The epithelial barrier theory: Development and exacerbation of allergic and other chronic inflammatory diseases

Abstract

It is now longer than half a century, humans, animals, and nature of the world are under the influence of exposure to many newly introduced noxious substances. These exposures are nowadays pushing the borders to be considered as the causative or exacerbating factors for many chronic disorders including allergic, autoimmune/inflammatory, and metabolic diseases. The epithelial linings serve as the outermost body's primary physical, chemical, and immunological barriers against external stimuli. The "epithelial barrier theory" hypothesizes that these diseases are aggravated by an ongoing periepithelial inflammation triggered by exposure to a wide range of epithelial barrier-damaging insults that lead to "epithelitis" and the release of alarmins. A leaky epithelial barrier enables the microbiome's translocation from the periphery to interepithelial and even deeper subepithelial areas together with allergens, toxins, and pollutants. Thereafter, microbial dysbiosis, characterized by colonization of opportunistic pathogen bacteria and loss of the number and biodiversity of commensal bacteria take place. Local inflammation, impaired tissue regeneration, and remodeling characterize the disease. The infiltration of inflammatory cells to affected tissues shows an effort to expulse the tissue invading bacteria, allergens, toxins, and pollutants away from the deep tissues to the surface, representing the "expulsion response." Cells that migrate to other organs from the inflammatory foci may play roles in the exacerbation of various inflammatory diseases in distant organs. The purpose of this review is to highlight and appraise recent opinions and findings on epithelial physiology and its role in the pathogenesis of chronic diseases in view of the epithelial barrier theory.

Keywords: Allergy; asthma; autoimmune diseases; barrier dysfunction; epithelial barrier theory; epithelitis; microbiota; tight junctions.

Figure 1.

Epithelial barrier–damaging agents. A defective epithelial barrier is underlying a number of inflammatory disorders including allergy and autoimmune diseases. Epithelial barriers of the skin, respiratory, or gastrointestinal systems are disrupted upon synergistic or additive effects of a number of agents or factors. These include detergents, shampoos, toothpaste, diesel particles, cigarette smoke, food additives, allergens with protease activity, viruses, ozone, and also alterations in climate. Translocation of the microbiota occurs as the result of leaky epithelial barrier formation.

Figure 2.

Immune mechanisms underlying epithelial barrier disruption. The epithelial barrier–damaging exposome disrupts epithelial barrier integrity, which is followed by development of epithelitis and release of alarmins. TSLP, IL-25, and IL-33 are secreted from the epithelial cells, and immune responses are triggered. At the same time, because of disruption of the epithelial barrier, microbial translocation is initiated. Following the differentiation of Th2 cells, type 2 cytokines including IL-4, IL-5, IL-13, and GM-CSF are produced, and B cells isotype-switch to IgE. Eosinophils and mast cells bind IgE, become potentiated thanks to the rich cytokine milieu and start producing their mediators such as LTs, MBP, and histamine, LTC4, PGD2, and tryptase, respectively. Th9 cells produce IL-9, which further potentiates the activity of mast cells. ILC2s produce type 2 cytokines and contribute to the cytokine milieu. The cytokines and mediators collectively initiate the development of a chronic expulsion response including IL-4, IL-13, IFN-γ, TNF-α, and TRAIL, and leads to further epithelial damage. DC, dendritic cell; EOS, eosinophil; GM-CSF, granulocyte colony-stimulating factor; IL, interleukin; ILC, innate lymphoid cell; LTs, leukotrienes; MBP, major basic protein; MC, mast cell; PGD, prostaglandin; TRAIL, TNF-related apoptosis inducing ligand; TSLP, thymic stromal lymphopoietin.

Figure 3.

The expulsion response against microbiome and opportunistic pathogens. Following epithelial damage, microbiome migrates inside and beneath the epithelium, which consequently triggers cell migration and stimulation of the immune system. Activated immune cells including macrophages, DCs, mast cells, T and B cells, and ILCs migrate to the area and initiate a type 2 expulsion response with Th2 cells, IgE-producing B cells, ILC2, IL-4, IL-5, and IL-13 against opportunistic pathogens, commensals, allergens, and pollutants. The opportunistic pathogens include Staphylococcus aureus, Pneumococcus, Haemophilus, and Moraxella. The inflammatory response together with translocated microbiome and microbial dysbiosis leads to defects in epithelium repair, and misclosure of the barrier, which instigate a vicious cycle of leaky barriers and chronic inflammatory responses as well as microbial dysbiosis. DC, dendritic cell; EOS, eosinophil, IL, interleukin; ILC, innate lymphoid cell; M∅, macrophage; MC, mast cell.

Figure 4.

The vicious circle of chronic epithelial barrier dysfunction. Disruption of epithelial barriers are induced by exposome and damaging agents, which is facilitated by genetic defects in barrier-related molecules. Chronic inflammation in the periepithelial area leads to chronic, defective epithelial barrier healing and aggravates the damage. Epigenetics play role in defective barrier healing capacity, which in turn leads to epithelial barrier damage, and is termed as epithelitis. Then, loss of biodiversity and microbial dysbiosis end up with translocation of microbiota to inter- and subepithelial areas. An expulsion response is initiated, leading to chronic inflammation in the periepithelial area.