Cutaneous barrier dysfunction in allergic diseases
2020; Elsevier BV; Volume: 145; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2020.02.021
ISSN1097-6825
AutoresDonald Y.M. Leung, Evgeny Berdyshev, Elena Goleva,
Tópico(s)Urticaria and Related Conditions
ResumoThe fundamental defect(s) that drives atopic dermatitis (AD) remains controversial. “Outside in” proponents point to the important association of filaggrin gene mutations and other skin barrier defects with AD. The “inside out” proponents derive support from evidence that AD occurs in genetic animal models with overexpression of type 2 immune pathways in their skin, and humans with gain-of-function mutations in their type 2 response develop severe AD. The observation that therapeutic biologics, targeting type 2 immune responses, can reverse AD provides compelling support for the importance of “inside out” mechanisms of AD. In this review, we propose a central role for epithelial cell dysfunction that accounts for the dual role of skin barrier defects and immune pathway activation in AD. The complexity of AD has its roots in the dysfunction of the epithelial barrier that allows the penetration of allergens, irritants, and microbes into a cutaneous milieu that facilitates the induction of type 2 immune responses. The AD phenotypes and endotypes that result in chronic skin inflammation and barrier dysfunction are modified by genes, innate/adaptive immune responses, and different environmental factors that cause skin barrier dysfunction. There is also compelling evidence that skin barrier dysfunction can alter the course of childhood asthma, food allergy, and allergic rhinosinusitis. Effective management of AD requires a multipronged approach, not only restoring cutaneous barrier function, microbial flora, and immune homeostasis but also enhancing skin epithelial differentiation. The fundamental defect(s) that drives atopic dermatitis (AD) remains controversial. “Outside in” proponents point to the important association of filaggrin gene mutations and other skin barrier defects with AD. The “inside out” proponents derive support from evidence that AD occurs in genetic animal models with overexpression of type 2 immune pathways in their skin, and humans with gain-of-function mutations in their type 2 response develop severe AD. The observation that therapeutic biologics, targeting type 2 immune responses, can reverse AD provides compelling support for the importance of “inside out” mechanisms of AD. In this review, we propose a central role for epithelial cell dysfunction that accounts for the dual role of skin barrier defects and immune pathway activation in AD. The complexity of AD has its roots in the dysfunction of the epithelial barrier that allows the penetration of allergens, irritants, and microbes into a cutaneous milieu that facilitates the induction of type 2 immune responses. The AD phenotypes and endotypes that result in chronic skin inflammation and barrier dysfunction are modified by genes, innate/adaptive immune responses, and different environmental factors that cause skin barrier dysfunction. There is also compelling evidence that skin barrier dysfunction can alter the course of childhood asthma, food allergy, and allergic rhinosinusitis. Effective management of AD requires a multipronged approach, not only restoring cutaneous barrier function, microbial flora, and immune homeostasis but also enhancing skin epithelial differentiation. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: June 2020. Credit may be obtained for these courses until May 31, 2021.Copyright Statement: Copyright © 2020-2021. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Donald Y. M. Leung, MD, PhD, Evgeny Berdyshev, PhD, and Elena Goleva, PhD (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: D. Y. M. Leung receives National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH) funding from the Atopic Dermatitis Research Network, the NIAID/Consortium for Food Allergy Research, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH and has also consulted for Boehringer-Ingelheim, Janssen Biotech, Regeneron, Sanofi-Genzyme, Genentech, and Incyte. The rest of the authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1.To identify gene mutations central to development of atopic dermatitis (AD).2.To recognize abnormalities in cytokine and barrier protein expression in AD patients.3.To identify structural differences between patients with and without AD.4.To understand differences in microbiota in patients with and without AD.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Sylwia Nowak, MD, Anuja Kapil, MD, and James Moy, MD, FAAAAI.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The examination authors declare no relevant conflicts of interest. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: June 2020. Credit may be obtained for these courses until May 31, 2021. Copyright Statement: Copyright © 2020-2021. