Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Recent Knowledge and Insights on the Mechanisms of Immediate Hypersensitivity and Anaphylaxis: IgE/FcεRI- and Non-IgE/FcεRI-Dependent Anaphylaxis

Author(s): Didier G. Ebo*, Michiel Beyens, Kevin Heremans, Marie-Line M. van der Poorten, Athina L. Van Gasse, Christel Mertens, Michel Van Houdt, Vito Sabato and Jessy Elst

Volume 29, Issue 3, 2023

Published on: 03 November, 2022

Page: [178 - 184] Pages: 7

DOI: 10.2174/1381612829666221025091827

Price: $65

Abstract

Immediate hypersensitivity reactions can pose a clinical and diagnostic challenge, mainly because of the multifarious clinical presentation and distinct underlying - frequently uncertain - mechanisms. Anaphylaxis encompasses all rapidly developing and life-threatening signs and may cause death. Evidence has accumulated that immediate hypersensitivity and anaphylaxis do not necessarily involve an allergen-specific immune response with cross-linking of specific IgE (sIgE) antibodies bound to their high-affinity IgE receptor (FcεRI) on the surface of mast cells (MCs) and basophils. Immediate hypersensitivity and anaphylaxis can also result from alternative specific and nonspecific MC and basophils activation and degranulation, such as complementderived anaphylatoxins and off-target occupancy of MC and/or basophil surface receptors such as the Masrelated G protein-coupled receptor X2 (MRGPRX2). Degranulation of MCs and basophils results in the release of inflammatory mediators, which can be, depending on the underlying trigger, in a different spatiotemporal manner. In addition, hypersensitivity and anaphylaxis can occur entirely independently of MC and basophil degranulation, as observed in hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) that divert normal arachidonic acid metabolism by inhibiting the cyclooxygenase (COX)-1 isoenzyme. Finally, one should remember that anaphylaxis might be part of the phenotype of particular - sometimes poorly recognizable - conditions such as clonal MC diseases (e.g. mastocytosis) and MC activation syndrome. This review provides a status update on the molecular mechanisms involved in both sIgE/FcεRI- and non-sIgE/FcεRI-dependent immediate hypersensitivity and anaphylaxis. In conclusion, there is increasing evidence for alternative pathophysiological hypersensitivity and anaphylaxis endotypes that are phenotypically and biologically indistinguishable, which are frequently difficult to diagnose, mainly because of uncertainties associated with diagnostic tests that might not enable to unveil the underlying mechanism.

Keywords: Anaphylaxis, mast cells, basophils, IgE, MRGPRX2, pathomechanisms.

