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The microbiome in patients with atopic dermatitis

2018; Elsevier BV; Volume: 143; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2018.11.015

1097-6825

Amy S. Paller, Heidi H. Kong, Patrick C. Seed, Shruti Naik, Tiffany C. Scharschmidt, Richard L. Gallo, Thomas A. Luger, Alan D. Irvine,

Exercise and Physiological Responses

As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies. As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies. A multitude of microbiota inhabit our human epithelial surfaces. Although there is increasing evidence that these microbiota, which live in and on our bodies, are important to human health and disease, the many functions and consequences of these resident microbiota remain poorly understood. Given the challenges in being able to adequately culture all microbes present in a given sample, technological advances in genome sequencing have increased the ability to interrogate human epithelial microbiomes (the full collection of microbiota). Several technical advances in the study of the composition and function of the microbiome have collectively enlightened our understanding of the role of the microbiome in both pathogenesis of atopic dermatitis (AD) and in disease modification (Fig 1).1Byrd A.L. Belkaid Y. Segre J.A. The human skin microbiome.Nat Rev Microbiol. 2018; 16: 143-155Crossref PubMed Scopus (917) Google Scholar Although animal models cannot fully recapitulate the human microbiome and disease states, the use of model organisms to deeply investigate host-microbial relationships has elucidated intriguing biological mechanisms. The continued integration of knowledge gleaned from patient-derived microbiota, animal models, and host-microbial interactions will be critical for developing and understanding therapeutic approaches. Prior publications have extensively reviewed the differences in the human skin microbiome based on various factors, including anatomic skin sites, sexual maturity, and skin physiology; this review provides a broad overview of the different aspects of microbiome, immunology, microbiology, and barrier research as related to AD, in particular early host-microbiome events in patients with AD. Here we review the role of the cutaneous microbiome in healthy and AD skin. The complexities of human microbial communities are reflected in the distinct microbiomes observed in the human skin, gut, and respiratory tract, among other body sites. Furthermore, the microbiota in distinct niches undergo changes over the human lifespan. The continual advances in our understanding of the human microbiome and its potential roles in human disease might subsequently lead to preventative and/or therapeutic strategies. Skin microbiome research has highlighted the diversity and skin site specificity of microbial communities on human subjects, such that the different regional skin surfaces have different compositions of microbial communities.2Findley K. Oh J. Yang J. Conlan S. Deming C. Meyer J.A. et al.Topographic diversity of fungal and bacterial communities in human skin.Nature. 2013; 498: 367-370Crossref PubMed Scopus (731) Google Scholar, 3Grice E.A. Kong H.H. Conlan S. Deming C.B. Davis J. Young A.C. et al.Topographical and temporal diversity of the human skin microbiome.Science. 2009; 324: 1190-1192Crossref PubMed Scopus (1840) Google Scholar, 4Oh J. Byrd A.L. Deming C. Conlan S. NISC program Kong H.H. et al.Biogeography and individuality shape function in the human skin metagenome.Nature. 2014; 514: 59-64Crossref PubMed Scopus (624) Google Scholar, 5Costello E.K. Lauber C.L. Hamady M. Fierer N. Gordon J.I. Knight R. Bacterial community variation in human body habitats across space and time.Science. 2009; 326: 1694-1697Crossref PubMed Scopus (2181) Google Scholar The skin hosts the most diverse commensal communities in the body, with more than 1000 different bacterial species from 19 different phyla.3Grice E.A. Kong H.H. Conlan S. Deming C.B. Davis J. Young A.C. et al.Topographical and temporal diversity of the human skin microbiome.Science. 2009; 324: 1190-1192Crossref PubMed Scopus (1840) Google Scholar, 6Kong H.H. Segre J.A. The molecular revolution in cutaneous biology: investigating the skin microbiome.J Invest Dermatol. 2017; 137: e119-e122Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Although there are unique features of specific skin sites, some shared features of skin microbial communities reflect shared skin physiology: sebaceous skin sites often have Cutibacterium acnes (formerly known as Propionibacterium acnes). Small studies in healthy adult volunteers have shown that skin microbiomes are relatively stable for months to years and that each person might possess a personalized skin microbiome.7Oh J. Byrd A.L. Park M. NISC Comparative Sequencing Program Kong H.H. Segre J.A. Temporal stability of the human skin microbiome.Cell. 2016; 165: 854-866Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar Studies have also demonstrated differences in the skin microbiomes of subjects at different life stages. For example, children who are less sexually mature have lower relative abundances of Corynebacterium and Cutibacterium species8Oh J. Conlan S. Polley E.C. Segre J.A. Kong H.H. Shifts in human skin and nares microbiota of healthy children and adults.Genome Med. 2012; 4: 77Crossref PubMed Scopus (224) Google Scholar and greater diversity of skin fungi9Jo J.H. Deming C. Kennedy E.A. Conlan S. Polley E.C. Ng W.L. et al.Diverse human skin fungal communities in children converge in adulthood.J Invest Dermatol. 