Skin barrier immunology from early life to adulthood

Our skin has a unique barrier function, which is imperative for the body’s protection against external pathogens and environmental insults. Although interacting closely and sharing many similarities with key mucosal barrier sites, such as the gut and the lung, the skin also provides protection for internal tissues and organs and has a distinct lipid and chemical composition. Skin immunity develops over time and is influenced by a multiplicity of different factors, including lifestyle, genetics, and environmental exposures. Alterations in early life skin immune and structural development may have long-term consequences for skin health. In this review, we summarize the current knowledge on cutaneous barrier and immune development from early life to adulthood, with an overview of skin physiology and immune responses. We specifically highlight the influence of the skin microenvironment and other host intrinsic, host extrinsic (e.g. skin microbiome), and environmental factors on early life cutaneous immunity. Our skin has a unique barrier function, which is imperative for the body’s protection against external pathogens and environmental insults. Although interacting closely and sharing many similarities with key mucosal barrier sites, such as the gut and the lung, the skin also provides protection for internal tissues and organs and has a distinct lipid and chemical composition. Skin immunity develops over time and is influenced by a multiplicity of different factors, including lifestyle, genetics, and environmental exposures. Alterations in early life skin immune and structural development may have long-term consequences for skin health. In this review, we summarize the current knowledge on cutaneous barrier and immune development from early life to adulthood, with an overview of skin physiology and immune responses. We specifically highlight the influence of the skin microenvironment and other host intrinsic, host extrinsic (e.g. skin microbiome), and environmental factors on early life cutaneous immunity. The skin is an active immune-rich barrier tissue, which also acts as the outermost barrier of the human body and is thus one of the first lines of defense against exogenous threats. The physical, chemical, microbial, and immune barrier components of the skin form an interactive system, which contributes to cutaneous host defense and skin homeostasis as a whole. Skin barrier immunology has been well-defined and described in the adult setting. However, limited knowledge is available on the development of skin barrier immunity in early life due to technical challenges and ethical concerns related to early life skin sampling (Box 1). Here, we provide an overview of the current knowledge on skin immune and structural development from early life to adulthood, with a focus on the timing of immune cell seeding and their localization, and alterations in physical, chemical, and microbial properties. We highlight the similarities or differences between human and rodent skin.Box 1Sampling techniques for assessment of skin immunological responsesThe pathophysiology of skin diseases, including atopic dermatitis (AD), has been extensively studied using skin biopsies. Due to the invasive nature of skin biopsy sampling and associated ethical issues, skin biopsies for diagnostic and research purposes in healthy infants and children and those with a skin disease are very limited. Hence, skin immune profiling in healthy subjects or in children with a skin disease is very limited. In addition, sampling limitations may bias our knowledge of skin immune responses as only localized sampling can be done in case of biopsies, and gene expression and lipid composition analysis of tape strips may only reflect the upper layers of the skin176Berdyshev E. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (148) Google Scholar, 177Broccardo C.J. Mahaffey S.B. Strand M. Reisdorph N.A. Leung D.Y. Peeling off the layers: skin taping and a novel proteomics approach to study atopic dermatitis.J. Allergy Clin. Immunol. 2009; 124 (1113–5.e1-11)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 178Dyjack N. et al.Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype.J. Allergy Clin. Immunol. 2018; 141: 1298-1309Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 179Kezic S. et al.Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy. 2011; 66: 934-940Crossref PubMed Scopus (216) Google Scholar, 180Li S. et al.Altered composition of epidermal lipids correlates with Staphylococcus aureus colonization status in atopic dermatitis.Br. J. Dermatol. 2017; 177: e125-e127Crossref PubMed Scopus (51) Google Scholar. However, side-by-side comparison of skin tape stripping and skin biopsies of taped skin and adjacent non-taped skin in adult healthy controls and subjects with AD, indicated that consecutive skin tape stripping removed the stratum corneum and the upper part of the granular layer181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Moreover, gene expression levels of epidermal differentiation markers (filaggrin, corneodesmosin, loricrin, involucrin, and keratin-1) from skin tape stripping samples positively correlated with staining intensities of these markers in matching skin biopsies following immunostaining, suggesting that skin tape stripping is reliable for the evaluation of epidermal differentiation markers181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Analysis of stratum corneum biomarkers in skin tape strips from children were performed using proteomic, transcriptomic and quantitative real-time polymerase chain reaction (qRT-PCR) analysis182Hulshof L. et al.A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.Br. J. Dermatol. 2019; 180: 621-630Crossref PubMed Scopus (48) Google Scholar, 183McAleer M.A. et al.Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and immunity and J. Dermatol. 2019; 180: PubMed Scopus Google Scholar, et skin atopic dermatitis with as a unique 2019; Scholar, E. et of tape strips to immune and barrier abnormalities in the skin of children with atopic Dermatol. 2019; PubMed Scopus Google Scholar, et strips atopic in skin PubMed Scopus Google Scholar. The that analysis of minimally invasive skin tape strips can be for of biomarkers associated with In addition, this may in which are to for the of the The pathophysiology of skin diseases, including atopic dermatitis (AD), has been extensively studied using skin biopsies. Due to the invasive nature of skin biopsy sampling and associated ethical issues, skin biopsies for diagnostic and research purposes in healthy infants and children and those with a skin disease are very limited. Hence, skin immune profiling in healthy subjects or in children with a skin disease is very limited. In addition, sampling limitations may bias our knowledge of skin immune responses as only localized sampling can be done in case of biopsies, and gene expression and lipid composition analysis of tape strips may only reflect the upper layers of the skin176Berdyshev E. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (148) Google Scholar, 177Broccardo C.J. Mahaffey S.B. Strand M. Reisdorph N.A. Leung D.Y. Peeling off the layers: skin taping and a novel proteomics approach to study atopic dermatitis.J. Allergy Clin. Immunol. 2009; 124 (1113–5.e1-11)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 178Dyjack N. et al.Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype.J. Allergy Clin. Immunol. 2018; 141: 1298-1309Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 179Kezic S. et al.Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy. 2011; 66: 934-940Crossref PubMed Scopus (216) Google Scholar, 180Li S. et al.Altered composition of epidermal lipids correlates with Staphylococcus aureus colonization status in atopic dermatitis.Br. J. Dermatol. 2017; 177: e125-e127Crossref PubMed Scopus (51) Google Scholar. However, side-by-side comparison of skin tape stripping and skin biopsies of taped skin and adjacent non-taped skin in adult healthy controls and subjects with AD, indicated that consecutive skin tape stripping removed the stratum corneum and the upper part of the granular layer181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Moreover, gene expression levels of epidermal differentiation markers (filaggrin, corneodesmosin, loricrin, involucrin, and keratin-1) from skin tape stripping samples positively correlated with staining intensities of these markers in matching skin biopsies following immunostaining, suggesting that skin tape stripping is reliable for the evaluation of epidermal differentiation markers181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Analysis of stratum corneum biomarkers in skin tape strips from children were performed using proteomic, transcriptomic and quantitative real-time polymerase chain reaction (qRT-PCR) analysis182Hulshof L. et al.A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.Br. J. Dermatol. 2019; 180: 621-630Crossref PubMed Scopus (48) Google Scholar, 183McAleer M.A. et al.Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and immunity and J. Dermatol. 2019; 180: PubMed Scopus Google Scholar, et skin atopic dermatitis with as a unique 2019; Scholar, E. et of tape strips to immune and barrier abnormalities in the skin of children with atopic Dermatol. 2019; PubMed Scopus Google Scholar, et strips atopic in skin PubMed Scopus Google Scholar. 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