« Previous Next »
[1]
Johansson SGO, Hourihane JOB, Bousquet J, et al. A revised nomenclature for allergy: An eaaci position statement from the EAACI nomenclature task force. Allergy 2001; 56(9): 813-24.
[http://dx.doi.org/10.1034/j.1398-9995.2001.t01-1-00001.x] [PMID: 11551246]
[2]
Castells MC. Drug allergy: Phenotypes, endotypes, and biomarkers. J Allergy Clin Immunol Pract 2017; 5(3): 626-7.
[http://dx.doi.org/10.1016/j.jaip.2017.03.026] [PMID: 28483316]
[3]
Cardona V, Ansotegui IJ, Ebisawa M, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J 2020; 13(10): 100472.
[http://dx.doi.org/10.1016/j.waojou.2020.100472] [PMID: 33204386]
[4]
Ebo DG, Clarke RC, Mertes PM, Platt PR, Sabato V, Sadleir PHM. Molecular mechanisms and pathophysiology of perioperative hypersensitivity and anaphylaxis: A narrative review. Br J Anaesth 2019; 123(1): e38-49.
[http://dx.doi.org/10.1016/j.bja.2019.01.031] [PMID: 30916022]
[5]
Xu H, Bin NR, Sugita S. Diverse exocytic pathways for mast cell mediators. Biochem Soc Trans 2018; 46(2): 235-47.
[http://dx.doi.org/10.1042/BST20170450] [PMID: 29472369]
[6]
Knol EF. Requirements for effective IgE cross-linking on mast cells and basophils. Mol Nutr Food Res 2006; 50(7): 620-4.
[http://dx.doi.org/10.1002/mnfr.200500272] [PMID: 16764017]
[7]
Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 2016; 137(6): 1674-80.
[http://dx.doi.org/10.1016/j.jaci.2016.02.015] [PMID: 27130857]
[8]
Reber LL, Hernandez JD, Galli SJ. The pathophysiology of anaphylaxis. J Allergy Clin Immunol 2017; 140(2): 335-48.
[http://dx.doi.org/10.1016/j.jaci.2017.06.003] [PMID: 28780941]
[9]
McLendon K, Sternard BT. Anaphylaxis. Treasure Island, (FL): StatPearls 2021.
[10]
Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: A large center experience. Am J Gastroenterol 2003; 98(6): 1315-24.
[http://dx.doi.org/10.1111/j.1572-0241.2003.07457.x] [PMID: 12818276]
[11]
Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Severe infusion reactions to infliximab: Aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2011; 34(1): 51-8.
[http://dx.doi.org/10.1111/j.1365-2036.2011.04682.x] [PMID: 21535447]
[12]
Steenholdt C, Svenson M, Bendtzen K, Thomsen OØ, Brynskov J, Ainsworth MA. Acute and delayed hypersensitivity reactions to infliximab and adalimumab in a patient with Crohn’s disease. J Crohn’s Colitis 2012; 6(1): 108-11.
[http://dx.doi.org/10.1016/j.crohns.2011.08.001] [PMID: 22261535]
[13]
Novey HS, Pahl M, Haydik I, Vaziri ND. Immunologic studies of anaphylaxis to iron dextran in patients on renal dialysis. Ann Allergy 1994; 72(3): 224-8.
[PMID: 7510461]
[14]
Umeda Y, Fukumoto Y, Miyauchi T, et al. Anaphylactic shock related to aprotinin induced by anti-aprotinin immunoglobulin G antibody alone; report of a case. Kyobu Geka 2007; 60(1): 69-71.
[PMID: 17249542]
[15]
Kober BJ, Scheule AM, Voth V, Deschner N, Schmid E, Ziemer G. Anaphylactic reaction after systemic application of aprotinin triggered by aprotinin-containing fibrin sealant. Anesth Analg 2008; 107(2): 406-9.
[http://dx.doi.org/10.1213/ane.0b013e31817e6043] [PMID: 18633016]
[16]
Kishimoto TK, Viswanathan K, Ganguly T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 2008; 358(23): 2457-67.
[http://dx.doi.org/10.1056/NEJMoa0803200] [PMID: 18434646]
[17]
Arroyave CM, Tan EM. Mechanism of complement activation by radiographic contrast media. Clin Exp Immunol 1977; 29(1): 89-94.
[PMID: 891038]
[18]
Tatemoto K, Nozaki Y, Tsuda R, et al. Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors. Biochem Biophys Res Commun 2006; 349(4): 1322-8.
[http://dx.doi.org/10.1016/j.bbrc.2006.08.177] [PMID: 16979137]
