Novel Insights on MRGPRX2-Mediated Hypersensitivity to Neuromuscular Blocking Agents And Fluoroquinolones

Abstract

Neuromuscular blocking agents (NMBAs) like atracurium and rocuronium as well as fluoroquinolones (FQs) cause mast cell-mediated anaphylaxis by activating Mas-related G protein-coupled receptor X2 (MRGPRX2), but many questions remain unanswered. Here, we address three of them, namely whether primary human mast cells show similar activation by these drugs as murine mast cells and mast cell lines, how sugammadex protects from atracurium-induced MRGPRX2-mediated mast cell activation, and why some but not all patients treated with rocuronium develop anaphylaxis. We used peripheral blood-derived cultured mast cells from healthy donors and patients, assessed mast cell activation and degranulation by quantifying intracellular calcium and CD63 expression, respectively, and made use of MRGPRX2-silencing, via electroporation with Dicer-substrate small interfering RNAs, and single cell flow cytometric analyses. Atracurium, ciprofloxacin, and levofloxacin activated and degranulated primary human mast cells, but only MRGPRX2-positive and not MRGPRX2-negative or -silenced mast cells. Sugammadex attenuated the atracurium-induced and MRGPRX2-mediated activation and degranulation of human mast cells by reducing free atracurium levels. The mast cells of patients with IgE-independent anaphylaxis to rocuronium were similar, in their MRGPRX2 expression and function, to those of patients with IgE-mediated anaphylaxis. These findings further improve our understanding of the role and relevance of MRGPRX2-driven mast cell activation in anaphylactic reactions to NMBAs and FQs and may help to improve their prediction, prevention, and treatment.

Pathophysiological, Cellular, and Molecular Events of the Vascular System in Anaphylaxis

“…Other reactions triggered by drugs (e.g., opioids, vancomycin) are also capable of activating mast cells and basophils as well as degranulation led by the Mas-related G-protein coupled receptor member X2 (MRGPRX2) (92)(93)(94)(95). This relevant pathway would explain those reactions absent of immunoglobulins, and therefore huge effort is being realized to elucidate its relevance in the setting of anaphylaxis (35,96,97). Even further, external factors (e.g., physical exercise, exposure to cold, or ultraviolet radiation) contribute as cofactors in the reactions (12,34,41,98).…”

Antibiotic Allergy De-Labeling: A Pathway against Antibiotic Resistance

“…IRs are mainly mediated by IgE antibodies. However, other underlying mechanisms have been recently described, so that the activation of basophil and mast cell may be derived by direct or indirect mechanism, an IgE/IgG or complement-mediated [ 27 ]. These recent insights make it more difficult to clinically diagnose an allergic reaction and claim to review the original classification ( Figure 1 ).…”

Tryptase release does not discriminate between IgE‐ and MRGPRX2‐mediated activation in human mast cells

“…Peripheral blood cultured mast cells, defined as CD117 + CD203c + , were cultured from peripheral blood progenitor cells, as previously described. 5,6 Briefly, CD34 + progenitor cells were isolated using the EasySep Human CD34 Selection Kit out of peripheral blood mononuclear cells according to the manufacturer's instructions. As shown earlier, interleukin-33 (IL-33) potentiates MC activation/ degranulation via cross-linking of the membrane-bound IgE/FcεRI complexes.…”

“…The data are not publicly available due to privacy or ethical restrictions. Jessy Elst 1,2 Marie-Line M. van der Poorten 1,2,3,4 Athina L. Van Gasse 1,2,3,4 Christel Mertens 1,2 Margo M. Hagendorens 1,2,3,4 Didier G. Ebo 1,2,5 Vito Sabato 1,2,5…”