Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) in Drug Hypersensitivity Reactions

Abstract

The human ortholog MRGPRX2 and the mice ortholog, Mrgprb2 are activated by basic secretagogues and neurokinins. A number of commonly used small-molecule drugs (e.g., neuromuscular blocking agents, fluoroquinolones, vancomycin) have been recently shown to activate these receptors under in vitro experimental conditions, what results in mast cell degranulation. The above drugs are also known to cause IgE-mediated anaphylactic reactions in allergic patients. The new findings on mechanisms of drug-induced mast cell degranulation may modify the current management of drug hypersensitivity reactions. Clinical interpretation of mild drug-provoked hypersensitivity reactions, interpretation of skin test with a drug of interest or further recommendations for patients suspected of drug allergy are likely to be reconsidered. In the paper we discussed future directions in research on identification and differentiation of MRGPRX2-mediated and IgE-dependent mast cell degranulation in patients presenting clinical features of drug-induced hypersensitivity reactions.

Keywords: MRGPRX2; anaphylaxis; drug allergy; drug hypersensitivity; mast cells.

Figure 1

Main receptor systems and examples of ligands involved in mast cell activation. Drugs can activate mast cells through both sIgE-dependent mechanism and the MRGPRX2 receptor (14, 26, 38). These activation routes are independent and inversely regulated by SCF (51). QWF inhibits activation of human MRGPRX2 by a number of basic secretagogues and medications (47, 50, 52), but not by LL-37 (53). Granule processing and response program after the MRGPRX2 engagement differ from FcεRI-mediated response (32, 33). Several other representative MC receptor systems and ligands are shown (28, 29). CR, complement receptor for corresponding complement components; CysLT1R/2R receptors, cysteinyl leukotrienes; FcγRII, a low-affinity receptor for IgG; FcεRI, the high affinity IgE receptor; GM-CSF, granulocyte/macrophage colony-stimulating factor; IL, interleukin; KIT, mast/stem cell growth factor receptor (CD117); LPS, lipopolysaccharide; LTC4, leukotriene C4; Abs, antibodies; MRGPRX2, Mas-Related G Protein-Coupled Receptor-X2; NMBA, neuromuscular blocking agents; PAR2, protease-activated receptor 2; PGN, peptidoglycan; SCF, stem cell factor; sIgE, specific IgE; TLR, Toll-like receptor; TNF, tumor-necrosis factor; QWF–tripeptide (the glutaminyl-D-tryptophylphenylalanine); VIP, vasoactive intestinal peptide. The schematic drawings were generated by modifying images obtained from Motifolio (Motifolio Inc., Elliocott City, MD, USA).