Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
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DOI：
10.1038/nature14022
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发表时间：
2015-03-12
期刊：
影响因子：
64.8
通讯作者：
Dong, Xinzhong
中科院分区：
文献类型：
--
作者：
McNeil, Benjamin D.;Pundir, Priyanka;Meeker, Sonya;Han, Liang;Undem, Bradley J.;Kulka, Marianna;Dong, Xinzhong
肥大细胞是过敏反应的主要效应细胞，通过分泌组胺和多种炎症及免疫调节物质在疾病中发挥重要作用。虽然经典地它们被IgE抗体激活，但肥大细胞的独特性质是它们对一系列阳离子物质的抗体非依赖性反应性，这些阳离子物质统称为碱性促分泌素，包括与过敏型反应相关的炎性肽和药物。这些物质在病理学中的作用促使人们对其受体进行了长达数十年的研究。在这里，我们报告说，基本促分泌素激活小鼠肥大细胞在体外和体内通过一个单一的受体，MrgprB 2，直系同源的人G蛋白偶联受体（GPCR）MrgprX 2。促分泌素诱导的组胺释放、炎症和气道收缩在MrgprB 2无效突变小鼠中被消除。此外，我们表明，大多数类FDA批准的肽能药物与过敏型注射部位反应也激活MrgprB 2和MrgprX 2，注射部位炎症是不存在的突变小鼠。最后，我们确定MrgprB 2和MrgprX 2是许多小分子药物与全身性假过敏或类过敏反应相关的靶点;我们表明，药物诱导的类过敏反应症状在基因敲除小鼠中显着减少，我们确定了这些分子中的几个共同的化学基序，这可能有助于预测其他化合物的副作用。这些发现引入了一种小鼠模型来研究基本促分泌素对肥大细胞的激活，并将MrgprX 2确定为潜在的治疗靶点，以减少药物诱导的不良反应的子集。
Mast cells are primary effectors in allergic reactions, and may have significant roles in diseases by secreting histamine and various inflammatory and immunomodulatory substances. While classically they are activated by IgE antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. Roles for these substances in pathology have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, MrgprB2, the orthologue of the human G-protein coupled receptor (GPCR) MrgprX2. Secretagogue-induced histamine release, inflammation, and airway contraction are abolished in MrgprB2 null mutant mice. Further, we show that most classes of FDA-approved peptidergic drugs associated with allergic-type injection-site reactions also activate MrgprB2 and MrgprX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that MrgprB2 and MrgprX2 are targets of many small molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice, and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MrgprX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
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影响因子：
3.2
作者：
Kelesidis T;Fleisher J;Tsiodras S
通讯作者：
Tsiodras S
DOI：
10.1016/j.bbrc.2005.03.088
发表时间：
2005-05-20
影响因子：
3.1
作者：
Kamohara, M;Matsuo, A;Katou, M
通讯作者：
Katou, M
影响因子：
5
作者：
Mori, K;Maru, C;Furuhama, K
通讯作者：
Furuhama, K
影响因子：
25
作者：
Han, Liang;Ma, Chao;Liu, Qin;Weng, Hao-Jui;Cui, Yiyuan;Tang, Zongxiang;Kim, Yushin;Nie, Hong;Qu, Lintao;Patel, Kush N.;Li, Zhe;McNeil, Benjamin;He, Shaoqiu;Guan, Yun;Xiao, Bo;LaMotte, Robert H.;Dong, Xinzhong
通讯作者：
Dong, Xinzhong
DOI：
10.1007/978-1-62703-496-8_10
发表时间：
2013-01-01
期刊：
MOUSE MODELS OF ALLERGIC DISEASE, METHODS AND PROTOCOLS
影响因子：
--
作者：
Doyle, Elizabeth;Trosien, Julia;Metz, Martin
通讯作者：
Metz, Martin