The epithelial barrier theory and its associated diseases

doi:10.1111/all.16318

Review

. 2024 Dec;79(12):3192-3237.

doi: 10.1111/all.16318. Epub 2024 Oct 7.

The epithelial barrier theory and its associated diseases

Na Sun^{1

2}, Ismail Ogulur¹, Yasutaka Mitamura¹, Duygu Yazici¹, Yagiz Pat¹, Xiangting Bu¹, Manru Li¹, Xueyi Zhu¹, Huseyn Babayev¹, Sena Ardicli^{1

3}, Ozge Ardicli^{1

4}, Paolo D'Avino¹, Ayca Kiykim^{1

5}, Milena Sokolowska¹, Willem van de Veen¹, Lukas Weidmann⁶, Deniz Akdis⁷, Banu Goker Ozdemir⁸, Marie Charlotte Brüggen^{9

10

11}, Luc Biedermann¹², Alex Straumann¹², Andrea Kreienbühl¹², Emma Guttman-Yassky¹³, Alexandra F Santos^{14

15

16}, Stefano Del Giacco¹⁷, Claudia Traidl-Hoffmann¹⁸, David J Jackson^{19

20}, De-Yun Wang²¹, Antti Lauerma²², Heimo Breiteneder²³, Luo Zhang^{24

25}, Liam O'Mahony^{26

27}, Oliver Pfaar²⁸, Robyn O'Hehir^{29

30}, Thomas Eiwegger^{31

32

33

34}, Wytske J Fokkens³⁵, Beatriz Cabanillas³⁶, Cevdet Ozdemir^{37

38}, Walter Kistler^{39

40

41}, Mahmut Bayik⁴², Kari C Nadeau⁴³, Maria J Torres⁴⁴, Mübeccel Akdis¹, Marek Jutel⁴⁵, Ioana Agache⁴⁶, Cezmi A Akdis¹

Affiliations

¹ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
² SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, P. R. China.
³ Department of Genetics, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey.
⁴ Division of Food Processing, Milk and Dairy Products Technology Program, Karacabey Vocational School, Bursa Uludag University, Bursa, Turkey.
⁵ Department of Pediatrics, Division of Pediatric Allergy and Immunology, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁶ Department of Nephrology, University Hospital Zurich, Zurich, Switzerland.
⁷ Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
⁸ Obstetrician and Gynecologist, Nisantasi, Istanbul, Turkey.
⁹ Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
¹⁰ Faculty of Medicine, University of Zurich, Zurich, Switzerland.
¹¹ Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
¹² Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
¹³ Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Women and Children's Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
¹⁵ Children's Allergy Service, Evelina London Children's Hospital, Guy's and St. Thomas' Hospital, London, UK.
¹⁶ Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.
¹⁷ Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
¹⁸ Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
¹⁹ Guy's Severe Asthma Centre, Guy's Hospital, Guy's & St Thomas' NHS Trust, London, UK.
²⁰ School of Immunology & Microbial Sciences, King's College London, London, UK.
²¹ Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore City, Singapore.
²² Department of Dermatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²³ Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
²⁴ Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
²⁵ Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.
²⁶ Department of Medicine and School of Microbiology, University College Cork, Cork, Ireland.
²⁷ APC Microbiome Ireland, Cork, Ireland.
²⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany.
²⁹ Allergy, Asthma & Clinical Immunology, The Alfred Hospital, Melbourne, Victoria, Australia.
³⁰ Department of Immunology, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
³¹ Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
³² Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
³³ Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
³⁴ Department of Pediatric and Adolescent Medicine, University Hospital St. Pölten, St. Pölten, Austria.
³⁵ Department of Otorhinolaryngology & Head and Neck Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³⁶ Department of Allergy, Instituto de Investigación Biosanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.
³⁷ Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Turkey.
³⁸ Istanbul Faculty of Medicine, Department of Pediatrics, Division of Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey.
³⁹ Department of Sports Medicine, Davos Hospital, Davos, Switzerland.
⁴⁰ Swiss Research Institute for Sports Medicine (SRISM), Davos, Switzerland.
⁴¹ Medical Committee International Ice Hockey Federation (IIHF), Zurich, Switzerland.
⁴² Department of Internal Medicine and Hematology, Marmara University, Istanbul, Turkey.
⁴³ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴⁴ Allergy Unit, IBIMA-Hospital Regional Universitario de Málaga-ARADyAL, UMA, Málaga, Spain.
⁴⁵ Department of Clinical Immunology, Wrocław Medical University, Wroclaw, Poland.
⁴⁶ Faculty of Medicine, Department of Allergy and Clinical Immunology, Transylvania University, Brasov, Romania.

