MRGPRX2 gain-of-function mutation drives enhanced mast cell reactivity in chronic spontaneous urticaria

IF 11.2 1区医学 Q1 ALLERGY Journal of Allergy and Clinical Immunology Pub Date : 2025-07-01 DOI:10.1016/j.jaci.2025.03.007

Dan Ye MD , Yuxin Zhang MD , Xi Zhao MD , Hongmei Zhou MD, PhD , Jiahua Guo MD , Mengyao Yang MD , Xinwu Niu MD, PhD , Xiaopeng Wang MD, PhD , Jingyi Yuan MD , Jianwen Ren MD, PhD , Songmei Geng MD, PhD , Weihui Zeng MD, PhD , Zhao Wang MD, PhD

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Abstract

Background

Mast cell (MC) activation plays a central role in the pathogenesis of chronic spontaneous urticaria (CSU). Mutations in MC receptors have been suggested as a potential mechanism underlying CSU. MRGPRX2 has been proposed to contribute to the pathogenesis of CSU. However, the relationship between mutations in MRGPRX2 and their impact on disease severity and receptor function remains poorly understood.

Objective

We sought to investigate the prevalence and functional impact of MRGPRX2 mutations in CSU patients.

Methods

The study included 80 patients with CSU. Peripheral blood was collected for DNA sequencing in the coding exon of MRGPRX2. Weekly Urticaria Activity Score and laboratory test results were recorded, and serum MRGPRX2 levels were measured by ELISA. RBL-2H3 cells were transfected with wild-type MRGPRX2 and mutant variants. Flow cytometry and immunofluorescence staining were used to assess MRGPRX2 cell surface expression. Functional assays were performed to measure degranulation by β-hexosaminidase release, calcium mobilization, and cytokine synthesis by quantitative RT-PCR. Additionally, phosphorylation of signaling kinases was detected by Western blotting.

Results

Missense variants of MRGPRX2 185A>G (n = 8, 10%) and 185A>G+46A>C co-mutations (n = 23, 28.75%) were identified in patients with CSU. Patients carrying 185A>G mutation had a significantly higher weekly Urticaria Activity Score and lower circulating basophil and lymphocyte counts than patients with wild-type MRGPRX2. The 185A>G mutation, but not 185A>G+46A>C, was associated with increased MRGPRX2 expression in both patients with CSU and RBL-2H3 cells expressing the 185A>G mutation. Cells transfected with the 185A>G mutation demonstrated increased MC degranulation, calcium mobilization, cytokine synthesis, and extracellular signal-regulated kinase phosphorylation on MRGPRX2 activation, whereas the 46A>C+185A>G co-mutation did not show these changes.

Conclusion

The 185A>G mutation in MRGPRX2 contributes to a gain-of-function phenotype that is associated with enhanced disease activity in patients with CSU.

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MRGPRX2 功能增益突变导致慢性自发性荨麻疹中肥大细胞反应性增强

背景：肥大细胞活化在慢性自发性荨麻疹（CSU）的发病机制中起核心作用。肥大细胞受体的突变被认为是CSU的潜在机制。MRGPRX2被认为参与了CSU的发病机制。然而，MRGPRX2突变与其对疾病严重程度和受体功能的影响之间的关系仍然知之甚少。方法：80例CSU患者纳入研究。采集外周血进行MRGPRX2编码外显子DNA测序。记录患者UAS7评分及实验室检查结果，ELISA法检测血清MRGPRX2水平。RBL-2H3细胞转染野生型（WT） MRGPRX2和突变变体。流式细胞术和免疫荧光染色检测MRGPRX2细胞表面表达情况。通过RT-qPCR检测β-己糖氨酸酶释放、钙动员和细胞因子合成的功能测定。此外，通过western blotting检测信号激酶的磷酸化。结果：在CSU患者中发现MRGPRX2 185A>G错义变异（n=8, 10%）和185A>G+46A>C共突变（n=23, 28.75%）。携带185A >g突变的患者与WT MRGPRX2患者相比，UAS7评分显著升高，循环嗜碱性粒细胞和淋巴细胞计数显著降低。在CSU患者和表达185A>G突变的RBL-2H3细胞中，185A>G突变与MRGPRX2表达增加有关，而185A>G+46A>C与MRGPRX2表达增加无关。转染185A>G突变的细胞在MRGPRX2激活后，肥大细胞脱颗粒、钙动员、细胞因子合成和ERK磷酸化增加，而46A>C+185A>G共突变的细胞没有表现出这些变化。结论：MRGPRX2中的185A>G突变有助于CSU患者的功能获得表型，该表型与疾病活动性增强相关。

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来源期刊

Journal of Allergy and Clinical Immunology 医学-过敏

CiteScore

25.90

自引率

7.70%

发文量

1302

审稿时长

38 days

期刊介绍： The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.