Advances in the Understanding of Drug Hypersensitivity: 2012 Through 2022

Macy, Eric; Trautmann, Axel; Chiriac, Anca Mirela; Démoly, P.; Phillips, Elizabeth

doi:10.1016/j.jaip.2022.10.025

Cited by 3 publications

(1 citation statement)

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“…Using a knockout mouse model and cell lines, they demonstrated that MRGPRX2 represents an alternative pathway to the classical IgE-dependent MC activation pathway and can be stimulated not only by its natural endogenous ligands, but also by a large group of exogenous compounds. This has drawn attention to IgE-independent mechanisms of mast cell activation, particularly in drug hypersensitivity reactions ( 10 ) and chronic spontaneous urticaria, where MRGPRX2 was found to be upregulated in skin mast cells of patients with severe course of disease ( 11 ). This in turn led to clinical trials of an oral synthetic MRGPRX2 antagonist ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Mast cell degranulation and bradykinin-induced angioedema - searching for the missing link

Porebski,

Dziadowiec,

Rybka

et al. 2024

Front. Immunol.

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Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.

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Section: Introductionmentioning

confidence: 99%