Tue 23rd December 2014

Xinzhong Dong Reports in Nature the Identification of a New Mast Cell Allergy Receptor

Xinzhong Dong, a primary faculty member in the Neuroscience department, reports in Nature the identification of a new receptor on mast cells linked to drug-induced allergic reactions. 

Many clinical used drugs including anti-cancer, diabetes, and HIV drugs, neuromuscular blocking drugs (NMBDs) to certain classes of antibiotics cause allergy-like reactions such as rash, dropping body temperature, and slowing heart beat. Some of the side-effects become non-compliance factors for the drug treatments. In the current study the Dong lab has identified a single cell surface receptor (called MRGPRX2 in humans and Mrgprb2 in mice) is the culprit of these side-effects. This receptor is exclusively found in a type of immune cells called mast cells. Once the receptor is triggered, it causes mast cells to release histamine and many other proinflammatory reagents. Strikingly, mice without this receptor exhibited no allergic symptom as seen in normal mice. Therefore, blocking the human receptor can potentially eliminate the side-effects caused by many drugs.

Nature Article abstract:

Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitroand in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.  McNeil et al, Nature (2014) doi:10.1038/nature14022;  Published online 17 December 2014

Also see article in Hopkins News, the BBC News, and in ScienceDaily.

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