Grzegorz Porebski

Background: Recent evidence indicates that the Mas-related G protein–coupled receptor X2 (MRGPRX2) can be activated by several drugs, including neuromuscular blocking agents, fluoroquinolones, and vancomycin. However, the contribution of this mechanism to drug hypersensitivity reactions (DHRs) observed in clinical practice remains incompletely understood. Single-nucleotide polymorphisms (SNPs) in the MRGPRX2 gene may alter receptor reactivity and thereby influence drug tolerance. In this study, we investigated whether selected SNPs—previously described in patients with DHRs (N62S, S313R), known but not previously tested with drugs (S325L, E164R), and predicted in silico (W248L)—affect in vitro responses to representative drug ligands. Methods: RBL-2H3 cells were transiently transfected with wild-type (WT) MRGPRX2 or its variants. Cell-surface expression of MRGPRX2 was assessed by flow cytometry. Intracellular calcium mobilization was measured after stimulation with ciprofloxacin, atracurium, and vancomycin; substance P served as a reference agonist and assay buffer as a negative control. Results: All variants exhibited comparable levels of cell-surface expression. No responses were observed in the presence of assay buffer. The S313R and S325L variants showed responses comparable to WT, with a tendency toward enhanced responses to substance P. In contrast, the E164R variant displayed a loss-of-function phenotype (p < 0.05 for all ligands vs. WT, S313R, and S325L variants), as did the in silico-predicted W248L variant (p < 0.05 for all ligands vs. WT, S313R, and S325L variants). The N62S variant demonstrated slightly reduced responses to the tested agonists compared with WT. Conclusions: Our findings indicate that under the investigated experimental conditions with ciprofloxacin, atracurium, and vancomycin: (1) N62S-transfected RBL-2H3 cells did not exhibit enhanced responses to the tested drug ligands; (2) the W248L variant exhibited the predicted loss-of-function phenotype, suggesting that in silico modeling may help assess the pathogenicity of specific MRGPRX2 variants; and (3) the remaining variants showed only partial concordance with previously published data, possibly reflecting differences in experimental design or assay conditions and highlighting the need for replication studies.

This update and revision of the international guideline for urticaria was developed in accordance with the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is an initiative of the Global Allergy and Asthma Excellence Network (GA ² LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), with the participation of 210 delegates from 107 national and international societies, from 59 countries. The consensus conference was held on December 6th, 2024. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell‐driven disease, defined by a rapid appearance of wheals, angioedema, or both. The lifetime prevalence of acute urticaria is estimated to be approximately 20%. Chronic urticaria, categorized as either chronic spontaneous urticaria or chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school, however, novel therapies are available. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert‐guided and evidence‐based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disease characterized by unpredictable episodes of tissue swelling (angioedema), which, in most cases, occur first under the age of 18 years, and entail a significant burden of disease not only for the patients but also for their families. Clinical symptoms of HAE are not specific, which may cause difficulties in differential diagnosis. Additionally, if not appropriately treated, HAE attacks can be life‐threatening. The international HAE guidelines published so far have focused mainly on adults. A guideline that refers to the age‐specific characteristics of pediatric patients, both in terms of diagnosis and management, was therefore needed. The International Steering Committee and Taskforce developed recommendations and provided evidence‐based grading based on expert opinion and strength of evidence. Recommendations were presented to, discussed, and electronically voted by healthcare professionals during the 14th C1 Inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary, 2025. This international guideline will ensure early diagnosis, standardized and up‐to‐date treatment, and promote the availability of effective therapies for all pediatric patients affected with this rare disease. It also draws attention to the importance of establishing HAE centers and registries, which solicit specialist care and research of the disease.

DOI: 10.20452/pamw.17187, Published online: January 07, 2026, Authors: Alicja Dziadowiec, Mateusz Kwitniewski, Peter Kopac, Lenka Sedlackova, Adriana Srotova, Ana Koren, Joanna Gluck, Grzegorz Porebski

