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By Hannah Millington
Health Reporter
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New understanding of a receptor key to allergic responses and anaphylaxis in conditions like asthma could offer a new treatment target for sufferers of a variety of conditions.
This the promise of a study by researchers from China's Shenzhen and Wuhan universities, which have identified a mechanism that sustains the release of allergy-stimulating molecules from cells.
Allergic conditions like asthma (affecting around 28 million people in the US) and eczema (31.6 million) have been on the rise in recent decades.
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The diseases are triggered by a type of white blood cell called mast cells, which release inflammatory molecules that promote allergic responses and create symptoms like itching, swelling and difficulty breathing.
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Allergic reactions begin when antibodies called 'lgE' produced by the immune system interact with 'FcεRI'—a receptor involved in allergies and parasite immunity—and antigens (a substance causing the immune system to react) on mast cells. This, the researchers explained, "set[s] the stage" for the release of allergic mediators.
While scientists have considered targeting FcεRI as a promising treatment approach, it has so far been challenging to implement in the clinic.
In the new study, however, the researchers focused on an enzyme called USP5, which controls the turnover of proteins and has been linked to inflammatory diseases like gum disease.
They discovered that mast cells are dependent on USP5 to release allergy signaling molecules called histamine (hence common allergy medications called antihistamines) and β-hexosaminidase in response to lgE and antigen.
The discovery, the researchers wrote, demonstrates "that USP5 may be an important target in the treatment of type I allergic diseases."
Type I allergic diseases include hay fever, food allergy, anaphylaxis, most types of asthma and urticaria.
"They are all IgE mediated reactions that involve mast cells as a shared target, but there are multiple pathways that contribute to their severity so it's not as simple as blocking one receptor, but it could be a useful addition to current treatment options," Dr. Elena Salagean, a consultant allergist at Holistic Allergy who was not involved in the present study, told Newsweek.
Promisingly, in a mouse model of the potentially life-threatening and rapid allergic reaction, anaphylaxis, knocking out USP5 or treatment with the USP5 inhibitor called WP1130 was found to prevent mast cells from releasing the molecules and weakened allergic reactions.
"The study shows a new potential target in reducing the release of histamine following contact with an allergen. Reducing histamine release from mast cells by blocking enzyme USP5 that's inside the mast cells means that less histamine will be released, so allergic reactions might be much milder," Dr. Salagean observed.
"Previous studies have tried to block the whole of the mast cell receptors, with varying success. Rather than trying that, the novel part in this study is that it's targeting the receptor machinery, an enzyme called USP5 inside the cells, and by doing so, it affects how well this receptor works."
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The research team also revealed that the interaction between IgE and FcεRI binding caused USP5 to perform a process called deubiquitylation, removing molecules from proteins.
The biochemical modification further increased the stability of FcεRI, making the allergic reaction worse in terms of both strength and the time it lasts.
"Current treatments work through various different ways, mostly blocking the downstream effects of mast cell activation. Antihistamines and steroids also block certain mediators, while biologics block chemicals and other enzymes in the allergy pathway," explained Dr. Salagean.
"A USP5 inhibitor would be a direct blocker that works upstream at the control system of the mast cell receptors. By blocking this, it could reduce several mediators at the same time and reduce the strength of the mast cells response to an allergic reaction."
Anaphylaxis is currently primarily treated with epinephrine (adrenaline), which can be administered with an auto-injector like an EpiPen, as well as urgent medical care.
"It's all still early animal study findings but if one can design a drug that specifically targets and inhibits the USP5 enzyme, then it might have real potential. The difficulty lies in delivering it to right cells and making it selective enough, so it doesn't affect other enzymes or pathways at the same time. It's a long way out from being relevant to patients yet," added Dr. Salagean.
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Reference
Zhou, Z.-W., Xu, X.-T., Liang, Q.-N., Zhou, Y.-M., Hu, W.-Z., Liu, S., Jiao, Y.-X., Zhang, S.-C., Ji, K., & Chen, J.-J. (2025). USP5 deubiquitylates and stabilizes FcεRIγ to enhance IgE-induced mast cell activation and allergic inflammation. Science Signaling, 18(799). https://doi.org/10.1126/scisignal.adr3411
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