Allergenic and Mas-Related G Protein-Coupled Receptor X2-Activating Properties of Drugs: Resolving the Two

Sabato, Vito; Ebo, Didier G.; Poorten, Marie-Line M. van der; Toscano, Alessandro; Gasse, Athina L. Van; Mertens, Christel; Houdt, Michel van; Beyens, Michiel; Elst, Jessy

doi:10.1016/j.jaip.2022.12.014

Cited by 19 publications

(32 citation statements)

References 112 publications

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“…At present, diagnostic investigation of MRGPRX2‐ and IgE/FcεRI‐mediated reactions is based on an initial clinical assessment, skin testing, antibody tests, mediator (in particular, tryptase and histamine) assays, plus basophil and mast cell activation tests, 1,11 that is, examinations developed for the identification of immune‐mediated mechanisms not specifically for non‐immune MRGPRX2‐mediated reaction mechanisms. Although MRGPRX2‐ and IgE/FcεRI‐mediated reactions may be clinically closely similar, there are also some differences.…”

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

“…Although MRGPRX2‐ and IgE/FcεRI‐mediated reactions may be clinically closely similar, there are also some differences. For example, with MRGPRX2 reactions, cutaneous symptoms are usually, but not invariably, present, except in rare cases, previous exposure is necessary for IgE antibody‐mediated reactions but not for MRGPRX2 reactions, a negative skin test does not necessarily preclude MRGPRX2 involvement, there is a lack of specific IgE antibody tests for many of the drugs and other diverse agents that activate each receptor, and, unlike immune reactions, sensitization and MRGPRX2 receptor activation cannot usually be predicted by structure/sequence similarity 1,2,7,11,47 . In addition, some agents, for example THIQ neuromuscular blocking drugs and fluoroisoquinolone antibiotics, may activate both receptors 2,11 …”

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

“…Given the similarities of MRGPRX2‐ and IgE/FceR1‐mediated reactions and difficulties of distinguishing the two mechanisms, clinical identification of MRGPRX2 activation and diagnosis of pseudoallergies is not straightforward and has, in fact, become an exercise of elimination of information and processes considered not relevant to the receptor's involvement. For example, Sabato et al 11 see the identification of MRGPRX2’s role in the diagnosis of pseudoallergic reactions as a process of exclusion once other non‐immune and immune processes, particularly IgE/FcεRI‐mediated degranulation of mast cells, are ruled out. However, the direct demonstration of specific MRGPRX2 activation rather than a fall‐back elimination approach is a more scientifically sound and precise strategy and should be the preferred basis of the diagnostic methodology.…”

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

“…After an initial clinical assessment of signs, symptoms, drug suspects, temporal associations and possible tryptase testing, skin and IgE tests are undertaken. The basophil activation test (BAT), mast cell activation test (MAT) and T‐lymphocyte activation test (TAT) 11 (grey arrows) may be used when skin and IgE tests prove negative or when appropriate IgE assays are not available. For distinguishing pseudoallergic reactions from IgE antibody immune‐mediated allergies, a sensitive MRGPRX2 activation assay for both β‐arrestin (G‐protein‐independent) and Ca 2+ (G‐protein‐dependent) endpoints is utilized.…”

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

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MRGPRX2, drug pseudoallergies, inflammatory diseases, mechanisms and distinguishing MRGPRX2‐ and IgE/FcεRI‐mediated events

Baldo

2023

Brit J Clinical Pharma

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MRGPRX2, a novel Gaq‐coupled human mast cell receptor, mediates non‐immune adverse reactions without the involvement of antibody priming. Constitutively expressed by human skin mast cells, MRGPRX2 modulates cell degranulation producing pseudoallergies manifesting as itch, inflammation and pain. The term pseudoallergy is defined in relation to adverse drug reactions in general and immune/non‐immune‐mediated reactions in particular. A list of drugs with MRGPRX2 activity is presented, including a detailed examination of three important and widely used approved therapies: neuromuscular blockers, quinolones and opioids. For the clinician, the significance of MRGPRX2 is considered as an aid in distinguishing and ultimately identifying specific immune and non‐immune inflammatory reactions. Anaphylactoid/anaphylactic reactions, neurogenic inflammation and inflammatory diseases with a clear or strongly suspected association with MRGPRX2 activation are examined. Inflammatory diseases include chronic urticaria, rosacea, atopic dermatitis, allergic contact dermatitis, mastocytosis, allergic asthma, ulcerative colitis and rheumatoid arthritis. MRGPRX2‐ and allergic IgE/FcεRI‐mediated reactions may be clinically similar. Importantly, the usual testing procedures do not distinguish the two mechanisms. Currently, identification of MRGPRX2 activation and diagnosis of pseudoallergic reactions is generally viewed as a process of exclusion once other non‐immune and immune processes, particularly IgE/FcεRI‐mediated degranulation of mast cells, are ruled out. This does not take into account that MRGPRX2 signals via β‐arrestin, which can be utilized to detect MRGPRX2 activation by employing MRGPRX2 transfected cells to assess MRGPRX2 activation via two pathways, the G‐protein‐independent β‐arrestin pathway and the G‐protein‐dependent Ca2+ pathway. Testing procedures, interpretations for distinguishing mechanisms, patient diagnosis, agonist identification and drug safety evaluations are addressed.