2016; 136: 2356-2363Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar compared with more sexually mature subjects. The infant skin microbiome is a particularly active area of investigation because it might provide insights into early-life exposures.10Capone K.A. Dowd S.E. Stamatas G.N. Nikolovski J. Diversity of the human skin microbiome early in life.J Invest Dermatol. 2011; 131: 2026-2032Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 11Costello E.K. Carlisle E.M. Bik E.M. Morowitz M.J. Relman D.A. Microbiome assembly across multiple body sites in low-birthweight infants.MBio. 2013; 4 (e00782-13)Crossref Scopus (106) Google Scholar, 12Dominguez-Bello M.G. Costello E.K. Contreras M. Magris M. Hidalgo G. Fierer N. et al.Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.Proc Natl Acad Sci U S A. 2010; 107: 11971-11975Crossref PubMed Scopus (2958) Google Scholar, 13Kennedy E.A. Connolly J. Hourihane J.O. Fallon P.G. McLean W.H. Murray D. et al.Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year.J Allergy Clin Immunol. 2017; 139: 166-172Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar Children as young as 2 days old have site-specific differences in their skin microbiomes13Kennedy E.A. Connolly J. Hourihane J.O. Fallon P.G. McLean W.H. Murray D. et al.Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year.J Allergy Clin Immunol. 2017; 139: 166-172Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar that might influence future development of disease.14Shi B. Bangayan N.J. Curd E. Taylor P.A. Gallo R.L. Leung D.Y.M. et al.The skin microbiome is different in pediatric versus adult atopic dermatitis.J Allergy Clin Immunol. 2016; 138: 1233-1236Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 15Chu D.M. Ma J. Prince A.L. Antony K.M. Seferovic M.D. Aagaard K.M. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery.Nat Med. 2017; 23: 314-326Crossref PubMed Scopus (556) Google Scholar Early life is also characterized by rapid immunologic maturation. As such, it represents an active period during which host-commensal interactions can formatively affect how our immune system responds to our microbial brethren.16Kollmann T.R. Levy O. Montgomery R.R. Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly.Immunity. 2012; 37: 771-783Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 17McGovern N. Shin A. Low G. Low D. Duan K. Yao L.J. et al.Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2.Nature. 2017; 546: 662-666Crossref PubMed Scopus (157) Google Scholar Future success of microbially directed interventions to prevent or treat inflammatory skin disease will require a deeper understanding of the mechanisms responsible for development of a healthy symbiosis during this critical window. Neonatal immune responses demonstrate a reduced propensity for activation or inflammation compared with those in adults. We now appreciate that this is not only due to immaturity of the immune system but also due to the existence of regulatory mechanisms unique to this early window. In infants, compared with older children or adults, activation of Toll-like receptors (TLRs), key sensors of the innate immune system, results in greater production of IL-6 and IL-23 and less production of TNF-α and IL-1.16Kollmann T.R. Levy O. Montgomery R.R. Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly.Immunity. 2012; 37: 771-783Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar Composition and function of the adaptive immune system evolves in parallel, with regulatory T (Treg) cells found in greater abundance during fetal life and infancy.17McGovern N. Shin A. Low G. Low D. Duan K. Yao L.J. et al.Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2.Nature. 2017; 546: 662-666Crossref PubMed Scopus (157) Google Scholar, 18Yang S. Fujikado N. Kolodin D. Benoist C. Mathis D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance.Science. 2015; 348: 589-594Crossref PubMed Scopus (283) Google Scholar, 19Thome J.J.C. Bickham K.L. Ohmura Y. Kubota M. Matsuoka N. Gordon C. et al.Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues.Nat Med. 2015; 22: 72-77Crossref PubMed Scopus (201) Google Scholar Although these differences place neonates at greater risk for disseminated infection, they also promote immune tolerance to self-antigens and foreign antigens, thereby preventing inflammation disadvantageous to healthy tissue development. Birth marks an abrupt transition, with increased exposure to microbial products and antigens. Composition of microbial communities in infants are distinct from those seen later in life and can be influenced, at least initially, by exogenous factors, such as birth delivery mode and maternal commensals.10Capone K.A. Dowd S.E. Stamatas G.N. Nikolovski J. Diversity of the human skin microbiome early in life.J Invest Dermatol. 