We are pleased to introduce the collection Frontiers in Allergy – Highlights in Skin Allergy 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Skin Allergy section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

Université de Bordeaux

Université de Bretagne Occidentale

Explore a wide range of innovative studies in the field of Skin Allergy

The global pandemic caused by SARS-CoV-2 has had a significant effect on skin disorders that are mediated by type 2 inflammation, such as atopic dermatitis and chronic spontaneous urticaria. This research topic provides guidance on treatment and vaccination considerations. MRGPRX2 is a novel receptor that is believed to be involved in pseudo-allergic reactions to drugs and in neuropeptide-elicited MC activation in skin diseases. β-arrestin-1 and β-arrestin-2 have been found to counter skin MC degranulation induced by MRGPRX2 agonists. Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive primary immune deficiency disease that has similar symptoms to atopic dermatitis (AD). Proteomics has been used to identify potential biomarkers that can differentiate between DOCK8-deficiency and AD, with the identified proteins centering around the dysregulation of ERK1/.

Frontiers in Allergy

Skin Allergy

Highlights in Skin Allergy 2021/22

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/53047/highlights-in-skin-allergy-202122">Highlights in skin allergy</a>As an interface organ between the inside and outside of our bodies, skin is an immune organ with many dendritic cells, especially Langerhans cells in the epidermis, and a number of more or less transient immune cells such as lymphocytes, mast cells, eosinophils, neutrophils, or basophils. Consequently, skin allergy is frequently the first manifestation of an allergy. We were proud to welcome four interesting papers presenting research in the field of dermato-allergology.<a href="https://doi.org/10.3389/falgy.2021.660447">Bettina Wedi</a>, from Hanover, provided an excellent overview of the contemporary grand challenges and opportunities in the field of skin allergies. In the field of atopic dermatitis, numerous new treatments may allow a choice, according to the endotype and/or inflammatory phase, for each patient in the future. Until now, chronic prurigo treatment was frequently very difficult, but the recent progress in research has opened fascinating new therapeutic options (<a href="#B1">1</a>). We hope that it could be the same regarding mastocytosis or angioedema without weals. In the field of urticaria, omalizumab is the main therapeutic option after antihistamines, according to the recent guidelines (<a href="#B2">2</a>), and new drugs are coming. Nonetheless, how it works has not been clarified in detail.Mas-related G protein–coupled receptor X2 (MRGPRX2) was proved to be the target of many of the agonists associated with a second route, inducing degranulation through the effects of neuropeptides, such as substance P, or numerous drugs, independently of IgE. β-arrestins act as opponents of G proteins and lead to signal termination with or without subsequent internalization. <a href="https://doi.org/10.3389/falgy.2022.930233">Zhao Wang et al.</a> from Berlin, demonstrated that β-arrestin-2 is chiefly involved in signal termination, whereas β-arrestin-1 exerts its effects on skin mast cells by controlling MRGPRX2 abundance.The diagnosis of hyperimmunoglobulinemia E syndrome is commonly delayed because patients are initially considered as presenting with atopic dermatitis. <a href="https://doi.org/10.3389/falgy.2021.774902">Minnie Jacob et al.</a> from Riyadh, performed a proteomic analysis on patients with this syndrome related to dedicator of cytokinesis 8 (DOCK-8) deficiency and atopic patients. They evidenced 24/85 distinct proteins. The use of this technique could help to distinguish between DOCK8 deficiency and atopic dermatitis, prevent complications, and initiate the appropriate treatment early.The occurrence of COVID-19 has rapidly and deeply modified all medical practices. <a href="https://doi.org/10.3389/falgy.2022.809646">Isabelle Haddad et al.</a> from Beirut, performed an interesting review on the management of patients with atopic dermatitis or chronic spontaneous urticaria in this context.Hence, the field of dermato-allergology is experiencing transformations, from basic research to patient management, and it is very interesting to observe them.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Highlights in skin allergy

A rapid spread of different strains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented pandemic. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the medical body has encountered major obstacles concerning disease management at different levels. Even though patients infected with this virus mainly present with respiratory symptoms, it has been associated with a plethora of well-documented cutaneous manifestations in the literature. However, little investigations have been conducted concerning COVID-19 and its impact on skin disorders mediated by type 2 inflammation leaving multiple dermatologists and other specialists perplexed by the lack of clinical guidelines or pathways. This review focuses on the effects of this pandemic in patients with skin disorders mediated by type 2 inflammation, specifically atopic dermatitis and chronic spontaneous urticaria. In addition, it will provide clinicians a guide on treatment and vaccination considerations for this stated set of patients.

A rapid spread of different strains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented pandemic. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the medical body has encountered major obstacles concerning disease management at different levels. Even though patients infected with this virus mainly present with respiratory symptoms, it has been associated with a plethora of well-documented cutaneous manifestations in the literature. However, little investigations have been conducted concerning COVID-19 and its impact on skin disorders mediated by type 2 inflammation leaving multiple dermatologists and other specialists perplexed by the lack of clinical guidelines or pathways. This review focuses on the effects of this pandemic in patients with skin disorders mediated by type 2 inflammation, specifically atopic dermatitis and chronic spontaneous urticaria. In addition, it will provide clinicians a guide on treatment and vaccination considerations for this stated set of patients.

