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Which Way Do We Go? Complex Interactions in Atopic Dermatitis Pathogenesis

Open ArchivePublished:September 15, 2020DOI:https://doi.org/10.1016/j.jid.2020.07.006
      Atopic dermatitis (AD) is a common, chronic, inflammatory skin condition characterized by recurrent and pruritic skin eruptions. Multiple factors contribute to the pathogenesis of AD, including skin barrier dysfunction, microbial dysbiosis, and immune dysregulation. Interactions among these factors form a complex, multidirectional network that can reinforce atopic skin disease but can also be ameliorated by targeted therapies. This review summarizes the complex interactions among contributing factors in AD and the implications on disease development and therapeutic interventions.

      Abbreviations:

      AD (atopic dermatitis), HBD (human β-defensin), HDP (host defense peptide), KC (keratinocyte), LOF (loss-of-function), NMF (natural-moisturizing factor), PLA2 (phospholipase A2), TEWL (transepidermal water loss), Th (T helper), Treg (T regulatory cell)

      Introduction

      Atopic dermatitis (AD) is the most common inflammatory skin disorder, with an estimated worldwide prevalence of 3–5% in adults and 15–20% in children (
      • Asher M.I.
      • Montefort S.
      • Björkstén B.
      • Lai C.K.W.
      • Strachan D.P.
      • Weiland S.K.
      • et al.
      Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys.
      ;
      • Weidinger S.
      • Beck L.A.
      • Bieber T.
      • Kabashima K.
      • Irvine A.D.
      Atopic dermatitis.
      ). AD is characterized by eczematous, pruritic skin patches and plaques that can severely affect QOL and result in high socioeconomic costs (
      • Chung J.
      • Simpson E.L.
      The socioeconomics of atopic dermatitis.
      ). AD has also been proposed to initiate the atopic march, a sequential development of allergic disorders, including food allergies, allergic rhinitis, and asthma, although this concept has been challenged as a clustering of diseases rather than a sequential march (
      • Dharmage S.C.
      • Lowe A.J.
      • Matheson M.C.
      • Burgess J.A.
      • Allen K.J.
      • Abramson M.J.
      Atopic dermatitis and the atopic march revisited.
      ;
      • Gustafsson D.
      • Sjöberg O.
      • Foucard T.
      Development of allergies and asthma in infants and young children with atopic dermatitis--a prospective follow-up to 7 years of age.
      ;
      • Paller A.S.
      • Kong H.H.
      • Seed P.
      • Naik S.
      • Scharschmidt T.C.
      • Gallo R.L.
      • et al.
      The microbiome in patients with atopic dermatitis.
      ). Therefore, a deeper understanding and targeted treatments against the pathogenic mechanisms in AD could have implications in the prevention of other allergic diseases.
      Several models have been proposed to explain the pathogenesis of AD. Initial studies focused on the role of altered immune responses, especially T helper (Th) type 2 and IgE responses, to be the major drivers of the disease (
      • van der Heijden F.L.
      • Wierenga E.A.
      • Bos J.D.
      • Kapsenberg M.L.
      High frequency of IL-4-producing CD4+ allergen-specific T lymphocytes in atopic dermatitis lesional skin.
      ;
      • Vestergaard C.
      • Yoneyama H.
      • Murai M.
      • Nakamura K.
      • Tamaki K.
      • Terashima Y.
      • et al.
      Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions.
      ). The so-called inside-out hypothesis postulated that immune dysregulation leads to a compromised skin barrier function, thus permitting allergens and pathogens to penetrate the skin (
      • Leung D.Y.M.
      Pathogenesis of atopic dermatitis.
      ). However, the discovery of inherited defects in factors that contribute to the skin barrier posited the alternative outside-in hypothesis, where an underlying barrier dysfunction allows antigen penetration to induce altered immune responses (
      • Proksch E.
      • Fölster-Holst R.
      • Jensen J.M.
      Skin barrier function, epidermal proliferation and differentiation in eczema.
      ). Recently, models have incorporated aspects of both, including an outside-inside-outside model where the skin microbiome and environmental factors penetrate the body from the outside through epidermal barrier defects and trigger immune dysregulation, which further exacerbates skin barrier defects (
      • Elias P.M.
      Skin barrier function.
      ).
      The complexity of the current AD models indicates significant potential for interaction and crosstalk between epidermal barrier defects, skin microbiome, and immune dysregulation. This review will summarize the current state of research into the complex interactions of these factors in the immunopathology of AD and the implications of this complexity for the development of therapeutics.