2011; 131: 2026-2032Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 12Dominguez-Bello M.G. Costello E.K. Contreras M. Magris M. Hidalgo G. Fierer N. et al.Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.Proc Natl Acad Sci U S A. 2010; 107: 11971-11975Crossref PubMed Scopus (2958) Google Scholar Notably, the identity and function of these microbes can shape host health trajectory. In animal models early-life immune responses to gut- and lung-resident microbes have been shown to influence adult susceptibility to colitis, asthma, and anaphylaxis.20Gensollen T. Iyer S.S. Kasper D.L. Blumberg R.S. How colonization by microbiota in early life shapes the immune system.Science. 2016; 352: 539-544Crossref PubMed Scopus (956) Google Scholar In human infants the presence or absence of certain gut bacteria has been associated with increased proinflammatory metabolites and heightened risk of asthma.21Fujimura K.E. Sitarik A.R. Havstad S. Lin D.L. Levan S. Fadrosh D. et al.Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation.Nat Med. 2016; 22: 1187-1191Crossref PubMed Scopus (586) Google Scholar Whether early disruption of the microbial community on skin directly affects future risk of inflammatory skin disease remains an open question. However, it is notable that recent longitudinal studies examining the skin microbiome in patients at risk for AD have found alterations in skin flora that predate disease onset.13Kennedy E.A. Connolly J. Hourihane J.O. Fallon P.G. McLean W.H. Murray D. et al.Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year.J Allergy Clin Immunol. 2017; 139: 166-172Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 22Meylan P. Lang C. Mermoud S. Johannsen A. Norrenberg S. Hohl D. et al.Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy.J Invest Dermatol. 2017; 137: 2497-2504Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Until recently, little was known about the effect of early-life microbial exposures on skin immune function. Modeling this complex relationship in mice has taught us that these early-life interactions are likely to be of equal or greater significance in skin as in other tissues. When neonatal mice are colonized by the commensal bacterium (coagulase-negative Staphylococcus [CoNS]) Staphylococcus epidermidis, they develop a large percentage of Treg cells specific for S epidermidis and mount less inflammation to this microbe on rechallenge in later life. In contrast, delaying S epidermidis exposure until adulthood prevents this protective effect and promotes skin inflammation in responses to this otherwise "healthy" bacterium (Fig 2).22Meylan P. Lang C. Mermoud S. Johannsen A. Norrenberg S. Hohl D. et al.Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy.J Invest Dermatol. 2017; 137: 2497-2504Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar At least 1 factor accounting for this age-dependent difference is the greater density of Treg cells found in neonatal compared with adult skin.23Scharschmidt T.C. Vasquez K.S. Truong H.-A. Gearty S.V. Pauli M.L. Nosbaum A. et al.A wave of regulatory t cells into neonatal skin mediates tolerance to commensal microbes.Immunity. 2015; 43: 1011-1021Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar Intriguingly, these Treg cells are markedly decreased in the skin of young mice raised under gnotobiotic ("germ-free") conditions and in those lacking hair follicles, a major tissue niche for skin CoNS species. Indeed, colonization of hair follicles by commensal microbes appears to stimulate production by isthmus keratinocytes of a chemokine, CCL20, which then helps recruit these Treg cells into the skin (Fig 2, left panel).24Scharschmidt T.C. Vasquez K.S. Pauli M.L. Leitner E.G. Chu K. Truong H.-A. et al.Commensal microbes and hair follicle morphogenesis coordinately drive Treg migration into neonatal skin.Cell Host Microbe. 2017; 21: 467-477Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Thus animal models suggest that mechanisms promoting establishment of a healthy immunologic symbiosis with our skin microbiota are preferentially active early in life and can be facilitated by microbes themselves. Of course, there are notable differences between mice and human subjects with regard to timing of adaptive immune development, composition of skin bacterial communities, and skin structure. Thus how these findings translate to human biology and their implications for disrupting the composition of the neonatal skin microbiota will be a fruitful area of active investigation. Although detailed immunologic phenotyping of neonatal human skin has not yet been undertaken, Treg cells are enriched in pediatric compared with adult human skin.25Cordoro K.M. Hitraya-Low M. Taravati K. Sandoval P.M. Kim E. Sugarman J. et al.Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis.J Am Acad Dermatol. 2017; 77: 417-424Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar In considering potential translational applications of skin microbiome research, one can envision both corrective interventions to treat an established skin disease and preventative measures to reduce risk of disease onset or mitigate future severity. The latter might be especially relevant for conditions such as AD, in which variable penetrance based on genetic susceptibility and an early age of onset are defining features.26Weidinger S. Beck L.A. Bieber T. Kabashima K. Irvine A.D. Atopic dermatitis.Nat Rev Dis Primers. 2018; 4: 1Crossref PubMed Scopus (273) Google Scholar Continued work to define the early-life influence of skin microbes on cutaneous immune function, both in the context of healthy and barrier-disrupted skin, will be critical to inform future development of prevention-oriented recommendations and microbe-based interventions. The skin presents a physical barrier to harmful agents while establishing a unique innate immune system to regulate resident microbial communities. In contrast to other epithelial surfaces, such as the gut, which maintain physical separation from microbes through establishment of a mucous layer, the dense distribution of skin appendages creates a large surface area for close communication with microbes.27Gallo R.L. Human skin is the largest epithelial surface for interaction with microbes.J Invest Dermatol. 2017; 137: 1213-1214Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar The skin strictly regulates a sophisticated set of innate antimicrobial gene products that include antimicrobial peptides and proteins, lipids, a pH barrier, and free radical production to control the surface microbial community.28Zhang L.J. Gallo R.L. Antimicrobial peptides.Curr Biol. 2016; 26: R14-R19Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar A network of immune cells patrol the skin to reinforce the physical barrier because commensal and many potential pathogens can penetrate the epidermis after even a minor breach.29Nakatsuji T. Chiang H.I. Jiang S.B. Nagarajan H. Zengler K. Gallo R.L. The microbiome extends to subepidermal compartments of normal skin.Nat Commun. 2013; 4: 1431Crossref PubMed Scopus (303) Google Scholar The interplay between the epithelial barrier, immune defense, and the cutaneous microbiome has emerged as a key system for maintaining balance between health and disease.30Williams M.R. Nakatsuji T. Gallo R.L. Staphylococcus aureus: master manipulator of the skin.Cell Host Microbe. 2017; 22: 579-581Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 31Belkaid Y. Segre J.A. Dialogue between skin microbiota and immunity.Science. 2014; 346: 954-959Crossref PubMed Scopus (371) Google Scholar Mounting clinical and experimental evidence suggests that modulating the microbiome might be efficacious for the treatment of inflammatory skin conditions.32Grice E.A. The skin microbiome: potential for novel diagnostic and therapeutic approaches to cutaneous disease.Semin Cutan Med Surg. 2014; 33: 98-103Crossref PubMed Scopus (135) Google Scholar However, the fundamental mechanisms underlying the immune-commensal crosstalk are only beginning to unfold. A nuanced understanding of the microbial factors that regulate skin immunity offers an opportunity to harness the power of the microbiome for therapeutic benefit. Studies in germ-free mice have revealed that optimal immune cell function in healthy skin requires cues from indigenous microbes (Fig 2).33Naik S. Bouladoux N. Wilhelm C. Molloy M.J. Salcedo R. Kastenmuller W. Deming C. et al.Compartmentalized control of skin immunity by resident commensals.Science. 2012; 337: 1115-1119Crossref PubMed Scopus (731) Google Scholar For instance, the ability of effector T cells to make cytokines, such as IL-17A and IFN-γ, is dramatically abrogated in the absence of commensals. This defect is only restored with association of a skin commensal, S epidermidis, and not microbes residing in the intestine, highlighting the nonredundant role of skin-resident microbes in immune modulation.33Naik S. Bouladoux N. Wilhelm C. Molloy M.J. Salcedo R. Kastenmuller W. Deming C. et al.Compartmentalized control of skin immunity by resident commensals.Science. 2012; 337: 1115-1119Crossref PubMed Scopus (731) Google Scholar, 34Belkaid Y. Naik S. Compartmentalized and systemic control of tissue immunity by commensals.Nat Immunol. 2013; 14: 646-653Crossref PubMed Scopus (243) Google Scholar S epidermidis controls T-cell effector function by co-opting existing innate immune pathways, in this case IL-1α production from keratinocytes and dendritic cells. Although skin-derived innate signals are dispensable for the specification of T cells in the lymph node, these commensally induced molecules stimulate T cells on entry into the skin and sustain their effector functions. Importantly, this homeostatic tuning of skin T-cell function occurs in the absence of overt inflammation and in the context of an intact epidermal barrier.35Naik S. Bouladoux N. Linehan J.L.1 Han S.J. Harrison O.J. Wilhelm C. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature. 2015; 520: 104-108Crossref PubMed Scopus (470) Google Scholar Several lines of evidence suggest that maintaining microbial diversity is advantageous to support the rich immune milieu of the skin. For instance, certain key microbes can elicit specific types of immune cells to the skin. Defined strains of S epidermidis induce IL-17A, producing CD8 (TC17) cells that reside in the epidermis.35Naik S. Bouladoux N. Linehan J.L.1 Han S.J. Harrison O.J. Wilhelm C. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature. 2015; 520: 104-108Crossref PubMed Scopus (470) Google Scholar This cell population is actively generated on S epidermidis colonization through dendritic cell–dependent antigen presentation of bacterial N-formyl methionine peptides.36Linehan J.L. Harrison O.J. Han S.J. Byrd A.L. Vujkovic-Cvijin I. Villarino A.V. et al.Non-classical immunity controls microbiota impact on skin immunity and tissue repair.Cell. 2018; 172: 784-796Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar In line with these experimental findings, human skin tropic T cells produce IL-17A and IFN-γ in response to stimulation with S epidermidis antigen.37Schlapbach C. Gehad A. Yang C. Watanabe R. Guenova E. Teague J.E. et al.Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity.Sci Transl Med. 2014; 6: 219ra8Crossref PubMed Scopus (157) Google Scholar Moreover, TC17 cells are constitutively found in normal human skin33Naik S. Bouladoux N. Wilhelm C. Molloy M.J. Salcedo R. Kastenmuller W. Deming C. et al.Compartmentalized control of skin immunity by resident commensals.Science. 2012; 337: 1115-1119Crossref PubMed Scopus (731) Google Scholar, 38Clark R.A. 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Indeed, the demonstration of increased TH17-driven gene expression in the skin of healthy pediatric control subjects and the significantly greater Th17-related gene expression in the lesional and nonlesional skin of infants with recent-onset AD potentially reflect this early period of response to environmental commensals.41Brunner 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 (139) Google Scholar, 42Esaki H. Brunner P.M. Renert-Yuval Y. Czarnowicki T. Huynh T. Tran G. et al.Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.J Allergy Clin Immunol. 2016; 138: 1639-1651Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar Specificity of commensal interactions with the host immune system is not limited to cognate T-cell responses. Indeed, the first detailed molecular description of the ability of commensal skin bacteria to benefit skin immunity came with the identification of chemical moieties displayed on commensals that interact with innate immune receptors to drive certain responses. A TLR2 ligand, lipoteichoic acid, from a commensal strain of S epidermidis and not pathogenic bacteria is uniquely able to dampen skin inflammation.43Lai Y. Di Nardo A. Nakatsuji T. Leichtle A. Yang Y. Cogen A.L. Wu Z.R. et al.Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury.Nat Med. 2009; 5: 1377-1382Crossref Scopus (514) Google Scholar S epidermidis can also enhance innate immune defense by enhancing antimicrobial peptide expression.44Lai Y. Cogen A.L. Radek K.A. Park H.J. Macleod D.T. Leichtle A. et al.Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections.J Invest Dermatol. 2010; 130: 2211-2221Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar Several members of the commensal genus Corynebacterium have the cell envelope component mycolic acid, which can specifically induce IL-17A+ dermal γδ T cells (Fig 2).45Ridaura V.K. Bouladoux N. Claesen J. Chen Y.E. Byrd A.L. Constantinides M.G. et al.Contextual control of skin immunity and inflammation by Corynebacterium.J Exp Med. 2018; 215: 785-799Crossref PubMed Scopus (92) Google Scholar By contrast, CD4+ TH17 programs are broadly triggered by a wide array of microbes on skin colonization.35Naik S. Bouladoux N. Linehan J.L.1 Han S.J. Harrison O.J. Wilhelm C. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature. 2015; 520: 104-108Crossref PubMed Scopus (470) Google Scholar Thus it is tempting to speculate that the cutaneous immune system has evolved to sense skin microbial complexity and to use this information as a rheostat to continuously calibrate its function. The myriad of immune cells elicited by commensals have several contextual roles in reinforcing the epidermal barrier. Commensal-specific immune responses help provide heterologous protection against dermal pathogens. By augmenting epidermal antimicrobial function, commensal-specific T cells limit the ability of pathogens, such as Candida albicans, to establish infections.35Naik S. Bouladoux N. Linehan J.L.1 Han S.J. Harrison O.J. Wilhelm C. Commensal-dendritic-cell interac