Epithelial Barrier Theory

Pat, Y. , Ogulur, I. Allergy. 2021 Nov;76(11):3560-3562. doi: 10.1111/all.14899. Epub 2021 May 28. PMID: 33982305.

The Epithelial Barrier Theory is rooted in studies from the beginning of the century that demonstrate immune-mediated epithelial barrier damage in chronic allergic inflammation. One of the first findings regarding the immune-mediated epithelial barrier damage was made in atopic dermatitis and allergic contact dermatitis patients. Skin infiltrating T cells were demonstrated to induce keratinocyte apoptosis, leading to eczema development, a skin barrier defect.1 Since then, many studies have elaborated on the concept of type 2 immunity mediated barrier damage in various diseases such as asthma, chronic rhinosinusitis, and colitis.2,3 Type 2 immunity, which is the default defence against parasites and venoms, plays a crucial role in epithelial barrier regulation. It was proposed in 2006 that the thickening of the airway basement membrane forms a barrier below the leaky epithelium between the environment that may include a dysbiotic microbiome and toxic substances and inner tissues to prevent the entry of harmful components.2 Factors that “keep away” the environmental knox and that “wash away” the toxic substances together with inflammation have been proposed. The opening of epithelial barriers, increased mucus production, and mucosal shedding are representatives of a mechanism that attempts to reduce allergen exposure (wash-away effect).2,3 It is well known that type 2 cytokines such as IL-4 and IL-13 open the epithelial barriers.4 Conditions characterised by a systemic type 2 immune response, such as asthma, chronic rhinosinusitis, and atopic dermatitis, are well-defined by an impaired epithelial barrier.3,4 “The Epithelial Barrier Theory” takes into account five facts: the steep increase in allergic and autoimmune diseases, the evidence of epithelial barrier disruption in these conditions, microbial dysbiosis and bacterial translocation, immune response to commensals and opportunistic pathogens, and changes in environmental exposure due to urbanisation and industrialisation.3 In the last century, humanity has faced new environmental challenges, including poor air quality, climate change, and increased use of toxic substances such as detergents, nanoparticles, and microplastics. These biological and chemical insults disrupt the barrier integrity and cause the release of epithelial cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin, which leads to a type 2 immune response in affected organs in asthma, rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, and atopic dermatitis.5,6

The Epithelial Barrier Theory presents an overarching idea that also embraces previous views from the Hygiene, Old Friends, and Biodiversity hypotheses. It includes all previous mechanisms and brings a promising rationale to explain the sudden increase of chronic noncommunicable inflammatory diseases observed in the last six decades. It offers new ideas for diagnosis, treatment, and prevention of diseases associated with epithelial barrier leakiness. Moreover, the theory further introduces novel mechanisms for the pathophysiology of autoimmune diseases, chronic neuropsychiatric conditions, and metabolic diseases. Read more.