      Contributing Factors: Inside and Out

      Barrier dysfunction

      The skin provides a key barrier between the body and the outside world, preventing transepidermal water loss (TEWL) and excluding pathogens and environmental antigens (
      • De Benedetto A.
      • Kubo A.
      • Beck L.A.
      Skin barrier disruption: a requirement for allergen sensitization?.
      ). A major component of this barrier function is the multifunctional epidermal protein FLG. FLG is produced as the large, insoluble pro-FLG in the keratohyalin granules of keratinocytes (KCs) (
      • Brown S.J.
      • McLean W.H.
      One remarkable molecule: filaggrin.
      ). These granules form liquid‒liquid phase separation droplets that contribute to barrier formation as they reach the skin surface (
      • Quiroz F.G.
      • Fiore V.F.
      • Levorse J.
      • Polak L.
      • Wong E.
      • Pasolli H.A.
      • et al.
      Liquid-liquid phase separation drives skin barrier formation.
      ). In addition, pro-FLG undergoes processing and crosslinking to ultimately contribute to a tightly interwoven lipid/protein matrix that acts as the mortar that holds KC bricks together in a strong, impermeable brick and mortar structure (
      • Nemes Z.
      • Steinert P.M.
      Bricks and mortar of the epidermal barrier.
      ). In addition to this structural role, FLG is degraded by proteases to release its component amino acids as one component of the so-called natural-moisturizing factors (NMFs) that help to keep the epidermis hydrated (
      • Rawlings A.V.
      • Harding C.R.
      Moisturization and skin barrier function.
      ).
      Lipids play an important role in barrier formation by maintaining lubrication and preventing dehydration as well as having antimicrobial activity (
      • Bhattacharya N.
      • Sato W.J.
      • Kelly A.
      • Ganguli-Indra G.
      • Indra A.K.
      Epidermal lipids: key mediators of atopic dermatitis pathogenesis.
      ). Epidermal lipids are mainly composed of ceramides, cholesterol, and free fatty acids, although the composition and amount vary across different body surfaces (
      • Greene R.S.
      • Downing D.T.
      • Pochi P.E.
      • Strauss J.S.
      Anatomical variation in the amount and composition of human skin surface lipid.
      ;
      • Pappas A.
      Epidermal surface lipids.
      ). These lipids make up a significant proportion of the extracellular matrix surrounding the crosslinked FLG, helping to make up the mortar of the brick and mortar structure (
      • Elias P.M.
      • Friend D.S.
      The permeability barrier in mammalian epidermis.
      ).
      Disruption of barrier function can have profound implications for the development of AD. FLG mutations are the strongest genetic risk factor in the development of AD (
      • Palmer C.N.A.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • Zhao Y.
      • Liao H.
      • Lee S.P.
      • et al.
      Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
      ) and correlate with increased disease severity, allergic sensitization, and overall higher healthcare costs (
      • Heede N.G.
      • Thyssen J.P.
      • Thuesen B.H.
      • Linneberg A.
      • Szecsi P.B.
      • Stender S.
      • et al.
      Health-related quality of life in adult dermatitis patients stratified by filaggrin genotype.
      ;
      • Soares P.
      • Fidler K.
      • Felton J.
      • Tavendale R.
      • Hövels A.
      • Bremner S.A.
      • et al.
      Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs.
      ). FLG mutations have also served as the basis for AD mouse models, including the flaky tail model (ft/ft mice) and the monogenic FLG-knockout mice (Flgft/ft mice) (
      • Nakajima S.
      • Nomura T.
      • Common J.
      • Kabashima K.
      Insights into atopic dermatitis gained from genetically defined mouse models.
      ). Despite this strong association, FLG mutations are only present in a minority of the population and are unevenly distributed across racial and ethnic groups. For example, FLG mutations are present in approximately 30–50% of European Americans with AD, 27% of Asians with AD, and 3–6% of African Americans with AD (
      • Czarnowicki T.
      • He H.
      • Krueger J.G.
      • Guttman-Yassky E.
      Atopic dermatitis endotypes and implications for targeted therapeutics.
      ;
      • Margolis D.J.
      • Apter A.J.
      • Gupta J.
      • Hoffstad O.
      • Papadopoulos M.
      • Campbell L.E.
      • et al.
      The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort.
      ), and the R501X and 2282del4 mutations account for 80% of FLG mutations in Ireland but only 1% in Singaporean Chinese (
      • Chen H.
      • Common J.E.A.
      • Haines R.L.
      • Balakrishnan A.
      • Brown S.J.
      • Goh C.S.M.
      • et al.
      Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations.
      ).
      In addition to FLG, other components of the skin barrier have been implicated in AD, including tight junction proteins (
      • Zaniboni M.C.
      • Samorano L.P.
      • Orfali R.L.
      • Aoki V.
      Skin barrier in atopic dermatitis: beyond filaggrin.
      ). For example, decreased claudin-1 expression in the affected skin of patients with AD correlated with disease severity (
      • De Benedetto A.
      • Rafaels N.M.
      • McGirt L.Y.
      • Ivanov A.I.
      • Georas S.N.
      • Cheadle C.
      • et al.
      Tight junction defects in patients with atopic dermatitis.
      ). The skin also produces host defense peptides (HDPs) that regulate and control skin microbes and trigger host immune responses, including inflammatory cytokine production (
      • Schauber J.
      • Gallo R.L.
      Antimicrobial peptides and the skin immune defense system.
      ). The levels of these skin barrier proteins are decreased or dysregulated in atopic skin, further disrupting the barrier (
      • Kuo I.H.
      • Yoshida T.
      • De Benedetto A.D.
      • Beck L.A.
      The cutaneous innate immune response in patients with atopic dermatitis.
      ). Furthermore, alterations in skin lipid composition are associated with barrier dysfunction in AD, including decreased ceramide chain length (
      • Ishikawa J.
      • Narita H.
      • Kondo N.
      • Hotta M.
      • Takagi Y.
      • Masukawa Y.
      • et al.
      Changes in the ceramide profile of atopic dermatitis patients.
      ;
      • Janssens M.
      • van Smeden J.
      • Gooris G.S.
      • Bras W.
      • Portale G.
      • Caspers P.J.
      • et al.
      Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.
      ), increased cholesterol-3-sulfate levels (
      • Liu H.
      • Archer N.K.
      • Dillen C.A.
      • Wang Y.
      • Ashbaugh A.G.
      • Ortines R.V.
      • et al.
      Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-Mediated T cell responses.
      ), and increased short-chain and monounsaturated free fatty acids (
      • Macheleidt O.
      • Sandhoff K.
      • Kaiser H.W.
