Barrier Impairment and Type 2 Inflammation in Allergic Diseases: The Pediatric Perspective

Abstract

Allergic diseases represent a global burden. Although the patho-physiological mechanisms are still poorly understood, epithelial barrier dysfunction and Th2 inflammatory response play a pivotal role. Barrier dysfunction, characterized by a loss of differentiation, reduced junctional integrity, and altered innate defence, underpins the pathogenesis of allergic diseases. Epithelial barrier impairment may be a potential therapeutic target for new treatment strategies Up now, monoclonal antibodies and new molecules targeting specific pathways of the immune response have been developed, and others are under investigation, both for adult and paediatric populations, which are affected by atopic dermatitis (AD), asthma, allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNP), or eosinophilic esophagitis (EoE). In children affected by severe asthma biologics targeting IgE, IL-5 and against IL-4 and IL-13 receptors are already available, and they have also been applied in CRSwNP. In severe AD Dupilumab, a biologic which inhibits both IL-4 and IL-13, the most important cytokines involved in inflammation response, has been approved for treatment of patients over 12 years. While a biological approach has already shown great efficacy on the treatment of severe atopic conditions, early intervention to restore epithelial barrier integrity, and function may prevent the inflammatory response and the development of the atopic march.

Involvement and repair of epithelial barrier dysfunction in allergic diseases

“…These connections are established by tight junctions (TJs), adherens junctions (AJs), and desmosome ( 16 ). AJs consist of diverse components such as E-cadherin, actinin, vinculin, α-catenin, and β-catenin, while TJs form a complex involving claudins, occludins, and junctional adhesion molecules ( 17 ). TJs create a barrier by sealing the apical boundary, preventing the unhindered entry of microorganisms, toxins, and pollutants, and regulating the paracellular transport of ions and certain small molecules ( 18 ).…”

“…In a healthy airway, TJs and AJs establish connections between epithelial cells, forming a closed barrier that effectively prevents the invasion of risk factors. This cell barrier is naturally coated with mucus containing antimicrobial agents, peptides, and antibodies, serving as a protective measure against the intrusion of pathogenic bacteria and allergens ( 17 , 31 ). However, patients with asthma often exhibit airway epithelial barrier disorders characterized by an increase in basal and goblet cells and a decrease in terminally differentiated ciliated cell ( 32 ), This is frequently accompanied by basement membrane thickening and epithelial exfoliation, resulting in the formation of Creola bodies composed of exfoliated epithelial clusters ( 4 ).…”

Blood-Based Biomarkers for Eosinophilic Esophagitis and Concomitant Atopic Diseases: A Look into the Potential of Extracellular Vesicles

“…Upon exposure to an allergen, sensitization occurs in the epithelial barrier of the esophagus (EoE), airways (BA), and skin (AD), the epithelial integrity of which is disrupted as a result of defects in cell–cell contacts [ 26 , 27 ]. Sensitized epithelial cells then orchestrate the immunological response by releasing alarmins (IL-25, IL-33, and TSLP) responsible for the polarization of CD4+ T cells towards Th2 phenotype [ 29 , 30 , 31 ]. Cytokines released by Th2 lymphocytes (IL-4, IL-5, and IL-13) stimulate, among others things, the proliferation of eosinophils that are subsequently recruited to the inflammatory foci from circulation, causing the eosinophilia characteristic of EoE, BA, and AD [ 32 , 33 , 34 , 35 ].…”

From Skin Barrier Dysfunction to Systemic Impact of Atopic Dermatitis: Implications for a Precision Approach in Dermocosmetics and Medicine

“…Other therapeutic targets for both AD and asthma are the alarmins TSLP and IL-33 [ 3 ], released from barrier tissues which activate the innate immune response [ 139 , 140 ]. The anti-TSLP mab, tezepelumab, has been approved in severe and uncontrolled asthma with significant reductions of exacerbations and improvements in lung function, symptom control and health-related quality of life, and is currently in phase III trials for asthma [ 140 ]. Conversely, results of a phase IIa study in AD were less convincing which might partly be due to the study design with use of topical corticosteroids in all patients [ 3 ].…”