title: Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
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 vitro and 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.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Department of Neurosurgery, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: McNeil
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Pundir
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Sonya
authors.initials: S
authors.lastname: Meeker
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Department of Neurosurgery, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Undem
authors.affiliation: 1] Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada [2] National Institute for Nanotechnology, National Research Council Canada, Edmonton, Alberta T6G 2M9, Canada.
authors.forename: Marianna
authors.initials: M
authors.lastname: Kulka
authors.affiliation: 1] The Solomon H. Snyder Department of Neuroscience, Department of Neurosurgery, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA [2] Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004342:Drug Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D057809:HEK293 Cells; D006636:Histamine Release; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C480039:MRGPRX2 protein, human; C000596389:Mrgprb2 protein, mouse; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide