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Medical Journal Review

November 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.

The mycobiome in atopic diseases: inducers and triggers
Glatthardt T, van Tilburg Bernardes E, Arrieta M-C
Journal of Allergy and Clinical Immunology 2023: S0091-6749(23)01288-5; Published online ahead of print (19-Oct)

Atopic diseases are characterized by type 2 inflammation, with high allergen-specific T helper type 2 (Th2) immune responses and elevated immunoglobulin E (IgE) production. These common disorders have increased in incidence around the world, which may be at least partly explained by detrimental disturbances to the early-life intestinal microbiome. While most studies have focused exclusively on bacterial members of the microbiome, intestinal fungi have started to gain an appreciation for their impact on host immune development and atopy pathogenesis. In this perspective, the authors explore recent findings demonstrating the strong interactions between members of the mycobiome and the host immune system early in life, leading to immune tolerance during eubiosis, or inducing sensitization and overt Th2 responses during dysbiosis. This article demonstrates that the current evidence places intestinal fungi as central players in the development of allergic diseases and potential targets for atopy prevention and treatments.

Multifaceted analysis of cross-tissue transcriptomes reveals phenotype-endotype associations in atopic dermatitis
Sekita A, Kawasaki H, Fukushima-Nomura A et al
Nature Communications 2023;14:6133  (2-Oct)

It is known that atopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. In this paper, Sekata and colleagues examine integrated RNA sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, to explore specific clinical presentations associated with matching differential molecular signatures. Through a regression model based on transcriptome modules they identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. They further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. The authors’ approach in this study serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases.

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper
Jutel M, Agache I, Zemelka-Wiacek M, Akdis M et al
Allergy 2023; Published online ahead of print (10-Oct)

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nanotechnologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The authors note that the clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime.

Breast feeding, obesity, and asthma association: clinical and molecular views
Kian N, Bagheri A, Salmanpour F et al
Clinical and Molecular Allergy 2023;21:8 (3-Oct)

Asthma is a chronic condition that affects children worldwide. Numerous studies have reported that the prevalence of pediatric obesity and asthma might be altered through breastfeeding. This article reviews the literature regarding this association.  It has been proposed that Leptin, which exists in human milk, is oppositely associated with weight increase in newborns. It may also influence peripheral immune system by promoting TH1 responses and suppressing TH2 cytokines. Leptin influences body weight and immune responses through complex signaling pathways at molecular level. Although previous studies provide explanations for the protective role of breastfeeding against both obesity and asthma, other factors such as duration of breastfeeding, parental, and prenatal factors may confound this relationship which requires further research.

A nerve-goblet cell association promotes allergic conjunctivitis through the rapid antigen passage
Kimura M, Ando T, Kume Y et al
JCI Insight 2023;8(21)e168596  (11-Oct)

The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although allergic patients manifest symptoms within minutes after pollen exposure, the mechanisms of the rapid allergen transport remain unclear. In the present study, the authors found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by the stromal cells including macrophages and CD11b+ dendritic cells correlated with the surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of the pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. They found that the inducible rapid GAP formation and antigen acquisition was suppressed by topical lidocaine or trigeminal ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a novel therapeutic target for allergic conjunctivitis.

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