PMID: 39370939
PMCID: PMC11657050
DOI: 10.1111/all.16318

Review

The epithelial barrier theory and its associated diseases

Na Sun et al. Allergy. 2024 Dec.

. 2024 Dec;79(12):3192-3237.

doi: 10.1111/all.16318. Epub 2024 Oct 7.

Authors

Affiliations

¹ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
² SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, P. R. China.
³ Department of Genetics, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey.
⁴ Division of Food Processing, Milk and Dairy Products Technology Program, Karacabey Vocational School, Bursa Uludag University, Bursa, Turkey.
⁵ Department of Pediatrics, Division of Pediatric Allergy and Immunology, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁶ Department of Nephrology, University Hospital Zurich, Zurich, Switzerland.
⁷ Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
⁸ Obstetrician and Gynecologist, Nisantasi, Istanbul, Turkey.
⁹ Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
¹⁰ Faculty of Medicine, University of Zurich, Zurich, Switzerland.
¹¹ Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
¹² Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
¹³ Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Women and Children's Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
¹⁵ Children's Allergy Service, Evelina London Children's Hospital, Guy's and St. Thomas' Hospital, London, UK.
¹⁶ Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.
¹⁷ Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
¹⁸ Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
¹⁹ Guy's Severe Asthma Centre, Guy's Hospital, Guy's & St Thomas' NHS Trust, London, UK.
²⁰ School of Immunology & Microbial Sciences, King's College London, London, UK.
²¹ Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore City, Singapore.
²² Department of Dermatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
²³ Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
²⁴ Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
²⁵ Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.
²⁶ Department of Medicine and School of Microbiology, University College Cork, Cork, Ireland.
²⁷ APC Microbiome Ireland, Cork, Ireland.
²⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany.
²⁹ Allergy, Asthma & Clinical Immunology, The Alfred Hospital, Melbourne, Victoria, Australia.
³⁰ Department of Immunology, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
³¹ Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
³² Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
³³ Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
³⁴ Department of Pediatric and Adolescent Medicine, University Hospital St. Pölten, St. Pölten, Austria.
³⁵ Department of Otorhinolaryngology & Head and Neck Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³⁶ Department of Allergy, Instituto de Investigación Biosanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.
³⁷ Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Turkey.
³⁸ Istanbul Faculty of Medicine, Department of Pediatrics, Division of Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey.
³⁹ Department of Sports Medicine, Davos Hospital, Davos, Switzerland.
⁴⁰ Swiss Research Institute for Sports Medicine (SRISM), Davos, Switzerland.
⁴¹ Medical Committee International Ice Hockey Federation (IIHF), Zurich, Switzerland.
⁴² Department of Internal Medicine and Hematology, Marmara University, Istanbul, Turkey.
⁴³ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴⁴ Allergy Unit, IBIMA-Hospital Regional Universitario de Málaga-ARADyAL, UMA, Málaga, Spain.
⁴⁵ Department of Clinical Immunology, Wrocław Medical University, Wroclaw, Poland.
⁴⁶ Faculty of Medicine, Department of Allergy and Clinical Immunology, Transylvania University, Brasov, Romania.

PMID: 39370939
PMCID: PMC11657050
DOI: 10.1111/all.16318

Abstract

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation.

Keywords: epidemiology; epithelial barrier; epithelial barrier dysfunction; inflammation; microbial dysbiosis.

