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Drug Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
On re-exposure to the drug, cross-linking of the drug-specific IgE occurs leading to activation of mast cells and subsequent release of mediators including histamine, tryptase and arachidonic acid metabolites leading to symptoms. Symptoms can consist of pruritus, flushing, urticaria, GI symptoms (pain, emesis or diarrhea), angioedema, wheezing, laryngeal edema and hypotension possibly leading to anaphylactic shock. Type I reactions usually occur within minutes to hours after exposure and therefore are referred to as immediate type hypersensitivity reactions. The most common causative agents include beta-lactam antibiotics, platinum-based chemotherapeutics and perioperative agents. Type I reactions that are not IgE mediated are believed to be caused by direct mast cell activation by a drug. This type of reaction is referred to as a ‘pseudoallergic’ reaction. Examples include reactions to opiates, vancomycin or iodinated radiocontrast media. The MRGPRX2 receptor is located on mast cells and has been implicated in pseudoallergic reactions (Subramnaian et al. 2016).
MRGPRX2 is critical for clozapine induced pseudo-allergic reactions
Published in Immunopharmacology and Immunotoxicology, 2021
Di Wei, Tian Hu, Ya-jing Hou, Xiang-jun Wang, Jia-yu Lu, Shuai Ge, Cheng Wang, Huai-zhen He
Next, the receptor of clozapine induced pseudo-allergic reactions was explored. Compared with WT mice, clozapine could not increase the Evans blue extravasation and paw thickness in mast cell-deficient W-sash c-kit mutant KitW−sh/W−sh mice, suggesting that clozapine might induce related effects by acting on mast cells. MRGPRX2 expressed on mast cells has been reported as a critical receptor in pseudo-allergic reaction. Therefore, we tried to confirm that clozapine triggered pseudo-allergic reactions through MRGPRX2. According to the calcium imaging experiment performed on MRGPRX2-HEK293 and NC-HEK293 cells, we found clozapine could selectively induce intracellular calcium ions release in MRGPRX2-HEK293 cells, not in NC-HEK293 cells, which indicated that clozapine might activate mast cells through MRGPRX2. Cell membrane chromatography further showed that clozapine had a good affinity ability on MRGPRX2 and competition with sinomenine for the binding of MRGPRX2. According to the docking results, clozapine and ZINC-3573 possessed the same docking site with their N-methyl structure. However, when the N-methyl was replaced by C-methyl, the docking site changed obviously, which is consistent with the literatures. Therefore, we found that the nitrogen atom in the piperazine structure of clozapine might play a critical role in the interaction between clozapine and MRGPRX2. This needs further verification.
In vitro prediction of in vivo pseudo-allergenic response via MRGPRX2
Published in Journal of Immunotoxicology, 2021
Linu M. John, Charlotte M. Dalsgaard, Claus B. Jeppesen, Kilian W. Conde-Frieboes, Katrine Baumann, Niels P. H. Knudsen, Per S. Skov, Birgitte S. Wulff
Activation of MRGPRX2 induces mast cell degranulation and histamine release (McNeil et al. 2015; Ding et al. 2019). Histamine is one of the mediators released from mast cell granules upon activation by various toxins and is associated with symptoms of dermal edema/swelling (Garafalo and Kaplan 1981; Wei et al. 2009; Kimura et al. 2015). Histamine release has long been used as a marker of anaphylaxis or pseudo-allergenic reactions (Charitos et al. 2020). Quantitative and qualitative measurements of histamine release in the ex vivo setting have been developed to test for allergenic activity induced by a diverse array of test agents with both rodent and human ex vivo skin samples (de Antonio and Rothschild 1969; Petersen 1997, 1998; Petersen et al. 1996, 1997; Suzuki et al. 2020).
Secreted phosphoprotein 1 regulates natural compound 3’,4’,5,7-tetrahydroxyflavone to inhibit mast cell-mediated allergic inflammation
Published in Immunopharmacology and Immunotoxicology, 2023
Shiling Hu, Jue Wang, Haoyun Bai, Chaohua Feng, Zhenqi Zhou, Zhuoyin Xue, Wen Zhang, Yongjing Zhang, Nan Wang, Langchong He
THF can inhibit C48/80 scratching behavior and vascular permeability in ICR mice [29], demonstrating the anti-allergic effect of THF at the animal level. In this study, we report the mechanism by which THF inhibits C48/80-induced anaphylaxis. MRGPRX2 is a newly reported receptor in MCs and is involved in the response to a type of allergic reaction [30]. MC degranulation induced by C48/80 is strictly related to MRGPRX2-related changes in the cytosolic calcium concentration [31]. Our results showed that THF attenuated the C48/80-induced MC cytosolic calcium concentration and the phosphorylation of IP3R, PLC, and PKC, thereby suppressing MC degranulation. MRGPRX2 induces calcium release from the endoplasmic reticulum via the PLC/IP3 pathway [32].