[19]
McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 2015; 519(7542): 237-41.
[http://dx.doi.org/10.1038/nature14022] [PMID: 25517090]
[20]
Porebski G, Kwiecien K, Pawica M, Kwitniewski M, Mas-Related G. Mas-related g protein-coupled Receptor-x2 (MRGPRX2) in drug hypersensitivity reactions. Front Immunol 2018; 9: 3027.
[http://dx.doi.org/10.3389/fimmu.2018.03027] [PMID: 30619367]
[21]
Ali H. Revisiting the role of MRGPRX2 on hypersensitivity reactions to neuromuscular blocking drugs. Curr Opin Immunol 2021; 72: 65-71.
[http://dx.doi.org/10.1016/j.coi.2021.03.011] [PMID: 33857758]
[22]
McNeil BD. MRGPRX2 and adverse drug reactions. Front Immunol 2021; 12: 676354.
[http://dx.doi.org/10.3389/fimmu.2021.676354] [PMID: 34421893]
[23]
Kolkhir P, Ali H, Babina M, et al. MRGPRX2 in drug allergy: What we know and what we do not know. J Allergy Clin Immunol 2022; S0091-6749(22): 01184-8.
[http://dx.doi.org/10.1016/j.jaci.2022.09.004] [PMID: 36089079]
[24]
Ebo DG, Van der Poorten ML, Elst J, et al. Immunoglobulin E cross-linking or MRGPRX2 activation: Clinical insights from rocuronium hypersensitivity. Br J Anaesth 2021; 126(1): e27-9.
[http://dx.doi.org/10.1016/j.bja.2020.10.006] [PMID: 33153719]
[25]
Blunk JA, Schmelz M, Zeck S, Skov P, Likar R, Koppert W. Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: An in vivo microdialysis study in human skin. Anesth Analg 2004; 98(2): 364-70.
[http://dx.doi.org/10.1213/01.ANE.0000097168.32472.0D] [PMID: 14742371]
[26]
Babina M, Wang Z, Li Z, et al. FcεRI‐ and MRGPRX2‐evoked acute degranulation responses are fully additive in human skin mast cells. Allergy 2022; 77(6): 1906-9.
[http://dx.doi.org/10.1111/all.15270] [PMID: 35246987]
[27]
Bruhns P, Chollet-Martin S. Mechanisms of human drug-induced anaphylaxis. J Allergy Clin Immunol 2021; 147(4): 1133-42.
[http://dx.doi.org/10.1016/j.jaci.2021.02.013] [PMID: 33832695]
[28]
Jönsson F, de Chaisemartin L, Granger V, et al. An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis. Sci Transl Med 2019; 11(500): eaat1479.
[http://dx.doi.org/10.1126/scitranslmed.aat1479] [PMID: 31292264]
[29]
Dona I, Salas M, Perkins J, et al. Hypersensitivity reactions to non-steroidal anti-inflammatory drugs. Curr Pharm Des 2017; 22(45): 6784-802.
[http://dx.doi.org/10.2174/1381612822666160928142814] [PMID: 27779082]
[30]
Nassiri M, Babina M, Dölle S, Edenharter G, Ruëff F, Worm M. Ramipril and metoprolol intake aggravate human and murine anaphylaxis: Evidence for direct mast cell priming. J Allergy Clin Immunol 2015; 135(2): 491-9.
[http://dx.doi.org/10.1016/j.jaci.2014.09.004] [PMID: 25441633]
[31]
Valent P, Akin C, Arock M, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: A consensus proposal. Int Arch Allergy Immunol 2012; 157(3): 215-25.
[http://dx.doi.org/10.1159/000328760] [PMID: 22041891]
[32]
Cruse G, Metcalfe DD, Olivera A. Functional deregulation of KIT. Immunol Allergy Clin North Am 2014; 34(2): 219-37.
[http://dx.doi.org/10.1016/j.iac.2014.01.002] [PMID: 24745671]
[33]
Lyons JJ, Chovanec J, O’Connell MP, et al. Heritable risk for severe anaphylaxis associated with increased α-tryptase–encoding germline copy number at TPSAB1. J Allergy Clin Immunol 2021; 147(2): 622-32.
[http://dx.doi.org/10.1016/j.jaci.2020.06.035] [PMID: 32717252]
[34]
Ebo DG, De Puysseleyr LP, Van Gasse AL, et al. Mast cell activation during suspected perioperative hypersensitivity: A need for paired samples analysis. J Allergy Clin Immunol Pract 2021; 9(8): 3051-3059.e1.
[http://dx.doi.org/10.1016/j.jaip.2021.03.050] [PMID: 33862269]
[35]