      Deficiency of epidermal protein-bound ω-hydroxyceramides in atopic dermatitis.
      ;
      • van Smeden J.
      • Janssens M.
      • Kaye E.C.J.
      • Caspers P.J.
      • Lavrijsen A.P.
      • Vreeken R.J.
      • et al.
      The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.
      ). A delicate balance between proteases, both intrinsic and environmental, and host-derived protease inhibitors regulate barrier formation through the cleavage of structural proteins to induce desquamation (
      • de Veer S.J.
      • Furio L.
      • Harris J.M.
      • Hovnanian A.
      Proteases: common culprits in human skin disorders.
      ). For example, excessive protease activity in the skin of patients with Netherton syndrome (that is caused by mutations in the protease inhibitor SPINK5) contributes to atopic skin disease and other systemic allergic conditions (
      • Chavanas S.
      • Bodemer C.
      • Rochat A.
      • Hamel-Teillac D.
      • Ali M.
      • Irvine A.D.
      • et al.
      Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.
      ).
      AD is an intensely pruritic condition driven by hyperinnervation, hypersensitivity, and the release of pruritogens including IL-31, histamine, TSLP, bradykinin, and substance P (
      • Furue M.
      • Chiba T.
      • Tsuji G.
      • Ulzii D.
      • Kido-Nakahara M.
      • Nakahara T.
      • et al.
      Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies.
      ;
      • Hosogi M.
      • Schmelz M.
      • Miyachi Y.
      • Ikoma A.
      Bradykinin is a potent pruritogen in atopic dermatitis: a switch from pain to itch.
      ;
      • Kantor R.
      • Silverberg J.I.
      Environmental risk factors and their role in the management of atopic dermatitis.
      ;
      • Kido-Nakahara M.
      • Furue M.
      • Ulzii D.
      • Nakahara T.
      Itch in atopic dermatitis.
      ;
      • Mollanazar N.K.
      • Smith P.K.
      • Yosipovitch G.
      Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
      ). As a result, skin injury from scratching significantly contributes toward impairment of skin barrier function through mechanical damage and upregulation of host proteases (
      • Hachem J.P.
      • Houben E.
      • Crumrine D.
      • Man M.Q.
      • Schurer N.
      • Roelandt T.
      • et al.
      Serine protease signaling of epidermal permeability barrier homeostasis.
      ). In addition, microbial and/or host proteases produced or induced by common environmental skin exposures to house dust mites, cockroaches, fungi, pollen, and bacteria can degrade intracellular junctions, disrupt the epithelial barrier, and decrease lamellar body secretion critical for the recovery of the epidermis (
      • Jeong S.K.
      • Kim H.J.
      • Youm J.K.
      • Ahn S.K.
      • Choi E.H.
      • Sohn M.H.
      • et al.
      Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery.
      ;
      • Takai T.
      • Ikeda S.
      Barrier Dysfunction caused by environmental proteases in the pathogenesis of allergic diseases.
      ). Weather conditions, especially cold temperatures and low humidity, can also increase the permeability of the skin through a variety of mechanisms, including decreased skin hydration, decreased extensibility, and increased sensation of itch (
      • Engebretsen K.A.
      • Johansen J.D.
      • Kezic S.
      • Linneberg A.
      • Thyssen J.P.
      The effect of environmental humidity and temperature on skin barrier function and dermatitis.
      ).