PubMed Disclaimer

Conflict of interest statement

M.S. has received research grants from the Swiss National Science Foundation (SNSF no.: 310030_189334/1), GSK, Novartis, Stiftung vorm. Bündner Heilstätte Arosa and OM Pharma as well as speaker's fee from AstraZeneca. W.V. has received research grants from PROMEDICA Stiftung, Switzerland, and EoE Stiftung, Switzerland, and consulting fees form Mabylon AG, Switzerland. M.C.B. reports grants from the Swiss National Science Foundation, Christine Kühne‐Center for Allergy Research and Education, Leo Foundation, LEO Pharmacy, and Freenovation, advisory board fees from AstraZeneca, Almirall, LEO Pharma, lecture honorarium from Almirall and AstraZeneca, and patient education grant from AstraZeneca and GSK. A.S. has currently consultant contracts with Astra‐Seneca, BMS‐Receptos, Calypso, EsoCap, Falk‐Pharma, GSK, and Sanofi‐Regeneron. E.G.Y. is an employee of Mount Sinai and has received research grants from and/or is a consultant for: Research Grants (paid to the institution): Boehringer Ingelheim, Leo Pharma, Pfizer, Cara Therapeutics, UCB, Kyowa Kirin, RAPT, Amgen, GSK, Incyte, Sanofi, Bristol Meyers Squibb, Aslan, Regeneron, Anaptysbio, Concert, Janssen. Consultant: Abbvie, Aclaris, Almirall, Amgen, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics Limited, Artax Biopharma Inc., AstraZeneca, Bristol Meyers Squibb, Boerhinger‐Ingelhiem, Cara Therapeutics, Centrexion Therapeutics Corporation, Connect Biopharm, DBV TECHNOLOGIES, Eli Lilly, Enveda Biosciences, Escient Pharmaceuticals, Inc., Fairmount Funds Management LLC, Forest Laboratories Galderma, Gate Bio, Google Ventures (GV), GSK Immunology, Horizon Therapeutics USA, Inc., Incyte, Inmagene, Janssen Biotech, JT Central Pharmaceutical Research Institute, Jasper Therapeutics, Kyowa Kirin, Leo Pharma, Merck, Nektar Therapeutics, Novartis Pharmaceuticals Corporation, NUMAB Therapeutics AG, OrbiMed Advisors LLC, OTSUKA, Pfizer, Pharmaxis Ltd, Pioneering Medicine VII, Inc., Proteologix US Inc, RAPT, Regeneron Pharmaceuticals, RibonTherapeutics, Inc., Sanofi, SATO, Schrödinger Inc., Sun Pharma Advanced Research Company (SPARC), Teva Branded Pharmaceutical Products R&D, UCB. A.F.S. reports grants from the Medical Research Council (MR/M008517/1; MC/PC/18052; MR/T032081/1), Food Allergy Research and Education (FARE), the Immune Tolerance Network/National Institute of Allergy and Infectious Diseases (NIAID, NIH), Asthma UK (AUK‐BC‐2015‐01), BBSRC, Rosetrees Trust and the NIHR through the Biomedical Research Centre (BRC) award to Guy's and St Thomas' NHS Foundation Trust, during the conduct of the study; personal fees from Thermo Scientific, Nestle, Novartis, Allergy Therapeutics, IgGenix, Buhlmann, as well as research support from IgGenix, Buhlmann, and Thermo Fisher Scientific through a collaboration agreement with King's College London. S.D.G. reports speaker fees from AstraZeneca, Chiesi, GSK, Novartis, Sanofi, Stallergenes and Takeda; advisory board fees from AstraZeneca, Chiesi, CSL‐Behring, GSK, Novartis, Sanofi, Takeda; unrestricted research grants from AstraZeneca, CSL‐Behring, GSK, Novartis, and Sanofi. O.P. reports grants and/or personal fees and/or travel support from ALK‐Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Laboratorios LETI/LETI Pharma, GlaxoSmithKline, ROXALL Medizin, Novartis, Sanofi‐Aventis and Sanofi‐Genzyme, Med Update Europe GmbH, streamedup! GmbH, Pohl‐Boskamp, Inmunotek S.L., John Wiley and Sons/AS, Paul‐Martini‐Stiftung (PMS), Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Institut für Disease Management, Springer GmbH, AstraZeneca, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Procter&Gamble, ALTAMIRA, Meinhardt Congress GmbH, Deutsche Forschungsgemeinschaft, Thieme, Deutsche AllergieLiga e.V., AeDA, Alfried‐Krupp Krankenhaus, Red Maple Trials Inc., Königlich Dänisches Generalkonsulat, Medizinische Hochschule Hannover, ECM Expro&Conference Management, Technical University Dresden, Lilly, Japanese Society of Allergy, Forum für Medizinische Fortbildung, Dustri‐Verlag, Pneumolive, ASIT Biotech, LOFARMA, Almirall, Paul‐Ehrlich‐Institut, outside