In Vivo Mast Cell Activation by the MRGPRX2 Receptor Ligands

RATIONALE: The MRGPRX2 receptor activates mast cells in a non-IgE mediated manner, and is upregulated in expression in patients with chronic spontaneous urticaria (CSU). While in vitro studies show MRGPRX2 activation by substance P, VIP, compound 48/80 and therapeutic drugs associated with pseudoallergic reactions, no human studies of MRGPRX2 activation have been performed. We examined skin mast cell responses to MRGPRX2 activation using 2 known MRGPRX2 ligands (icatibant and atracurium) in healthy and CSU subjects. We also examined skin response to histamine titration in healthy and CSU subjects.

METHODS: Healthy controls (n=9) and urticaria subjects (n=2) underwent serial intradermal skin titration testing with icatibant and atracurium (1 x 10^-6 to 1 x 10^-1 mg/ml) insulin and saline as negative controls, and histamine serial titration. Wheal size was calculated after 15 minutes. The mean concentration of each ligand that yielded a 5 mm wheal (ED5) or AUC was determined.

RESULTS: The ED5 for healthy and urticaria subjects for histamine was 2.8 x 10^-3 mg/ml and 2.1 x 10^-4 mg/ml and 6.9 x 10^-1 mg/ml and 2.8 x 10^-3 mg/ml for icatibant respectively. For atracurium, the mean wheal diameter for the healthy subjects did not reach 5 mm, and therefore, the area under the curve was calculated, 7.03 for healthy and 19.56 for urticaria subjects.

CONCLUSIONS: The ED5 for icatibant suggests that there is a heightened sensitivity to MRGX2 ligands in CSU subjects in support of heightened protein expression noted in past studies.