An alternative explanation for immediate hypersensitivity reactions to opioids
2017; Elsevier BV; Volume: 5; Issue: 6 Linguagem: Inglês
10.1016/j.jaip.2017.08.016
ISSN2213-2201
AutoresAthina L. Van Gasse, Vito Sabato, Margaretha A. Faber, Margo M. Hagendorens, Didier G. Ebo,
Tópico(s)Olfactory and Sensory Function Studies
ResumoWe read the publication on opioid hypersensitivity by Li et al1Li P.H. Ue K.L. Wagner A. Rutkowski R. Rutkowski K. Opioid hypersensitivity: predictors of allergy and role of drug provocation testing.J Allergy Clin Immunol Pract. 2017; 5: 1601-1606Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar with great interest. It clearly highlights the difficulties and uncertainties associated with a correct diagnosis of genuine IgE/FcεRI opioid allergy. The authors finally state that, for the time being, there is no in vitro nor in vivo test that enables us to differentiate between usually clinically indistinguishable IgE/FcεRI-dependent and non-IgE/FcεRI-dependent reactions with absolute certainty. However, we would like to draw attention to the Mas-related G protein coupled receptor X2 (MRGPRX2) as an alternative explanation of their findings and challenge their statement regarding the value of in vitro tests in "opioid allergy." The Mas-related G protein-coupled receptors (Mrgprs) comprise a subfamily of receptors named after the first discovered member, Mas. At present, more than 50 Mrgprs have been identified and are now divided into several subfamilies being renamed to a novel nomenclature (http://www.guidetopharmacology.org) including the primate-specific MRGPRX subfamily. Human MRGPRX are expressed by various cell types including dorsal root ganglion neurons and connective tissue mast cells (MCTC), the latter mainly expressing the MRGPRX2 that is activated by various basic small molecules, such as the neuropeptide substance P, antimicrobial host defense proteins, anaphylatoxins C3a and C5a, and compound 48/80, leading to degranulation independent from cross-linking of IgE/FcεRI complexes.2Subramanian H. Gupta K. Ali H. Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases.J Allergy Clin Immunol. 2016; 138: 700-710Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar Recently, McNeil et al3McNeil B.D. Pundir P. Meeker S. Han L. Undem B.J. Kulka M. et al.Identification of a mast-cell- specific receptor crucial for pseudo-allergic drug reactions.Nature. 2015; 519: 237-241Crossref PubMed Scopus (743) Google Scholar demonstrated that the MRGPRX2 might also be involved in mast cell-driven immediate drug hypersensitivity reactions (IDHR) toward compounds such as the bradykinin receptor 2 antagonist icatibant, curarizing neuromuscular blocking agents (atracurium, rocuronium), and several fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin). Recently similar observations were made for many opioid compounds (including morphine, codeine and different major metabolites).4Lansu K. Karpiak J. Liu J. Huang X.P. McCorvy J.D. Kroeze W.K. et al.In silico design of novel probes for the atypical opioid receptor MRGPRX2.Nat Chem Biol. 2017; 13: 529-536Crossref PubMed Scopus (177) Google Scholar The quintessence of these studies is clear, namely off-target occupancy of the MRGPRX2 receptor is increasingly recognized as a novel nonimmune endotype of mast cell-driven IDHR. Moreover, the cellular distribution of the MRGPRX2 might explain some clinical and biological peculiarities of the opioid hypersensitivity scene. Actually, the observation that the MRGPRX2 is mainly expressed on skin mast cells might explain the almost invariant presence of cutaneous symptoms in both index and challenge reactions as described by Li et al,1Li P.H. Ue K.L. Wagner A. Rutkowski R. Rutkowski K. Opioid hypersensitivity: predictors of allergy and role of drug provocation testing.J Allergy Clin Immunol Pract. 2017; 5: 1601-1606Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar as well as the uncertainties associated with skin testing for opiates. Alternatively, as basophils barely express the MRGPRX2,5Sabato V. Van Gasse A.L. Cop N. Claesen K. Decuyper I. Faber M. et al.The Mas-related G protein-coupled receptor MRGPRX2 is expressed on human basophils and up-regulated upon activation.J Allergy Clin Immunol. 2017; 139: AB168Abstract Full Text Full Text PDF Google Scholar and as described in this journal,6Van Gasse A.L. Hagendorens M.M. Sabato V. Bridts C.H. De Clerck L.S. Ebo D.G. IgE to poppy seed and morphine are not useful tools to diagnose opiate allergy.J Allergy Clin Immunol Pract. 2015; 3: 396-399Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar because these cells do not respond nonspecifically on opiates in control individuals uneventfully challenged with morphine and/or codeine, it seems justified to speculate that basophil activation experiments might constitute a reliable diagnostic to document genuine IgE/FcεRI-mediated opiate hypersensitivity and related cross-reactivities.7Leysen J. De Witte L. Sabato V. Faber M. Hagendorens M. Bridts C. et al.IgE-mediated allergy to pholcodine and cross-reactivity to neuromuscular blocking agents: lessons from flow cytometry.Cytometry B Clin Cytom. 2013; 84: 65-70Crossref PubMed Scopus (49) Google Scholar Moreover, it is likely that conditioned basophils, namely basophils expressing the MRGPRX2,5Sabato V. Van Gasse A.L. Cop N. Claesen K. Decuyper I. Faber M. et al.The Mas-related G protein-coupled receptor MRGPRX2 is expressed on human basophils and up-regulated upon activation.J Allergy Clin Immunol. 2017; 139: AB168Abstract Full Text Full Text PDF Google Scholar might allow entrance of a readily accessible human model to further explore the ability of opioids to activate the MRGPRX2 receptor. In essence, we appreciated the study by Li et al.1Li P.H. Ue K.L. Wagner A. Rutkowski R. Rutkowski K. Opioid hypersensitivity: predictors of allergy and role of drug provocation testing.J Allergy Clin Immunol Pract. 2017; 5: 1601-1606Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar However, we felt it was appropriate to draw attention to (a) off-target activation of the MRGPRX2 receptor as an alternative explanation for their observations, and (b) the potential of basophil activation experiments in distinguishing between IgE/FcεRI-mediated and MRGPRX2-mediated opioid hypersensitivity. ALVG is a fellow of the Fonds voor Wetenschappelijk Onderzoek - Vlaanderen (FWO) (1113617N). VS is a senior clinical researcher of the FWO (1804518N). DGE is a senior clinical researcher of the FWO (1800614N). Opioid Hypersensitivity: Predictors of Allergy and Role of Drug Provocation TestingThe Journal of Allergy and Clinical Immunology: In PracticeVol. 5Issue 6PreviewTrue IgE-mediated hypersensitivity to opioids is rare and many reactions are due to direct mast cell degranulation. Opioid drug provocation testing (DPT) is the gold standard for diagnosis but is underutilized. Full-Text PDF ReplyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 5Issue 6PreviewWe thank Van Gasse et al1 for their interest in our paper2 and discussing the role of Mas-related G protein-coupled receptors in the pathomechanism of opioid allergy. Their activation might indeed explain certain aspects of opioid hypersensitivity reactions. Full-Text PDF
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