the submitted work, and he is member of EAACI Excom, member of ext. board of directors DGAKI; coordinator, main‐ or co‐author of different position papers and guidelines in rhinology, allergology and allergen‐immunotherapy; he is associate editor (AE) of Allergy and Clinical Translational Allergy. T.E. reports personal fees from Danone/Nutricia/Milupa, grants from DBV, non‐financial support from Novartis, personal fees from Thermo Fisher, personal fees from Aimmune, grants and personal fees from ALK, non‐financial support from MADX, personal fees from EFSA, outside the submitted work, and I am the Co‐I or scientific lead in three investigator‐initiated oral immunotherapy trials supported by the Food Allergy and Anaphylaxis Program Sickkids and serve as associate editor for Allergy. Site PI of company sponsored trials by DBV, Novartis, and Stallergen. C.O. is Assistant Editor of Allergy, EAACI Allied Health & Primary Care Section chair. K.N. currently reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS); Stock options from IgGenix, Seed Health, ClostraBio, Cour, Alladapt; Consultant for Excellergy, Red tree ventures, Regeneron, and IgGenix; Co‐founder of Alladapt, Latitude, and IgGenix; National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers; patents include, “Mixed allergen com‐position and methods for using the same,” “Granulocyte‐based methods for detecting and monitoring immune system disorders,” and “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders.” M.A. has received research grants from the Swiss National Science Foundation, Bern; research grant from the Stanford University; Leading House for the Latin American Region, Seed Money Grant. She is in the Scientific Advisory Board member of Stanford University Sean Parker Asthma Allergy Center, CA; Advisory Board member of LEO Foundation Skin Immunology Research Center, Copenhagen; and Scientific Co‐Chair of World Allergy Congress (WAC) Istanbul, 2022, Scientific Programme Committee Chair, EAACI. M.J. reports personal fees outside of submitted work from Allergopharma, ALK‐Abello, Stallergenes, Anergis, Allergy Therapeutics, Leti, HAL, GSK, Novartis, Teva, Takeda, Chiesi, Pfizer, Regeneron, Astra‐Zeneka, Lallemand, Shire, Celltrion Inc., Genentech, Roche, Verona, Lek Pharmaceuticals, Arcutis Biotherapeutics and FAES FARMA. I.A. reports Deputy Editor of Allergy journal. C.A.A. has received research grants from the Swiss National Science Foundation, European Union (EU CURE, EU Syn‐Air‐G), Novartis Research Institutes (Basel, Switzerland), Stanford University (Redwood City, Calif), Seed Health (Boston, USA) and SciBase (Stockholm, Sweden); is the Co‐Chair for EAACI Guidelines on Environmental Science in Allergic diseases and Asthma; Chair of the EAACI Epithelial Cell Biology Working Group is on the Advisory Boards of Sanofi/Regeneron (Bern, Switzerland, New York, USA), Stanford University Sean Parker Asthma Allergy Center (CA, USA), Novartis (Basel, Switzerland), Glaxo Smith Kline (Zurich, Switzerland), Bristol‐Myers Squibb (New York, USA), Seed Health (Boston, USA), and SciBase (Stockholm, Sweden); and is the Editor‐in‐Chief of Allergy. N.S., I.O., Y.M., D.Y., Y.P., X.B., M.L., X.Z., H.B., S.A., O.A., P.D., A.K., L.W., D.A., B.G.O. L.B., A.K., C.T.H., D.J.J., D.Y.W., A.L., H.B., L.Z., L.O.M., R.O.H., W.J.F., B.C., K.W., M.B., and M.J.T declare no relevant conflict of interest. N.S. reports grants from CSC scholarship program of China (No. 202008210164). D.A. reports grants and personal fees, outside the submitted work, from the Swiss National Science Foundation, the Swiss Heart Foundation and Boehringer Ingelheim. L.B. reports advisory from Abbvie, Amgen, BMS, Falk, Janssen, Pfizer, Lilly, Takeda, Sanofi, Esocap, and speaker fees from Takeda, Sanofi, Abbvie, Lilly, Falk, BMS and Pfizer. D.J.J. has received speaker fees and consultancy fees from AZ, GSK and Sanofi. L.O.M. is a consultant to PrecisionBiotics and has received research funding from GSK, Chiesi, Reckitt and Fonterra. He has participated in speaker's bureau for Nestle, Nutricia, Reckitt and Abbott.

