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 and providing a tissue interface balancing the communication between the internal and external environments. We now understand that in patients with allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed toward 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 initiation of allergic disease, many important questions remain to be answered regarding mechanisms disrupting normal barrier function. Although our external environment (proteases, allergens, and 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, and 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 allergic patients.

Keywords: Epithelial barrier; allergic predisposition; allergic sensitization; differentiation; extracellular matrix; hormones; mesenchyme; metabolism; tight junctions.

Figure 1. Key features of epithelial dysfunction common to all allergic disease

Epithelial barriers predisposed to Type 2 allergic disease are characterized by increased permeability and aberrant behavior of morphogenetic programs that maintain epithelial homeostasis. Both exogenous (inhaled allergens, respiratory viruses, chemical sensitizers, air pollutants) and endogenous (hormones, dietary factors, altered circadian clock) disruptors of epithelial homeostasis may drive predisposition to allergic sensitization by altering homeostatic activity of developmental pathways (WNT, Notch, Hedgehog) that maintain proper epithelial-to-mesenchymal communication, epithelial differentiation, and barrier integrity. Transition to a remodeling state in disease typically follows allergic sensitization and inflammatory responses. This transition features further loss of differentiation signals, downregulation of innate defense molecules, pro-fibrotic processes, deposition of extracellular matrix, and potentiated activity of the mesenchymal unit.

Figure 2. Changing states of the epithelial barrier on a homeostasis-allergic disease continuum

Dysregulation of normal epithelial barrier function is a gradual process involving multiple causal factors. This includes genetics, epigenetics and influences of the external and internal epithelial environments.