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Medical Journal Review

June 2023

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

T helper 2 cells in asthma
Harker JA, Lloyd CM
Journal of Experimental Medicine 2023; 220(6):e20221094 (10 May)

In this review, the authors provide an update of our current understanding of Th2 cells in human asthma, highlighting their many functions in asthma, both pathogenic and regulatory, and how these are influenced by the tissue location and disease stage and severity. It also explores how biologics targeting type 2 immune pathways impact asthma, and how they have the potential to reveal hitherto underappreciated roles for Th2 cells in lung inflammation.

Allergy to stings and bites from rare or locally important arthropods: Worldwide distribution, available diagnostics and treatment
Sturm GJ, Boni E, Antolín-Amérigo D et al
Allergy 2023; Published online ahead of print (16 May)

This Task Force position paper from the European Academy of Allergy and Clinical Immunology (EAACI) aims to identify either rare or locally important insects causing systemic sting reactions (SSR). Insect venom allergy is the most frequent cause of anaphylaxis in Europe and possibly worldwide. It is known that most systemic allergic reactions after insect stings are caused by Hymenoptera and among these, vespid genera induce most of the SSRs. Honeybees are the second leading cause of SSR. Depending on the global region, other Hymenoptera such as different ant genera are responsible for SSR. Widely distributed hornets and bumblebees or local vespid or bee genera rarely induce SSR. Hematophagous insects such as mosquitoes and horse flies usually cause large local reactions while SSR rarely occur. In this paper, the authors summarize relevant venom or saliva allergens and intend to identify possible cross-reactivities between the insect allergens. Moreover, they explore diagnostic tests both for research and routine diagnosis, as well as treatment.

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Choi YJ, Yoo JS, Jung K et al
Nature Communications 2023;14:2045 (11 April)

It is known that lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT–stem cell factor (SCF) and FcεRI–immunoglobulin E interactions have been shown to be critical for the proliferation and activation of mast cells, respectively. In this report Choi and colleagues demonstrate that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. Overall, this study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation.

A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma
Alladina J, Smith NP, Kooistra T et al
Science Immunology 2023;8(83):eabq6352 (5 May)

Asthma is a chronic disease most commonly associated with allergies and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, the authors compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. They found that in response to allergen exposure, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9-expressing pathogenic TH2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C) and CCR2-expressing monocyte-derived cells (MCs) were enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a TH2-mononuclear phagocyte-basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Overall, that authors note that their study suggests that pathogenic effector circuits and the absence of pro-resolution programs drive structural airway disease in response to type 2 inflammation.

Quantitative proteomics profiling of plasma from children with asthma
Zhou Y, Kuai S, Pan R et al
International Immunopharmacology 2023;119:110249 (3 May)

Zhou and colleagues suggest that a lack of validated blood diagnostic markers presents an obstacle to asthma control. They thus sought to profile the plasma proteins of children with asthma to attempt to find potential biomarkers. Plasma samples from children in acute exacerbation (n = 4), in clinical remission (n = 4), and from healthy children (n = 4, control) were analyzed using a tandem mass tag (TMT)-labeling quantitative proteomics and the candidate biomarkers were validated using liquid chromatography-parallel reaction monitoring (PRM)/mass spectrometry (MS) with enzyme-linked immunosorbent assay (ELISA). They identified 347 proteins with differential expression between groups: 125 (50 upregulated, 75 downregulated) between acute exacerbation and control, 142 (72 upregulated, 70 downregulated) between clinical remission and control, and 55 (22 upregulated, 33 downregulated) between acute and remission groups (all between-group fold changes > 1.2; P < 0.05 by Student’s t-test). Gene ontology analysis implicated differentially expressed proteins among children with asthma in immune response, the extracellular region, and protein binding. Further, KEGG pathway analysis of differentially expressed proteins identified complement and coagulation cascades and Staphylococcus aureus infection pathways as having the highest protein aggregation. Analysis of protein interactions identified potentially important node proteins, particularly KRT10. Among 11 differentially expressed proteins, seven proteins (IgHD, IgHG4, AACT, IgHA1, SAA, HBB, and HBA1) were verified through PRM/MS. Protein levels of AACT, IgA, SAA, and HBB were verified through ELISA and may be useful as biomarkers to identify individuals with asthma. The authors conclude that this study presents a novel comprehensive analysis of changes in plasma proteins in children with asthma and identifies a potential panel for accessory diagnosis of pediatric asthma.

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