Meglumine gadoterate induces immunoglobulin-independent human
mast cell activation and MRGPRX2 internalization
To the Editor,
Gadolinium-based contrast agents (GBCA) are intravenous drugs used to
enhance resolution in magnetic resonance imaging. They can induce
immediate hypersensitivity reactions, yet their pathogenic mechanisms
remain poorly characterized. This hampers the ability to predict which
patients are at risk of developing them.1 In fact,
affected patients usually show negative skin-tests and can react upon
the first known GBCA exposure, which implies that IgE-independent
mechanisms might be driving this inflammatory response.
The Mas-related G protein-coupled receptor member X2 (MRGPRX2) has been
recently associated with non-IgE mediated immediate hypersensitivity
reactions.2 Some drugs, such as fluoroquinolones,
vancomycin, neuromuscular blockade agents, icatibant, morphine,
leuprolide and iodinated contrast media, have been reported to activate
MRGPRX2, which is highly expressed in mast cells
(MCs).3
To assess the ability of GBCA to induce non-IgE-mediated
hypersensitivity reactions, we stimulated the human MC line LAD2 with
several commercial GBCA, namely, meglumine gadoterate, gadobutrol,
gadoxetate disodium and gadoteridol. Then, we determined cell viability
and degranulation by flow cytometry4 (see a detailed
material and methods section in this article´s online
supplementary ).
Of the GBCA tested, only meglumine gadoterate was able to induce
significant MC activation (Figure 1A ) without compromising cell
viability (Figure 1B ), as compared to unstimulated MCs. We
further assessed MRGPRX2 expression on LAD2 cells by flow cytometry, as
well as changes in its expression following stimulations with either
meglumine gadoterate or vancomycin (a known agonist of
MRGPRX2).5 Under basal conditions, LAD2 cells
expressed high levels of MRGPRX2 (Figure 1C ). Following
incubation with vancomycin, the level of MRGPRX2 expression was reduced,
as compared to untreated LAD2 cells. Interestingly, we observed a
similar decrease in MRGPRX2 expression levels upon meglumine gadoterate
and vancomycin challenges, as compared to controls, suggesting both the
signaling and the internalization of this receptor (Figure 1D ).
Meglumine gadoterate is an ionic macrocyclic paramagnetic contrast
media. It is composed by gadolinium, which together with the chelating
agent tetraxetan (also known as
DOTA), yields gadoteric acid. The base meglumine and gadoteric acid form
the salt meglumine gadoterate (Figure 2A ). Given that MRGPRX2
has affinity for cationic amphiphilic compounds,6 we
ascertained the ability of meglumine to induce MC activation. Meglumine
itself induced MC degranulation without affecting cell viability, as
compared to untreated cells (Figure 2B ), although a reduction
in MRGPX2 expression could not be confirmed (data not shown).
Interestingly, meglumine caused MC activation at lower concentrations
than meglumine gadoterate, according to the half maximal effective
concentration (EC50) of both substances (Figure
2C ). The logarithmically transformed EC50 for meglumine
gadoterate was 2.04 (R2= 0.75), and for meglumine was
about one order of magnitude lower (1.06; R2= 0.71).
Considering the EC50 for meglumine and its proportion in meglumine
gadoterate (~26%), meglumine could be its main
component responsible for MC degranulation.
In conclusion, our study demonstrates the ability of meglumine
gadoterate to induce MC activation, by an immunoglobulin-independent
mechanism that is likely mediated by MRGPRX2. Furthermore, we have
delved into the meglumine gadoterate components that are involved in MC
activation, and identified meglumine as a potential causative of non-IgE
mediated hypersensitivity reactions. These data raise the possibility
that immediate hypersensitivity reactions following intravascular
administration of ionic iodinated contrast media may be at least partly
mediated by meglumine. Further studies should be performed to define
clinically relevant interactions between diverse radiological contrast
media and MRGPRX2.
Authors: Paula H. Ruiz de Azcárate,1#Rodrigo Jiménez-Saiz,1-4 #* Celia
López-Sanz,1 Azahara López-Raigada,5Francisco Vega,5 Carlos Blanco,5*
# First authors
* Corresponding authors
Affiliations: 1Department of Immunology,
Instituto de Investigación Sanitaria Hospital Universitario de La
Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid,
Spain.
2Department of Immunology and Oncology, Centro
Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain.
3Faculty of Experimental Sciences, Universidad
Francisco de Vitoria (UFV), Madrid, Spain.
4Department of Medicine, McMaster Immunology Research
Centre (MIRC), Schroeder Allergy and Immunology Research Institute
(SAIRI), McMaster University, Hamilton, ON, Canada.
5Department of Allergy, Instituto de Investigación
Sanitaria Hospital Universitario de La Princesa (IIS-Princesa),
Universidad Autónoma de Madrid (UAM), Madrid, Spain.
*Co-correspondence to :
1) Rodrigo Jiménez-Saiz, Department of Immunology, Instituto de
Investigación Sanitaria Hospital Universitario de La Princesa
(IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address:
rodrigo.jimenez@ufv.es
2) Carlos Blanco, Department of Allergy, Instituto de Investigación
Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de
León 62, 28006, Madrid, Spain. Email address:
cblague@gmail.com
Funding information: RJS reports grants by the FSE/FEDER
through the Instituto de Salud Carlos III (CP20/00043; PI22/00236;
Spain), The Nutricia Research Foundation (NRF-2021-13; The Netherlands),
New Frontiers in Research Fund (NFRFE-2019-00083; Canada) and SEAIC
(BECA20A9; Spain). PHR is supported by the INVESTIGO Program of the
Community of Madrid (Spain), which is funded by “Plan de Recuperación,
Transformación y Resiliencia” and “NextGenerationEU” of the European
Union (09-PIN1-00015.6/2022).
Conflict of interest : All the authors have no significant
conflicts of interest to declare in relation to this manuscript.
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