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Donald Y. M. Leung, MD, PhD, Evgeny Berdyshev, PhD, and Elena Goleva, PhD (authors); Zuhair K. Ballas, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: D. Y. M. Leung receives National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH) funding from the Atopic Dermatitis Research Network, the NIAID/Consortium for Food Allergy Research, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH and has also consulted for Boehringer-Ingelheim, Janssen Biotech, Regeneron, Sanofi-Genzyme, Genentech, and Incyte. The rest of the authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships. Activity Objectives:1.To identify gene mutations central to development of atopic dermatitis (AD).2.To recognize abnormalities in cytokine and barrier protein expression in AD patients.3.To identify structural differences between patients with and without AD.4.To understand differences in microbiota in patients with and without AD. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Sylwia Nowak, MD, Anuja Kapil, MD, and James Moy, MD, FAAAAI. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The examination authors declare no relevant conflicts of interest. Allergic diseases such as atopic dermatitis (AD), food allergy (FA), and asthma affect more than 30% of the general population.1Martin P.E. Koplin J.J. Eckert J.K. Lowe A.J. Ponsonby A.L. Osborne N.J. et al.The prevalence and socio-demographic risk factors of clinical eczema in infancy: a population-based observational study.Clin Exp Allergy. 2013; 43: 642-651PubMed Google Scholar, 2Holgate S.T. Wenzel S. Postma D.S. Weiss S.T. Renz H. Sly P.D. Asthma.Nat Rev Dis Primers. 2015; 1: 15025Crossref PubMed Google Scholar, 3Peters R.L. Koplin J.J. Gurrin L.C. Dharmage S.C. Wake M. Ponsonby A.L. et al.The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: HealthNuts age 4-year follow-up.J Allergy Clin Immunol. 2017; 140: 145-153Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar These diseases have significant health and socioeconomic effects. Allergic diseases are well documented to be associated with epithelial barrier dysfunction, allowing tissue penetration of allergens, irritants, and microbes. These then lead to the release of epithelial cytokines such as thymic stromal lymphopoietin (TSLP) and IL-33, which play a pivotal role in driving type 2 immune and inflammatory responses.4Walker M.T. Green J.E. Ferrie R.P. Queener A.M. Kaplan M.H. Cook-Mills J.M. Mechanism for initiation of food allergy: dependence on skin barrier mutations and environmental allergen costimulation.J Allergy Clin Immunol. 2018; 141: 1711-1725Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar,5Kennedy K. Heimall J. Spergel J.M. Advances in atopic dermatitis in 2017.J Allergy Clin Immunol. 2018; 142: 1740-1747Abstract Full Text Full Text PDF PubMed Google Scholar Although cytokines such as IFN-γ, IL-17, and IL-22 can modify the course of allergic responses, type 2 cytokines such as IL-4, IL-13, TSLP, and IL-33 play a central role in the development of allergic diseases.6Renert-Yuval Y. Guttman-Yassky E. New treatments for atopic dermatitis targeting beyond IL-4/IL-13 cytokines.Ann Allergy Asthma Immunol. 2020; 124: 28-35Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,7Brunner P.M. Israel A. Zhang N. Leonard A. Wen H.C. Huynh T. et al.Early-onset pediatric atopic dermatitis is characterized by TH2/TH17/TH22-centered inflammation and lipid alterations.J Allergy Clin Immunol. 2018; 141: 2094-2106Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar AD, in particular, is the most atopic of all allergic diseases as environmental antigens and foods, processed in the skin, elicit an IgE response. Childhood onset of AD is often associated with FA, asthma, and allergic rhinitis, that is, the atopic march.8Davidson W.F. Leung D.Y.M. Beck L.A. Berin C.M. Boguniewicz M. Busse W.W. et al.Report from the National Institute of Allergy and Infectious Diseases workshop on “Atopic dermatitis and the atopic march: Mechanisms and interventions.”.J Allergy Clin Immunol. 2019; 143: 894-913Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The skin barrier dysfunction in AD is thought to play a key role in the atopic march. It starts with AD, followed by epicutaneous allergen sensitization and FA. The link from AD to respiratory allergy is more controversial; however, progression of the atopic march is facilitated in patients who develop IgE to foods and inhalant allergens,9Tran M.M. Lefebvre D.L. Dharma C. Dai D. Lou W.Y.W. Subbarao et al.Predicting the atopic march: results from the Canadian Healthy Infant Longitudinal Development study.J Allergy Clin Immunol. 2018; 141: 601-607Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and is strongly associated with filaggrin (FLG) loss-of-function gene mutations. Childhood asthma onset-specific gene loci have identified the skin as an important target tissue.10Pividori M. Schoettler N. Nicolae D.L. Ober C. Im H.K. Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies.Lancet Respir Med. 2019; 7: 509-522Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Severity, age of onset, and duration of AD are risk factors for the atopic march.11Martin P.E. Eckert J.K. Koplin J.J. Lowe A.J. Gurrin L.C. Dharmage S.C. et al.Which infants with eczema are at risk of food allergy? Results from a population-based cohort.Clin Exp Allergy. 2015; 45: 255-264Crossref PubMed Scopus (120) Google Scholar,12Hill D.A. Spergel J.M. The atopic march: critical evidence and clinical relevance.Ann Allergy Asthma Immunol. 2018; 120: 131-137Abstract Full Text Full Text PDF PubMed Google Scholar In this review, we will discuss the role of cutaneous barrier dysfunction in the pathogenesis of AD, particularly the relationship of AD with FA. The relative importance of these individual abnormalities can be teased out using animal models and therapeutic interventions; however, in most patients, the progression of AD requires both the skin barrier defect and immune pathway activation. For a discussion of the contributions of an excessive type 2 innate and acquired immune response in AD, the reader is referred to a recent review by Honda and Kabashima.13Honda T, Kabashima K. Reconciling innate and acquired immunity in atopic dermatitis [published online ahead of print February 25, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.02.008.Google Scholar We propose that the dualistic role of skin barrier and immune abnormalities has its roots in the lack of terminal keratinocyte differentiation in the skin and propose that durable therapeutic approaches require combination therapy to target both the defective skin barrier and type 2 immune activation in AD. This has important clinical implications for new approaches to controlling AD and progression of the atopic march. Skin barrier dysfunction is the hallmark of AD. A strong skin barrier in healthy individuals is needed to repel the invasion of microbes, allergens, and irritants from the environment, thereby preventing engagement of the type 2–enhancing immune pathway that occurs in the skin. In a birth cohort study, increased transepidermal water loss (TEWL) at day 2 of life occurred 1 year before the onset of AD and FA.14Kelleher M. Dunn-Galvin A. Hourihane J.O. Murray D. Campbell L.E. McLean W.H. et al.Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year.J Allergy Clin Immunol. 2015; 135: 930-935Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar,15Kelleher M.M. Dunn-Galvin A. Gray C. Murray D.M. Kiely M. Kenny L. et al.Skin barrier impairment at birth predicts food allergy at 2 years of age.J Allergy Clin Immunol. 2016; 137: 1111-1116Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Because increased TEWL is a biomarker of skin barrier dysfunction, this study suggests that early intervention is required to prevent epicutaneous allergen sensitization. Increased TSLP has also been found in the skin before the onset of AD, suggesting that prevention of the atopic march also requires intervention with type 2 pathways.16Kim J. Kim B.E. Lee J. Han Y. Jun H.Y. Kim H. et al.Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy.J Allergy Clin Immunol. 2016; 137: 1282-1285Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Loss-of-function FLG gene mutations are the strongest known genetic risk factor for AD17Irvine A.D. McLean W.H. Leung D.Y. Filaggrin mutations associated with skin and allergic diseases.N Engl J Med. 2011; 365: 1315-1327Crossref PubMed Scopus (640) Google Scholar (Fig 1). The presence of FLG mutations increases AD risk more than 3-fold compared with the general population. It is also a disease modifier predisposing to earlier AD onset, persistence of AD, and increased disease severity. There are ethnic differences in the types of FLG mutations found in AD. FLG mutations are particularly common in northern Europeans, with R501X and 2282del4 as the major FLG mutations. In Asian populations, FLG P478S and C3321delA variants, not commonly found in European populations, are associated with increased risk of AD.18Drislane C. Irvine A.D. The role of filaggrin in atopic dermatitis and allergic disease.Ann Allergy Asthma Immunol. 2020; 124: 36-43Abstract Full Text Full Text PDF PubMed Google Scholar In black children, loss-of-function mutations in FLG2 are associated with increased AD risk. Several novel FLG gene mutations, not commonly seen in European Americans, were recently described in blacks with AD. Mouse models have demonstrated that FLG gene mutations are associated with enhanced percutaneous microbial and allergen penetration and reduced inflammatory thresholds to irritants and haptens.19Scharschmidt T.C. Man M.Q. Hatano Y. Crumrine D. Gunathilake R. Sundberg J.P. et al.Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.J Allergy Clin Immunol. 2009; 124: 496-506Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,20Fallon P.G. Sasaki T. Sandilands A. Campbell L.E. Saunders S.P. Mangan N.E. et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming.Nat Genet. 