Karhausen J, Abraham SN. How mast cells make decisions. J Clin Invest 2016; 126(10): 3735-8.
[http://dx.doi.org/10.1172/JCI90361] [PMID: 27643441]
[36]
Gaudenzio N, Sibilano R, Marichal T, et al. Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest 2016; 126(10): 3981-98.
[http://dx.doi.org/10.1172/JCI85538] [PMID: 27643442]
[37]
Elst J, van der Poorten MLM, Van Gasse AL, et al. Tryptase release does not discriminate between IgE and MRGPRX2‐mediated activation in human mast cells. Clin Exp Allergy 2022; 52(6): 797-800.
[http://dx.doi.org/10.1111/cea.14110] [PMID: 35152504]
[38]
Elst J, Maurer M, Sabato V, et al. Novel insights on MRGPRX2-mediated hypersensitivity to neuromuscular blocking agents and fluoroquinolones. Front Immunol 2021; 12: 668962.
[http://dx.doi.org/10.3389/fimmu.2021.668962] [PMID: 34385999]
[39]
Vitte J, Sabato V, Tacquard C, et al. Use and interpretation of acute and baseline tryptase in perioperative hypersensitivity and anaphylaxis. J Allergy Clin Immunol Pract 2021; 9(8): 2994-3005.
[http://dx.doi.org/10.1016/j.jaip.2021.03.011] [PMID: 33746087]
[40]
Sabato V, Van De Vijver E, Hagendorens M, et al. Familial hypertryptasemia with associated mast cell activation syndrome. J Allergy Clin Immunol 2014; 134(6): 1448-1450.e3.
[http://dx.doi.org/10.1016/j.jaci.2014.06.007] [PMID: 25086867]
[41]
Sabato V, Chovanec J, Faber M, Milner JD, Ebo D, Lyons JJ. First identification of an inherited tpsab1 quintuplication in a patient with clonal mast cell disease. J Clin Immunol 2018; 38(4): 457-9.
[http://dx.doi.org/10.1007/s10875-018-0506-y] [PMID: 29748908]
[42]
Lyons JJ. Hereditary alpha tryptasemia. Immunol Allergy Clin North Am 2018; 38(3): 483-95.
[http://dx.doi.org/10.1016/j.iac.2018.04.003] [PMID: 30007465]
[43]
Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol 2017; 140(2): 321-33.
[http://dx.doi.org/10.1016/j.jaci.2017.06.012] [PMID: 28780940]
[44]
Sala-Cunill A, Guilarte M, Cardona V. Phenotypes, endotypes and biomarkers in anaphylaxis: Current insights. Curr Opin Allergy Clin Immunol 2018; 18(5): 370-6.
[http://dx.doi.org/10.1097/ACI.0000000000000472] [PMID: 30048251]
[45]
Van Gasse AL, Ebo DG, Faber MA, et al. Cross-reactivity in IgE-mediated allergy to cefuroxime: Focus on the R1 side chain. J Allergy Clin Immunol Pract 2020; 8(3): 1094-1096.e1.
[http://dx.doi.org/10.1016/j.jaip.2019.08.033] [PMID: 31479769]
[46]
van der Poorten MLM, Van Gasse AL, Hagendorens MM, et al. Serum specific IgE antibodies in immediate drug hypersensitivity. Clin Chim Acta 2020; 504: 119-24.
[http://dx.doi.org/10.1016/j.cca.2020.02.005] [PMID: 32035852]
[47]
Ebo DG, Bridts CH, Rihs HP. hevea latex-associated allergies: Piecing together the puzzle of the latex IgE reactivity profile. Expert Rev Mol Diagn 2020; 20(4): 367-73.
[http://dx.doi.org/10.1080/14737159.2020.1730817] [PMID: 32056456]
[48]
Ebo DG, Bridts CH, Stevens WJ. IgE-mediated anaphylaxis from chlorhexidine: Diagnostic possibilities. Contact Dermat 2006; 55(5): 301-2.
[http://dx.doi.org/10.1111/j.1600-0536.2006.00924.x] [PMID: 17026697]
[49]
Elst J, Moonen N, van der Poorten MLM, et al. The passively sensitized mast cell activation test is a reliable diagnostic for chlorhexidine allergy. J Allergy Clin Immunol Pract 2021; 9(10): 3826-3828.e2.
[http://dx.doi.org/10.1016/j.jaip.2021.06.016] [PMID: 34182163]
[50]
Ebo DG, Venemalm L, Bridts CH, et al. Immunoglobulin E antibodies to rocuronium: A new diagnostic tool. Anesthesiology 2007; 107(2): 253-9.
[http://dx.doi.org/10.1097/01.anes.0000270735.40872.f2] [PMID: 17667569]
[51]
