MRGPRX2 and Adverse Drug Reactions

Abstract

Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.

MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

“…Hypersensitivity reactions can be owed to allergic or the clinically indistinguishable pseudo-allergic activation of MCs and depend on the acute release of high amounts of preformed mediators in a process termed degranulation or granule exocytosis [1,3,5,8,45]. As the receptor of pseudo-allergic and neurogenic MC responses, MRGPRX2 has come to the forefront of scientific interest in recent years.…”

“…With the discovery of Mas-related G protein-coupled receptor member X2 (MRGPRX2) as a key receptor of IgE-independent mast cell (MC) degranulation, two similarly effective routes of degranulation are now established in skin MCs [1,2]. The presumed clinical significance of MRGPRX2 stems from the plethora of ligands, both endogenous and exogenous, that reportedly activate the receptor [1,[3][4][5][6][7][8][9].…”

FcεRI‐ and MRGPRX2‐evoked acute degranulation responses are fully additive in human skin mast cells

“…The study also received funding from ECARF (European Center for Allergy Research Foundation) to TZ. Magda Babina 1,2,3 Zhao Wang 1,2,4 Zhuoran Li 1,2,3 Kristin Franke 1,2,3 Sven Guhl 1,2,3 Metin Artuc 1,2,3 Torsten Zuberbier…”

“…We have previously addressed the hypothesis of a hyperreactive MC phenotype in ISM by in vivo provocation. 2 None of the used triggers mounted a response that was different between ISM patients and healthy volunteers (HV). To further investigate the hypothesis of a hyper-reactive MC phenotype, we also developed MCs in vitro from 14 ISM patients and 13 HV (same subjects as included in 2 ) (Tables S1 and S2).…”

Editorial: The Role of Mast Cells in Immediate Hypersensitivity Reactions

“…This receptor is expressed by different mast cell subsets and it induces degranulation upon binding by different ligands such as quinolone antibiotics, general anesthetics such as atracuronium and rocuronium and positively charged, hydrophobic molecules such as vancomycin and morphine, as cited in a recent review manuscript by McNeil. ( 3 , 4 ). Working on in vitro cells, Hermans et al showed that HMC1 cells express the receptor MRGPRX2, at lower levels compared to LAD2 and HuMC cells and pre-incubating these cells with latrunculin-B leads to overexpression of MRGPRX2, which can be activated by compound 48/80, resulting in efficient HMC1 degranulation.…”