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Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

Section: Distinguishing and Diagnosing Mrgprx2‐ And Ige/fcεri‐mediate...mentioning

confidence: 99%

See 2 more Smart Citations

MRGPRX2, drug pseudoallergies, inflammatory diseases, mechanisms and distinguishing MRGPRX2‐ and IgE/FcεRI‐mediated events

Baldo

2023

Brit J Clinical Pharma

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“…Beside classical IgE‐mediated DHRs, BAT could have a potential role in non‐IgE‐mediated reactions; however, at this moment, no studies have been able to demonstrate the value of BAT in these reactions. Moreover, some recent ongoing studies are considering the usefulness of BAT in the evaluation of the role of the MRGPRX2 (Mas‐related G protein‐coupled receptor X2) receptor, which is minimally expressed on basophils; this new data arise questions on the existence of a new endotype of IDHRs 22 that needs further investigation.…”

Section: How To Choosementioning

confidence: 99%

In vitro diagnostic testing for drug allergy in children

Saretta

Tomei

Mori

et al. 2023

Pediatric Allergy Immunology

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Diagnosing Drug Hypersensitivity Reactions (DHRs) could be a complicated process especially in children, since allergic-like manifestation at this age is more often the expression of concomitant infections rather than a actual DHRs. In vivo tests are usually suggested as a first step; however, prick and intradermal tests could be painful and have shown different sensitivity and specificity among published studies. In some cases, in vivo tests such as Drug Provocation test (DPT) could be even contraindicated. Therefore, the need for in vitro testing is compelling, to add useful information along the diagnostic pathway and to limit the need of DPT. In this review, we analyze the different types of in vitro tests, focusing on those used more widely such as specific IgE and on those that are still for research settings, such as basophil activation test and lymphocyte transformation test, but that have shown some useful diagnostic potential.

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Allergic and other adverse reactions to drugs used in anesthesia and surgery

Baldo

2023

APS

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The list of drugs patients may be exposed to during the perioperative and postoperative periods is potentially extensive. It includes induction agents, neuromuscular blocking drugs (NMBDs), opioids, antibiotics, sugammadex, colloids, local anesthetics, polypeptides, antifibrinolytic agents, heparin and related anticoagulants, blue dyes, chlorhexidine, and a range of other agents depending on several factors related to individual patients’ clinical condition and progress in the postoperative recovery period. To avoid poor or ultrarapid metabolizers to a particular drug (for example tramadol and codeine) or possible adverse drug reactions (ADRs), some drugs may need to be avoided during or after surgery. This will be the case for patients with a history of anaphylaxis or other adverse events/intolerances to a known drug. Other drugs may be ceased for a period before surgery, e.g., anticoagulants that increase the chance of bleeding; diuretics for patients with acute renal failure; antihypertensives relative to kidney injury after major vascular surgery; and serotonergic drugs that together with some opioids may rarely induce serotonin toxicity. Studies of germline variations shown by genotyping and phenotyping to identify a predisposition of genetic factors to ADRs offer an increasingly important approach to individualize drug therapy. Studies of associations of human leukocyte antigen (HLA) genes with some serious delayed immune-mediated reactions are ongoing and variations of drug-metabolizing cytochrome CYP450 enzymes, P-glycoprotein, and catechol-O-methyltransferase show promise for the assessment of ADRs and non-responses to drugs, particularly opioids and other analgesics. Surveys of ADRs from an increasing number of institutions often cover small numbers of patients, are retrospective in nature, fail to clearly identify culprit drugs, and do not adequately distinguish immune-mediated from non-immune-mediated anaphylactoid reactions. From the many surveys undertaken, the large list of agents identified during and after anesthesia and surgery are examined for their ADR involvement. Drugs are classified into those most often involved, (NMBD and antibiotics); drugs that are becoming more frequently implicated, namely antibiotics (particularly teicoplanin), and blue dyes; those becoming less frequently involved; and drugs more rarely involved in perioperative, and postoperative adverse reactions but still important and necessary to keep in mind for the occasional potential sensitive patient. Clinicians should be aware of the similarities between drug-induced true allergic type I IgE/FcεRI- and pseudoallergic MRGPRX2-mediated ADRs, the clinical features of each, and their distinguishing characteristics. Procedures for identifying MRGPRX2 agonists and diagnosing and distinguishing pseudoallergic from allergic reaction mechanisms are discussed. Graphical Abstract

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Allergenic and Mas-Related G Protein-Coupled Receptor X2-Activating Properties of Drugs: Resolving the Two

Cited by 19 publications

References 112 publications

MRGPRX2, drug pseudoallergies, inflammatory diseases, mechanisms and distinguishing MRGPRX2‐ and IgE/FcεRI‐mediated events

MRGPRX2, drug pseudoallergies, inflammatory diseases, mechanisms and distinguishing MRGPRX2‐ and IgE/FcεRI‐mediated events

In vitro diagnostic testing for drug allergy in children

Allergic and other adverse reactions to drugs used in anesthesia and surgery

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