      Dysbiosis

      As part of the interface with the environment, the skin is normally colonized by diverse commensal microorganisms while also preventing penetration by pathogenic microorganisms (
      • Byrd A.L.
      • Belkaid Y.
      • Segre J.A.
      The human skin microbiome.
      ;
      • Paller A.S.
      • Kong H.H.
      • Seed P.
      • Naik S.
      • Scharschmidt T.C.
      • Gallo R.L.
      • et al.
      The microbiome in patients with atopic dermatitis.
      ). The balance of microorganisms that compose the skin microbiome is dynamic, and there are differences in the composition, depending on the anatomic skin site, age, sex, and disease state (
      • Findley K.
      • Oh J.
      • Yang J.
      • Conlan S.
      • Deming C.
      • Meyer J.A.
      • et al.
      Topographic diversity of fungal and bacterial communities in human skin.
      ;
      • Grice 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.
      ). AD is associated with drastic shifts of the skin microbiome, notably the loss of commensal diversity and the dominant colonization with pathogenic Staphylococcus aureus and commensal S. epidermidis (
      • Byrd A.L.
      • Deming C.
      • Cassidy S.K.B.
      • Harrison O.J.
      • Ng W.I.
      • Conlan S.
      • et al.
      Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis.
      ). AD skin lesions have an estimated 90% S. aureus colonization rate that correlates with increased disease burden (
      • Higaki S.
      • Morohashi M.
      • Yamagishi T.
      • Hasegawa Y.
      Comparative study of staphylococci from the skin of atopic dermatitis patients and from healthy subjects.
      ). Clonotypic analysis of S. aureus clinical isolates shows that highly pathogenic, antimicrobial-resistant, toxigenic strains predominate in AD skin that correlate with the disease severity (
      • Guzik T.J.
      • Bzowska M.
      • Kasprowicz A.
      • Czerniawska-Mysik G.
      • Wójcik K.
      • Szmyd D.
      • et al.
      Persistent skin colonization with Staphylococcus aureus in atopic dermatitis: relationship to clinical and immunological parameters.
      ;
      • Pascolini C.
      • Sinagra J.
      • Pecetta S.
      • Bordignon V.
      • De Santis A.
      • Cilli L.
      • et al.
      Molecular and immunological characterization of Staphylococcus aureus in pediatric atopic dermatitis: implications for prophylaxis and clinical management.
      ). Conversely, recovery of commensal diversity can precede and indicate the resolution of an AD disease flare (
      • Kong H.H.
      • Oh J.
      • Deming C.
      • Conlan S.
      • Grice E.A.
      • Beatson M.A.
      • et al.
      Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis.
      ;
      • Shi B.
      • Leung D.Y.M.
      • Taylor P.A.
      • Li H.
      Methicillin-resistant Staphylococcus aureus colonization is associated with decreased skin commensal bacteria in atopic dermatitis.
      ).