2009; 41: 602-608Crossref PubMed Scopus (337) Google Scholar Knockdown of FLG expression has been shown to impair keratinocyte differentiation of human keratinocyte organotypic cultures.21Pendaries V. Malaisse J. Pellerin L. Le Lamer M. Nachat R. Kezic S. et al.Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation.J Invest Dermatol. 2014; 134: 2938-2946Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Epithelial damage leads to innate immune activation, including release of proinflammatory cytokines and chemokines by keratinocytes,22Kezic S. O’Regan G.M. Lutter R. Jakasa I. Koster E.S. Saunders S. et al.Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.J Allergy Clin Immunol. 2012; 129: 1031-1039Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar and enhanced antigen presentation by Langerhans cells and dermal dendritic cells.23Yoshida K. Kubo A. Fujita H. Yokouchi M. Ishii K. Kawasaki H. et al.Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 856-864Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Reduced levels of acidic FLG breakdown products raise skin pH and activate skin proteases,24Elias P.M. Wakefield J.S. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 781-791Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 25Vávrová K. Henkes D. Strüver K. Sochorová M. Školová B. Witting M.Y. et al.Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct.J Invest Dermatol. 2014; 134: 746-753Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 26Hachem J.P. Man M.Q. Crumrine D. Uchida Y. Brown B.E. 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For example, type 2–mediated cutaneous inflammation can result in reduced FLG expression in AD skin, even in subjects without FLG mutations.28Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. Debenedetto A. et al.Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2007; 120: 150-155Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar The combination of type 2 cytokines with heterozygote FLG gene mutations can profoundly reduce FLG to almost undetectable levels. Reduced FLG intragenic copy number is an independent risk factor of AD.29Brown S.J. Kroboth K. Sandilands A. Campbell L.E. Pohler E. Kezic S. et al.Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect.J Invest Dermatol. 2012; 132: 98-104Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar DNA methylation of the CpG site in the FLG gene region has also been reported to significantly increase AD risk.30Ziyab A.H. Karmaus W. Holloway J.W. Zhang H. Ewart S. Arshad S.H. DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants.J Eur Acad Dermatol Venereol. 2013; 27: e420-e423Crossref PubMed Scopus (0) Google Scholar The FLG gene is only 1 of approximately 45 genes within the epidermal differentiation complex on chromosome 1q21. Many of these genes, including involucrin and loricrin, may also contribute to AD cutaneous barrier dysfunction. The levels of hornerin and other FLG-like proteins, including FLG2, are also decreased in the skin of patients with AD,31Pellerin L. Henry J. Hsu C.Y. 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Asadullah K. et al.IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis.Eur J Immunol. 2006; 36: 1309-1323Crossref PubMed Scopus (670) Google Scholar; however, in contrast to type 2 cytokines, it does not inhibit keratinocyte antimicrobial peptide production.34Nograles K.E. Zaba L.C. Guttman-Yassky E. Fuentes-Duculan J. Suárez-Fariñas M. Cardinale I. et al.Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.Br J Dermatol. 2008; 159: 1092-1102PubMed Google Scholar Other proinflammatory cytokines, such as TNF-α,35Kim B.E. Howell M.D. Guttman-Yassky E. Gilleaudeau P.M. Cardinale I.R. 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Boguniewicz M. et al.Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis.J Allergy Clin Immunol. 2011; 128: 242-246Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Knockdown of CLDN1 expression in keratinocytes enhances HSV-1 infectivity. S100A7, S100A8, and S100S9 proteins are upregulated in AD skin.44Jin S. Park C.O. Shin J.U. Noh J.Y. Lee Y.S. Lee N.R. et al.DAMP molecules S100A9 and S100A8 activated by IL-17A and house-dust mites are increased in atopic dermatitis.Exp Dermatol. 2014; 23: 938-941Crossref PubMed Scopus (0) Google Scholar,45Gittler J.K. Shemer A. Suárez-Fariñas M. Fuentes-Duculan J. Gulewicz K.J. Wang C.Q. et al.Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.J Allergy Clin Immunol. 2012; 130: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar These proteins act as amplifiers of the immune response. As an example, S100A9-activated keratinocytes cause a selective increase in IL-33 production. TH2 cytokines inhibit S100A11 protein expression, which is required for the regulation of skin barrier integrity.46Howell M.D. Fairchild H.R. Kim B.E. Bin L. Boguniewicz M. Redzic J.S. et al.Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation.J Invest Dermatol. 2008; 128: 2248-2258Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Evolving research suggests that keratinocyte
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