Revisiting the role of MRGPRX2 on hypersensitivity reactions to neuromuscular blocking drugs

Abstract

Anaphylaxis is caused by a variety of triggers including Food and Drug Administration (FDA)-approved antibiotics, contrast media and neuromuscular blocking drugs (NMBDs). Traditionally, drug-induced anaphylaxis was thought to result mainly from IgE-mediated histamine release from mast cells. Recently, a G protein-coupled receptor known as MRGPRX2 has been identified and shown to be highly expressed on human skin but not lung mast cells. The demonstration that many NMBDs induce degranulation in human mast cells via MRGPRX2 led to the idea that this receptor contributes to NMBD-induced hypersensitivity reactions. However, other studies have raised doubts regarding its role in drug-induced hypersensitivity. This review discusses the current status and controversy on MRGPRX2's role on NMBD-induced hypersensitivity.

Figure 1

Potential mechanism for NMBD–mediated anaphylaxis. (a) Most individuals that develop anaphylaxis to NMBDs generate IgE antibodies, which bind to their cell surface high affinity receptors (FcεRI) mainly on mast cells (also basophils not shown). Subsequent administration of the drug results in the cross-linking of FcεRI-bound IgE leading to massive histamine release, which is responsible for the manifestations of anaphylaxis. (b) IgG antibodies are also be generated in response to certain NMBDs. These antibodies bind to FcγRI on the surface of basophils, macrophages and neutrophils. Subsequent exposure to the drug leads to immune complex formation and activation of FcγRI, resulting in the generation of PAF. This pathway could aggravate IgE-mediated anaphylaxis or could form the underlying mechanism of anaphylaxis in the absence of IgE [6^••]. (c) It has been proposed that activation of cutaneous MCs by NMBDs via MRGPRX2 and the subsequent mediator release leads to pseudoallergy. Whether or not this pathway plays an important role in NMBD-induced anaphylaxis remains to be confirmed. NMBDs that activate cutaneous MCs via MRGPRX2 likely cause local erythema and swelling (injection site reaction) due to histamine release.

Figure 2

Missense MRGPRX2 variants and their responsiveness to rocuronium. (a) Snake diagram of MRGPRX2 indicating three missense mutations identified in a patient diagnosed with non-IgE-mediated rocuronium hypersensitivity [30^•]. (b) Data summarizing expression of wild-type (WT), single, double and triple variants of MRGPRX2 in transiently transfected RBL-2H3 cells and their responsiveness to rocuronium for degranulation [50^••].