Background Neuromuscular blocking agents (NMBAs) may trigger severe perioperative hypersensitivity reactions. A recently proposed mechanism involves off-target activity of NMBAs. They are thought to directly activate the Mas-related G protein-coupled receptor X2 (MRGPRX2), leading to mast cell degranulation and drug-induced hypersensitivity reactions. This study investigated which NMBAs exert this effect, whether in silico findings are consistent with cell-based experiments, and how the affinity of NMBAs for MRGPRX2 compares with that of fluoroquinolones, known MRGPRX2 agonists. We also sought to predict MRGPRX2 binding-site mutations that might enhance interactions with these drugs. Methods Molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area binding free-energy calculations were combined with a β-hexosaminidase release assay in MRGPRX2-expressing RBL-2H3 stable cell line. Computational alanine scanning was performed to predict the impact of receptor mutations. Results We demonstrated that atracurium-induced mast cell degranulation can be attributed to its immediate metabolite, laudanosine, which binds strongly to MRGPRX2. Pipecuronium, but not rocuronium, suxamethonium, or vecuronium, exhibited high affinity for MRGPRX2 in MD simulations. Complexes of ciprofloxacin, levofloxacin, and moxifloxacin with MRGPRX2 demonstrated excellent stability in MD simulations. RBL-MX2 responses to NMBAs and fluoroquinolones were highly consistent with our MD findings. Alanine substitutions reduced the affinity of ligands for MRGPRX2. Conclusions In contrast to fluoroquinolones, NMBAs displayed different affinity for MRGPRX2. Cellular responses in bench experiments closely reflected the MD predictions. Alanine scanning revealed that the MRGPRX2 binding pocket exhibits low susceptibility to single-site mutations that enhance receptor responsiveness.

Background: Neuromuscular blocking agents (NMBAs) may induce life-threatening perioperative hypersensitivity reactions (POH). In addition to the known IgE-dependent allergic background, a mechanism dependent on Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) on mast cells has been postulated. This does not explain why NMBA-induced POH is sporadic and only occurs in some patients. We hypothesised that this phenomenon depends on single nucleotide polymorphisms (SNPs) in MRGPRX2 that enhance the response to NMBA.Methods: The protein coding sequence of the MRGPRX2 gene was sequenced in 31 patients with NMBA-induced POH and 42 controls. Medical history and skin tests were used to diagnose patients. Based on basophil activation test (BAT) and specific IgE, patients were classified as having a history of IgE-mediated or likely MRGPRX2-mediated reactions. Severity of POH was defined according to a commonly accepted scale. Molecular dynamics simulations were conducted to assess the functional and structural effects of the SNPs.Results: The most common causative drugs were rocuronium (n = 17) and atracurium (n = 7), the others were cisatracurium, vecuronium, suxamethonium (n = 2 each) and pipecuronium (n = 1). We detected one missense SNP: N62S, present in 38.7% of the study group and in 45.2% of the controls. Prevalence of this SNP in patients was not dependent on causative drug, BAT and sIgE results, or severity of POH or its skin manifestations. Analysis of root mean square deviation and fluctuation plots showed no significant differences between wild-type and N62S variants.Conclusion: SNPs detected within the protein coding sequence of the MRGPRX2 gene were not risk factor in NMBA-induced POH, regardless of the clinical characteristics of the patients and the causative drug in question.

Background: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by unpredictable attacks of angioedema. MENTALIST (UnMEt Needs in herediTAry angioedema—a gLobal physIcian perSpecTive) is the first international survey uncovering unmet needs and identifying barriers to optimal management in HAE following the latest update of the World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) HAE guidelines. Methods: This web-based survey comprised 24 questions on HAE management and unmet needs. HAE-expert physicians from the Angioedema Centers of Reference and Excellence network ranked unmet needs according to their own perspectives and their patients’ perspectives, using a 10-point Likert scale ranging from 0 (not a challenge/unmet need at all) to 10 (huge challenge/unmet need). Results: Of 64 respondents from 32 countries, most (91%) had > 5 years of experience in managing HAE. Overall, 48% of respondents (n = 31/64) reported that < 50% of their patients had achieved the WAO/EAACI HAE treatment goals of total disease control and “normalization” of life at the time of the survey. Implementation of consensus recommendations was found to be inconsistent across regions. Gaps in non–HAE-expert physician knowledge, treatment costs, and reimbursement for long-term prophylaxis were the highest-priority challenges according to the respondents. Burden of disease remains a challenge among patients, as reported by their physicians. Conclusions: The MENTALIST findings highlight a need for removal of barriers to HAE treatment goals and propose a call to action to improve access to treatments, for greater provision of education for physicians and patients, critical collaboration with patient organizations and industry stakeholders and ultimately to optimize HAE care.

Hereditary angioedema due to a genetically determined deficiency of the C1 complement inhibitor (HAE-C1INH) is a rare disease that significantly impairs daily functioning and may be life-threatening in severe cases. Angioedema attacks are triggered by a transient, localized increase in bradykinin...

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.