Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Abstract

Epithelial barriers of the skin, gastrointestinal tract and airway serve common critical functions such as maintaining a physical barrier against environmental insults and allergens, as well as providing a tissue interface balancing the communication between the internal and external environments. We now understand that in allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed towards loss of differentiation, reduced junctional integrity and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in the initiation of allergic disease, many important questions remain to be answered regarding the mechanisms disrupting the normal barrier function. Although our external environment (proteases, allergens, injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction, using both systems biology tools and causality-driven laboratory experimentation, will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergy.

FcγRIII stimulation breaks the tolerance of human nasal epithelial cells to bacteria through cross-talk with TLR4

“…Indeed, previous findings advocate a strong role for Gram-positive bacteria such as S. aureus in chronic nasal inflammation. 26 However, this distinction between Gram-positive and negative bacteria is most likely not black and white, since pathogens are mostly recognized by multiple PRRs simultaneously. Therefore, upon bacterial recognition the relative contribution of a PRR (TLR4, TLR2, NOD-like receptors, etc.)…”

Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease

“…For example, normal mammary gland development has been described as wound‐like in both mice and humans . Similarly, morphogenesis of the lung continues during postnatal development, characterized by the deposition of the provisional extracellular matrix, increased mesenchymal–epithelial communication, differentiation of mature stratified epithelium, as well as processes associated with the loss of epithelial differentiation in chronic allergic disease . The only apparent difference between normal and pathological states of the tissue undergoing remodeling is in heterochrony; timing of the onset, offset, and persistence of these signals.…”

“…1 16,17 Similarly, morphogenesis of the lung continues during postnatal development, characterized by the deposition of the provisional extracellular matrix, increased mesenchymal-epithelial communication, differentiation of mature stratified epithelium, 18,19 as well as processes associated with the loss of epithelial differentiation in chronic allergic disease. 20,21 The only apparent difference between normal and pathological states of the tissue undergoing remodeling is in heterochrony; timing of the onset, offset, and persistence of these signals. In normal development and injury repair, homeostatic modeling programs are perfectly timed, while in disease they are perpetuated, perhaps associated with a continuous attempt to return tissue to a homeostatic state.…”

Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma

“…By contrast, several authors Abbreviations used AMP: Antimicrobial peptide BAL: Bronchoalveolar lavage CC16: Club cell protein PAF: Platelet activating factor have mentioned in passing that plasma exudation can be part of the first line of defense in the airway mucosa. 22,23 Is it then possible that epithelial transmission of extravasated plasma is so swift that subepithelial edema does not develop? Furthermore, is there an asymmetry in airway epithelial lining cells such that it can let through bulk plasma macromolecules without allowing increased penetration of inhaled molecules?…”