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Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?

Abstract

There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a ‘leaky gut’ and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended ‘epithelial barrier hypothesis’, which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases.

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Fig. 1: Exposure to barrier-damaging agents or genetic deficiency in barrier molecules cause the colonization of opportunistic pathogens and epithelial inflammation.
Fig. 2: Immune cells activated in the leaky gut or lung can migrate and contribute to inflammation in distant organs.

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Acknowledgements

The laboratory of the author has been supported by Swiss National Science Foundation Grants, Christine Kühne-Center for Allergy Research and Education (CK-CARE) and EU Grants, Medall, Predicta and CURE. I sincerely thank Mübeccel Akdis and Laura Alberch for critical reading of the manuscript and Anna Globinska for the figures.

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Correspondence to Cezmi A. Akdis.

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C.A.A. received research grants from the Swiss National Science Foundation, European Union FP7, Mechanisms of Allergy Development (MedAll), FP7 Viral infections and Allergy Development (Predicta), Horizon 2020, Constructing a ‘Eubiosis Reinstatement Therapy’ for Asthma (CURE) and Christine Kühne-Center for Allergy Research and Education to perform research on epithelial barriers and the microbiome.

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Glossary

Type 2 inflammatory diseases

Allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, chronic sinusitis with nasal polyps and helminth infections, which are characterized by type 2 immune responses.

Microbial dysbiosis

Microbial imbalance due to the gain or loss of microbial species and changes in the relative abundance.

Microinflammation

Describes a cell or a tissue that shows upregulated pro-inflammatory proteins detected by molecular analyses methods without systemic signs of inflammation.

Type 2 responses

Eosinophilic immune responses with a dominance of T helper 2 cells, type 2 innate lymphoid cells and cytokines such as IL-4, IL-5 and IL-13. These mainly take place in allergies and anti-helminth responses.

Type 1 responses

Cell-mediated immune responses, typically against intracellular bacteria and protozoa as observed in autoimmunity, delayed type hypersensitivity and tuberculosis. Typically involves CD8+ T cells and TH1 cells that produce IFNγ.

Inflammasome

Multi-protein complexes that activate caspase 1 to induce the processing of pro-IL-1β and pro-IL-18, which can induce cell death.

Type 17 responses

IL-17-dominated immune response to extracellular bacteria and fungi, observed in autoimmune diseases such as psoriasis.

Zonulin

A precursor of the haptoglobin protein, which downregulates tight junction function and reflects intestinal barrier permeability as a marker of an impaired gut barrier.

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Akdis, C.A. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?. Nat Rev Immunol 21, 739–751 (2021). https://doi.org/10.1038/s41577-021-00538-7

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