Figures

**FIGURE 1**
Exposure to allergens, chemical pollutants, toxic substances, and nanoparticles causes epithelial damage, microbial dysbiosis, and inflammation. The resulting epithelial damage and microbial translocation across epithelial barriers increase the production of alarmins and multiple chemokines, altering the activation thresholds of resident immune cells and leading to cell migration. This cascade results in an inflammatory state, contributing to chronic inflammatory diseases.

**FIGURE 2**
Defects in epithelial barrier function with different allergens and environmental toxic substances are required to initiate epithelial immune responses. The secretion of alarmins IL‐25, IL‐33, and TSLP leads to the development of type 2 inflammation, which is characterized by the presence of ILC2s, Th2 cells, B cells, eosinophils (EOS), neutrophils, and mast cells (MC). ILC2s and Th2 cells secrete IL‐4, IL‐5, IL‐9, and IL‐13 that induce an inflammatory immune response.

**FIGURE 3**
Exposome and/or risk factors in contact with neuropsychiatric diseases, airway diseases, skin diseases, and digestive tract diseases.

See this image and copyright information in PMC

Cited by

Interleukin-4 and Atopic Dermatitis: Why Does it Matter? A Narrative Review.
Torres T, Mendes-Bastos P, Cruz MJ, Duarte B, Filipe P, Lopes MJP, Gonçalo M. Torres T, et al. Dermatol Ther (Heidelb). 2025 Mar;15(3):579-597. doi: 10.1007/s13555-025-01352-y. Epub 2025 Feb 10. Dermatol Ther (Heidelb). 2025. PMID: 39930311 Free PMC article. Review.
Epigenetic changes and serotype-specific responses of alveolar type II epithelial cells to Streptococcus pneumoniae in resolving influenza A virus infection.
Boehme JD, Jeron A, Schultz K, Melcher L, Schott K, Gelmez E, Kröger A, Stegemann-Koniszewski S, Bruder D. Boehme JD, et al. Cell Commun Signal. 2025 Jun 12;23(1):278. doi: 10.1186/s12964-025-02284-y. Cell Commun Signal. 2025. PMID: 40506708 Free PMC article.
Aerosol Measurements and Decadal Changes: The Role of Climatic Changes and How It Reflects in Respiratory Allergies and Asthma.
Kazadzis S, Fountoulakis I, Damialis A, Masoom A, Papachristopoulou K, Gilles S, Coen MC, Tummon F, Crouzy B, Clot B, Pat Y, Brüggen MC, Nyeki S, Raptis IP, Solomos S, Gkikas A, Moustaka A, Kouremeti N, Akdis CA. Kazadzis S, et al. Allergy. 2025 Jun;80(6):1613-1628. doi: 10.1111/all.16602. Epub 2025 May 31. Allergy. 2025. PMID: 40448467 Free PMC article. Review.
T1-T2 Interplay in the Complex Immune Landscape of Severe Asthma.
Gauthier M, Kale SL, Ray A. Gauthier M, et al. Immunol Rev. 2025 Mar;330(1):e70011. doi: 10.1111/imr.70011. Immunol Rev. 2025. PMID: 39991821 Free PMC article. Review.
Skin Barrier Dysfunction in Chronic Dermatoses: From Pathophysiology to Emerging Therapeutic Strategies.
