| 1909 LETTERS 2 Berlin Institute of Health, Berlin, Germany 3 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany 4 Department of Dermatology, The Second Affiliated Hospital, Northwest Hospital, Xi'an Jiaotong University, Xi'an, China Correspondence Magda Babina, Institute for Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany. Email: magda.babina@charite.de Babina and Wang contributed equally. ORCID Magda Babina https://orcid.org/0000-0002-4500-7615 Kristin Franke https://orcid.org/0000-0002-7402-4211 Torsten Zuberbier https://orcid.org/0000-0002-1466-8875 REFERENCES 1. Gaudenzio N, Sibilano R, Marichal T, et al. Different activation sig- nals induce distinct mast cell degranulation strategies. J Clin Invest. 2016;126(10):3981-3998. doi:10.1172/JCI85538 2. McNeil BD. MRGPRX2 and Adverse Drug Reactions. Front Immunol. 2021;12:676354. doi:10.3389/fimmu.2021.676354 3. Babina M. The pseudo-allergic/neurogenic route of mast cell acti- vation via MRGPRX2: discovery, functional programs, regulation, relevance to disease, and relation with allergic stimulation. Itch. 2020;5(2):e32. doi:10.1097/itx.0000000000000032 4. Wedi B, Gehring M, Kapp A. The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function. Allergy. 2020;75(9):2229-2242. doi:10.1111/all.14213 5. Babina M, Wang Z, Artuc M, Guhl S, Zuberbier T. MRGPRX2 is negatively targeted by SCF and IL-4 to diminish pseudo- allergic stimulation of skin mast cells in culture. Exp Dermatol. 2018;27(11):1298-1303. doi:10.1111/exd.13762 6. Babina M, Wang Z, Roy S, et al. MRGPRX2 is the codeine receptor of human skin mast cells: desensitization through beta-arrestin and lack of correlation with the FcepsilonRI pathway. J Invest Dermatol. 2021;141(5):1286-1296. doi:10.1016/j.jid.2020.09.017 7. Babina M, Guhl S, Artuc M, Zuberbier T. Allergic FcepsilonRI- and pseudo-allergic MRGPRX2-triggered mast cell activation routes are independent and inversely regulated by SCF. Allergy. 2018;73(1):256-260. doi:10.1111/all.13301 SUPPORTING INFORMATION Additional supporting information may be found in the online version of the article at the publisher’s website. DOI: 10.1111/all.15277 Mast cells derived from systemic mastocytosis exhibit an increased responsiveness to hyperosmolarity To the Editor, Systemic mastocytosis (SM) is a disease characterized by increased number of aberrant mast cells in one or several organs and increased systemic levels of mast cell (MC) mediators. 1 Indolent SM (ISM) is the most common form of SM, constituting approximately 80% of the patients diagnosed with SM. Individuals with ISM often have media- tor mediated symptoms, most commonly from the skin, the gastro- intestinal tract, cardiovascular, and respiratory system, but also in the form of anaphylaxis. Although basal mediator levels, including serum tryptase and metabolites of histamine and prostaglandin D 2 in the urine, are increased at steady state, 1-3 the symptoms often come as spells without any obvious trigger suggesting an intrinsic defect causing a hyper-reactive state of the mast cells, or an endog- enous trigger. We have previously addressed the hypothesis of a hyper- reactive 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 in- cluded in 2 ) (Tables S1 and S2). Peripheral blood was obtained, and CD34-selected progenitor cells were cultured under MC promoting conditions 4 (see supplement). When the cells were mature, they were plated and exposed to IgE-receptor activation, morphine, or This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. Theo Gülen Shared last authorship.