      Immune dysregulation

      AD is an inflammatory skin disease in which immune dysregulation results in subsequent systemic immune complications (
      • Gavrilova T.
      Immune dysregulation in the pathogenesis of atopic dermatitis.
      ). AD is strongly associated with type 2 immunity (
      • Brandt E.B.
      • Sivaprasad U.
      Th2 cytokines and atopic dermatitis.
      ). Robust Th2 polarization is seen as early as in the cord blood of infants that develop AD and continues to be present through adulthood (
      • Herberth G.
      • Heinrich J.
      • Röder S.
      • Figl A.
      • Weiss M.
      • Diez U.
      • et al.
      Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life.
      ). This polarization toward Th2 immunity promotes the development of IgE-producing B cell and plasma cells, thus contributing to other allergic diseases such as food allergies, allergic rhinitis, and asthma (
      • Dharmage S.C.
      • Lowe A.J.
      • Matheson M.C.
      • Burgess J.A.
      • Allen K.J.
      • Abramson M.J.
      Atopic dermatitis and the atopic march revisited.
      ).
      Recent studies have expanded on this Th2 paradigm to include the roles for other immune subsets (
      • Berker M.
      • Frank L.J.
      • Geßner A.L.
      • Grassl N.
      • Holtermann A.V.
      • Höppner S.
      • et al.
      Allergies - A T cells perspective in the era beyond the TH1/TH2 paradigm.
      ) such as Th17 (
      • Esaki 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.
      ;
      • Sugaya M.
      The role of Th17-related cytokines in atopic dermatitis.
      ), Th22 (
      • Gittler J.K.
      • Shemer A.
      • Suárez-Fariñas M.
      • Fuentes-Duculan J.
      • Gulewicz K.J.
      • Wang C.Q.F.
      • et al.
      Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.
      ), T regulatory cells (Tregs) (
      • Fyhrquist N.
      • Lehtimäki S.
      • Lahl K.
      • Savinko T.
      • Lappeteläinen A.M.
      • Sparwasser T.
      • et al.
      Foxp3+ cells control Th2 responses in a murine model of atopic dermatitis.
      ), and Th9 cells (
      • Ciprandi G.
      • De Amici M.
      • Giunta V.
      • Marseglia A.
      • Marseglia G.
      Serum interleukin-9 levels are associated with clinical severity in children with atopic dermatitis.
      ;
      • Ma L.
      • Xue H.B.
      • Guan X.H.
      • Shu C.M.
      • Zhang J.H.
      • Yu J.
      Possible pathogenic role of T helper type 9 cells and interleukin (IL)-9 in atopic dermatitis.
      ) in AD pathogenesis. Even Th1 immunity, although downregulated in acute AD, plays a crucial role in the maintenance of chronic AD (
      • Su C.
      • Yang T.
      • Wu Z.
      • Zhong J.
      • Huang Y.
      • Huang T.
      • et al.
      Differentiation of T-helper cells in distinct phases of atopic dermatitis involves Th1/Th2 and Th17/Treg.
      ). Components of the innate immune system contribute significantly to the development of AD skin inflammation, including IL-5 and IL-13 from group 2 innate lymphoid cells, IL-4 from basophils, and IL-25, IL-33, and TSLP from epithelial cells (
      • Divekar R.
      • Kita H.
      Recent advances in epithelium-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin) and allergic inflammation.
      ;
      • Hussain M.
      • Borcard L.
      • Walsh K.P.
      • Rodriguez M.P.
      • Mueller C.
      • Kim B.S.
      • et al.
      Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy.
      ;
      • Mashiko S.
      • Mehta H.
      • Bissonnette R.
      • Sarfati M.
      Increased frequencies of basophils, type 2 innate lymphoid cells and Th2 cells in skin of patients with atopic dermatitis but not psoriasis.
      ;
      • Salimi M.
      • Barlow J.L.
      • Saunders S.P.
      • Xue L.
      • Gutowska-Owsiak D.
      • Wang X.
      • et al.
      A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis.
      ). This immune milieu is dependent on a patient’s age, sex, and ethnic background, thereby adding to the complexity of this disease (
      • Brunner P.M.
      • He H.
      • Pavel A.B.
      • Czarnowicki T.
      • Lefferdink R.
      • Erickson T.
      • et al.
      The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
      ;
      • Brunner P.M.
      • Guttman-Yassky E.
      Racial differences in atopic dermatitis.
      ;
      • Kanda N.
      • Hoashi T.
      • Saeki H.
      The roles of sex hormones in the course of atopic dermatitis.
      ).
      As an inflammatory skin condition, associations between HLA loci and AD were thought to be likely. Multiple large studies have identified HLA loci, including HLA-DRB1, HLA-DQA1, and HLA-DQB1, that demonstrate linkage to AD (
      • Margolis D.J.
      • Mitra N.
      • Kim B.
      • Gupta J.
      • Hoffstad O.J.
      • Papadopoulos M.
      • et al.
      Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis.
      ;
      • Paternoster L.
      • Standl M.
      • Waage J.
      • Baurecht H.
      • Hotze M.
      • Strachan D.P.
      • et al.
      Multi-ethnic genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.
      ;
      • Saeki H.
      • Kuwata S.
      • Nakagawa H.
      • Etoh T.
      • Yanagisawa M.
      • Miyamoto M.
      • et al.
      Analysis of disease-associated amino acid epitopes on HLA class II molecules in atopic dermatitis.
      ). Interestingly, all the coassociated HLA loci between psoriasis and AD display opposing effects in accordance with lower than expected concomitance of these two disparate diseases in patients (
      • Baurecht H.
      • Hotze M.
      • Brand S.
      • Büning C.
      • Cormican P.
      • Corvin A.
      • et al.
      Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.
      ;
      • Nanda A.
      Concomitance of psoriasis and atopic dermatitis.
      ).

      Multidirectional Interactions Between the Contributing Factors in AD Pathogenesis

