published in the journal Natural immunology.

It is well established that when mast cells, a type of immune cell, take on a harmless substance (like a peanut or a dust mite) as a threat, they immediately release an initial 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. .

Now, Duke-NUS researchers have discovered 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.

“We discovered that inflammasome components play a surprisingly crucial role in transporting mast cell particulate granules – which are usually packaged in the cell center – to the cell surface, where they are released,” said Professor Soman Abraham, who led this research when he was working. in the Emerging Infectious Diseases Program at Duke-NUS. “This surprising discovery gives us a precise target on which we can intervene to prevent the cascade of events initiated in mast cells and leading to anaphylactic shock. »

Abraham and his team's eureka moment came while looking at 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 a granulosome, 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”.

“During mast cell activation, we observed rapid movement of granules on dynamic tracks called microtubules to the cell membrane, where these granules were rapidly released from the cell,” said co-first author, Dr. Pradeep Bist, principal investigator at Emerging Infectious. Disease Program. “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.”

After demonstrating the trafficking role of NLRP3 and ASC, the team 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.

“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 mast cells without impacting other potentially beneficial activities. mast cells,” said study co-author Dr. Andrea Mencarelli. – first wrote the article while working in the Emerging Infectious Diseases Program.

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, but these treatments must be administered within a narrow time frame to be effective and also carry serious side effects.

“I think this will provide 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,” said Abraham, whose team is currently working on optimizing the dosage and frequency of meals. use of the drug to achieve the best protective effects against anaphylactic shock.

“While we don’t want to disable this part of the immune system for prolonged periods, it could potentially provide short-term protection.”

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

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