Navigating patients with atopic dermatitis or chronic spontaneous urticaria during the COVID-19 pandemic

As a novel receptor that efficiently elicits degranulation upon binding to one of its numerous ligands, MRGPRX2 has moved to the center of attention in mast cell (MC) research. Indeed, MRGPRX2 is believed to be a major component of pseudo-allergic reactions to drugs and of neuropeptide-elicited MC activation in skin diseases alike. MRGPRX2 signals via G proteins which organize downstream events ultimately leading to granule discharge. Skin MCs require both PI3K and ERK1/2 cascades for efficient exocytosis. β-arrestins act as opponents of G proteins and lead to signal termination with or without subsequent internalization. We recently demonstrated that ligand-induced internalization of MRGPRX2 requires the action of β-arrestin-1, but not of β-arrestin-2. Here, by using RNA interference, we find that both isoforms counter skin MC degranulation elicited by three MRGPRX2 agonists but not by FcεRI-aggregation. Analyzing whether this occurs through MRGPRX2 stabilization under β-arrestin attenuation, we find that reduction of β-arrestin-1 indeed leads to increased MRGPRX2 abundance, while this is not observed for β-arrestin-2. This led us speculate that β-arrestin-2 is involved in signal termination without cellular uptake of MRGPRX2. This was indeed found to be the case, whereby interference with β-arrestin-2 has an even stronger positive effect on ERK1/2 phosphorylation compared to β-arrestin-1 perturbation. Neither β-arrestin-1 nor β-arrestin-2 had an impact on AKT phosphorylation nor affected signaling via the canonical FcεRI-dependent route. We conclude that in skin MCs, β-arrestin-2 is chiefly involved in signal termination, whereas β-arrestin-1 exerts its effects by controlling MRGPRX2 abundance.

As a novel receptor that efficiently elicits degranulation upon binding to one of its numerous ligands, MRGPRX2 has moved to the center of attention in mast cell (MC) research. Indeed, MRGPRX2 is believed to be a major component of pseudo-allergic reactions to drugs and of neuropeptide-elicited MC activation in skin diseases alike. MRGPRX2 signals via G proteins which organize downstream events ultimately leading to granule discharge. Skin MCs require both PI3K and ERK1/2 cascades for efficient exocytosis. β-arrestins act as opponents of G proteins and lead to signal termination with or without subsequent internalization. We recently demonstrated that ligand-induced internalization of MRGPRX2 requires the action of β-arrestin-1, but not of β-arrestin-2. Here, by using RNA interference, we find that both isoforms counter skin MC degranulation elicited by three MRGPRX2 agonists but not by FcεRI-aggregation. Analyzing whether this occurs through MRGPRX2 stabilization under β-arrestin attenuation, we find that reduction of β-arrestin-1 indeed leads to increased MRGPRX2 abundance, while this is not observed for β-arrestin-2. This led us speculate that β-arrestin-2 is involved in signal termination without cellular uptake of MRGPRX2. This was indeed found to be the case, whereby interference with β-arrestin-2 has an even stronger positive effect on ERK1/2 phosphorylation compared to β-arrestin-1 perturbation. Neither β-arrestin-1 nor β-arrestin-2 had an impact on AKT phosphorylation nor affected signaling via the canonical FcεRI-dependent route. We conclude that in skin MCs, β-arrestin-2 is chiefly involved in signal termination, whereas β-arrestin-1 exerts its effects by controlling MRGPRX2 abundance.

β-arrestin-1 and β-arrestin-2 Restrain MRGPRX2-Triggered Degranulation and ERK1/2 Activation in Human Skin Mast Cells

Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p < 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.

Dedicator of cytokinesis 8 deficiency is an autosomal recessive primary immune deficiency disease belonging to the group of hyperimmunoglobulinemia E syndrome (HIES). The clinical phenotype of dedicator of cytokinesis 8 (DOCK8) deficiency, characterized by allergic manifestations, increased infections, and increased IgE levels, overlaps with the clinical presentation of atopic dermatitis (AD). Despite the identification of metabolomics and cytokine biomarkers, distinguishing between the two conditions remains clinically challenging. The present study used a label-free untargeted proteomics approach using liquid-chromatography mass spectrometry with network pathway analysis to identify the differentially regulated serum proteins and the associated metabolic pathways altered between the groups. Serum samples from DOCK8 (n = 10), AD (n = 9) patients and healthy control (Ctrl) groups (n = 5) were analyzed. Based on the proteomics profile, the PLS-DA score plot between the three groups showed a clear group separation and sample clustering (R2 = 0.957, Q2 = 0.732). Significantly differentially abundant proteins (p &lt; 0.05, FC cut off 2) were identified between DOCK8-deficient and AD groups relative to Ctrl (n = 105, and n = 109) and between DOCK8-deficient and AD groups (n = 85). Venn diagram analysis revealed a differential regulation of 24 distinct proteins from among the 85 between DOCK8-deficient and AD groups, including claspin, haptoglobin-related protein, immunoglobulins, complement proteins, fibulin, and others. Receiver-operating characteristic curve (ROC) analysis identified claspin and haptoglobin-related protein, as potential biomarkers with the highest sensitivity and specificity (AUC = 1), capable of distinguishing between patients with DOCK8 deficiency and AD. Network pathway analysis between DOCK8-deficiency and AD groups revealed that the identified proteins centered around the dysregulation of ERK1/2 signaling pathway. Herein, proteomic profiling of DOCK8-deficiency and AD groups was carried out to determine alterations in the proteomic profiles and identify a panel of the potential proteomics biomarker with possible diagnostic applications. Distinguishing between DOCK8-deficiency and AD will help in the early initiation of treatment and preventing complications.