Espinoza Urzua I, Vidal Vidal MI, Vega Solano M, Bedoya Jaramillo JE, de la Cruz Donis GG, Valverde AR. Espinoza Urzua I, et al. Cureus. 2025 Jun 28;17(6):e86937. doi: 10.7759/cureus.86937. eCollection 2025 Jun. Cureus. 2025. PMID: 40734872 Free PMC article. Review.

See all "Cited by" articles

References

1. Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol. 2021;21(11):739‐751. - PubMed
1. D'Amato G, Akdis CA. Desert dust and respiratory diseases: further insights into the epithelial barrier hypothesis. Allergy. 2022;77:3490‐3492. - PubMed
1. Akdis CA. The epithelial barrier hypothesis proposes a comprehensive understanding of the origins of allergic and other chronic noncommunicable diseases. J Allergy Clin Immunol. 2022;149(1):41‐44. - PubMed
1. Pat Y, Ogulur I, Yazici D, et al. Effect of altered human exposome on the skin and mucosal epithelial barrier integrity. Tissue Barriers. 2022;11:2133877. - PMC - PubMed
1. Sözener ZC, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol. 2020;145(6):1517‐1528. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Miscellaneous
- NCI CPTAC Assay Portal

[1] Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol. 2021;21(11):739‐751. - PubMed

[2] Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol. 2021;21(11):739‐751. - PubMed

[3] D'Amato G, Akdis CA. Desert dust and respiratory diseases: further insights into the epithelial barrier hypothesis. Allergy. 2022;77:3490‐3492. - PubMed

[4] D'Amato G, Akdis CA. Desert dust and respiratory diseases: further insights into the epithelial barrier hypothesis. Allergy. 2022;77:3490‐3492. - PubMed

[5] Akdis CA. The epithelial barrier hypothesis proposes a comprehensive understanding of the origins of allergic and other chronic noncommunicable diseases. J Allergy Clin Immunol. 2022;149(1):41‐44. - PubMed

[6] Akdis CA. The epithelial barrier hypothesis proposes a comprehensive understanding of the origins of allergic and other chronic noncommunicable diseases. J Allergy Clin Immunol. 2022;149(1):41‐44. - PubMed

[7] Pat Y, Ogulur I, Yazici D, et al. Effect of altered human exposome on the skin and mucosal epithelial barrier integrity. Tissue Barriers. 2022;11:2133877. - PMC - PubMed

[8] Pat Y, Ogulur I, Yazici D, et al. Effect of altered human exposome on the skin and mucosal epithelial barrier integrity. Tissue Barriers. 2022;11:2133877. - PMC - PubMed

[9] Sözener ZC, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol. 2020;145(6):1517‐1528. - PubMed

[10] Sözener ZC, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol. 2020;145(6):1517‐1528. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The epithelial barrier theory and its associated diseases

Affiliations

The epithelial barrier theory and its associated diseases

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Miscellaneous

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Related information

LinkOut - more resources

Full Text Sources

Miscellaneous