Leysen J, De Witte L, Sabato V, et al. IgE-mediated allergy to pholcodine and cross-reactivity to neuromuscular blocking agents: Lessons from flow cytometry. Cytometry B Clin Cytom 2013; 84B(2): 65-70.
[http://dx.doi.org/10.1002/cyto.b.21074] [PMID: 23355309]
[52]
Pinnobphun P, Buranapraditkun S, Kampitak T, Hirankarn N, Klaewsongkram J. The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Ann Allergy Asthma Immunol 2011; 106(5): 387-93.
[http://dx.doi.org/10.1016/j.anai.2010.12.020] [PMID: 21530870]
[53]
Brockow K, Romano A, Aberer W, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - A european multicenter study. Allergy 2009; 64(2): 234-41.
[http://dx.doi.org/10.1111/j.1398-9995.2008.01832.x] [PMID: 19178403]
[54]
Salas M, Gomez F, Fernandez TD, et al. Diagnosis of immediate hypersensitivity reactions to radiocontrast media. Allergy 2013; 68(9): n/a.
[http://dx.doi.org/10.1111/all.12214] [PMID: 23991759]
[55]
Stone CA Jr, Liu Y, Relling MV, et al. Immediate hypersensitivity to polyethylene glycols and polysorbates: More common than we have recognized. J Allergy Clin Immunol Pract 2019; 7(5): 1533-1540.e8.
[http://dx.doi.org/10.1016/j.jaip.2018.12.003] [PMID: 30557713]
[56]
Zhou ZH, Stone CA Jr, Jakubovic B, et al. Anti-PEG IgE in anaphylaxis associated with polyethylene glycol. J Allergy Clin Immunol Pract 2021; 9(4): 1731-1733.e3.
[http://dx.doi.org/10.1016/j.jaip.2020.11.011] [PMID: 33217616]
[57]
Alvarez-Arango S, Yerneni S, Tang O, et al. Vancomycin hypersensitivity reactions documented in electronic health records. J Allergy Clin Immunol Pract 2021; 9(2): 906-12.
[http://dx.doi.org/10.1016/j.jaip.2020.09.027] [PMID: 33011300]
[58]
Cesana P, Scherer K, Bircher AJ. Immediate type hypersensitivity to heparins: Two case reports and a review of the literature. Int Arch Allergy Immunol 2016; 171(3-4): 285-9.
[http://dx.doi.org/10.1159/000453525] [PMID: 28049195]
[59]
Anders D, Trautmann A. Allergic anaphylaxis due to subcutaneously injected heparin. Allergy Asthma Clin Immunol 2013; 9(1): 1.
[http://dx.doi.org/10.1186/1710-1492-9-1] [PMID: 23305328]
[60]
Hamad I, Hunter AC, Szebeni J, Moghimi SM. Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. Mol Immunol 2008; 46(2): 225-32.
[http://dx.doi.org/10.1016/j.molimm.2008.08.276] [PMID: 18849076]
[61]
Merkel OM, Urbanics R, Bedőcs P, et al. In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers. Biomaterials 2011; 32(21): 4936-42.
[http://dx.doi.org/10.1016/j.biomaterials.2011.03.035] [PMID: 21459440]
[62]
Elst J, Sabato V, Faber MA, et al. MRGPRX2 and immediate drug hypersensitivity: Insights from cultured human mast cells. J Investig Allergol Clin Immunol 2021; 31(6): 489-99.
[http://dx.doi.org/10.18176/jiaci.0557] [PMID: 32732181]
[63]
Chompunud Na Ayudhya C, Amponnawarat A, Roy S, Oskeritzian CA, Ali H. MRGPRX2 activation by rocuronium: Insights from studies with human skin mast cells and missense variants. Cells 2021; 10(1): 156.
[http://dx.doi.org/10.3390/cells10010156] [PMID: 33467419]
[64]
Fukuoka Y, Schwartz DL, Ward BR. Activation of human skin mast cells by vancomycin via MrgX2: Comparison to the effects of brimonidine. J Immunol 2021; 206(23): 10-23.
[65]
Sarkar P, Nicholson G, Hall G. Brief review: Angiotensin converting enzyme inhibitors and angioedema: Anesthetic implications. Can J Anaesth 2006; 53(10): 994-1003.
[http://dx.doi.org/10.1007/BF03022528] [PMID: 16987854]
[66]
Stojiljkovic L. Renin-angiotensin system inhibitors and angioedema. Curr Opin Anaesthesiol 2012; 25(3): 356-62.
[http://dx.doi.org/10.1097/ACO.0b013e328352dda5] [PMID: 22552531]

Rights & Permissions Print Cite
Article Metrics
51
3
World Health Day
© 2024 Bentham Science Publishers | Privacy Policy