      Barrier dysfunction and dysbiosis

      Barrier dysfunction alters the skin microbiome

      One of the crucial roles of the skin barrier is to exclude pathogenic microorganisms and maintain a healthy layer of commensal bacteria (
      • Gallo R.L.
      Human skin is the largest epithelial surface for interaction with microbes.
      ). Disruptions to barrier function can result in deleterious changes to the microbiome known as dysbiosis (Figure 1a) (
      • Zeeuwen P.L.
      • Boekhorst J.
      • van den Bogaard E.H.
      • de Koning H.D.
      • van de Kerkhof P.M.
      • Saulnier D.M.
      • et al.
      Microbiome dynamics of human epidermis following skin barrier disruption.
      ). Patients with loss-of-function (LOF) FLG mutations have profound shifts in their microbiome, including increased colonization with S. aureus as well as decreased microbial diversity (
      • Clausen M.L.
      • Edslev S.M.
      • Andersen P.S.
      • Clemmensen K.
      • Krogfelt K.A.
      • Agner T.
      Staphylococcus aureus colonization in atopic eczema and its association with filaggrin gene mutations.
      ;
      • Zeeuwen P.L.J.M.
      • Ederveen T.H.A.
      • van der Krieken D.A.
      • Niehues H.
      • Boekhorst J.
      • Kezic S.
      • et al.
      Gram-positive anaerobe cocci are underrepresented in the microbiome of filaggrin-deficient human skin.
      ). LOF mutations in FLG results in increased surface accessibility of fibronectin and fibrinogen, which S. aureus binds to for surface adherence (
      • Cho S.H.
      • Strickland I.
      • Tomkinson A.
      • Fehringer A.P.
      • Gelfand E.W.
      • Leung D.Y.M.
      Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
      ). In addition, FLG deficiency decreases skin-hydrating NMFs, further disrupting the skin barrier and increasing accessibility of S. aureus‒binding proteins (
      • Kezic S.
      • O’Regan G.M.
      • Yau N.
      • Sandilands A.
      • Chen H.
      • Campbell L.E.
      • et al.
      Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.
      ). S. aureus clonotypes with increased avidity to adherence proteins are shown to be enriched in the skin of patients with FLG mutations (
      • Clausen M.L.
      • Edslev S.M.
      • Andersen P.S.
      • Clemmensen K.
      • Krogfelt K.A.
      • Agner T.
      Staphylococcus aureus colonization in atopic eczema and its association with filaggrin gene mutations.
      ;
      • Fleury O.M.
      • McAleer M.A.
      • Feuillie C.
      • Formosa-Dague C.
      • Sansevere E.
      • Bennett D.E.
      • et al.
      Clumping factor B promotes adherence of Staphylococcus aureus to corneocytes in atopic dermatitis.
      ). In addition to structural roles, FLG also plays a role in the expression and release of enzymes crucial to antimicrobial defense. LOF mutations in FLG results in decreased sphingomyelinase, an enzyme that can decrease the levels of sphingomyelin. Sphingomyelin is employed by S. aureus in the binding of its pore-forming α-toxin, and the loss of sphingomyelinase results in increased lysis of KCs and dermonecrosis (
      • Brauweiler A.M.
      • Bin L.
      • Kim B.E.
      • Oyoshi M.K.
      • Geha R.S.
      • Goleva E.
      • et al.
      Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin–induced keratinocyte death.
      ). In addition to the important role of FLG in impacting the skin microbiome, disruptions in the lipid envelope have also been implicated in promoting dysbiosis, including increases in S. aureus burden (
      • Baurecht H.
      • Rühlemann M.C.
      • Rodríguez E.
      • Thielking F.
      • Harder I.
      • Erkens A.S.
      • et al.
      Epidermal lipid composition, barrier integrity, and eczematous inflammation are associated with skin microbiome configuration.
      ).
      Figure thumbnail gr1
      Figure 1Complex interactions in AD. AD pathogenesis involves directional interactions between (a) dysbiosis and barrier dysfunction, (b) barrier dysfunction and immune dysregulation, (c) dysbiosis and immune dysregulation, or (d) barrier dysfunction, dysbiosis, and immune dysregulation. For example, barrier dysfunction mediated by FLG deficiency promotes dysbiosis, resulting in dysregulated IL-1α production that is released on skin injury to drive chronic skin inflammation (
      • Archer N.K.
      • Jo J.H.
      • Lee S.K.
      • Kim D.
      • Smith B.
      • Ortines R.V.
      • et al.
      Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.
      ). AD, atopic dermatitis; DC, dendritic cell; HDP, host defense peptide; Th, T helper; Treg, T regulatory cell.

      Microbiome composition affects skin barrier function

      Dysbiosis can also have consequences for skin barrier function. Clinical studies have shown that TEWL is increased with S. aureus colonization and positively correlates with bacterial burden (
      • Jinnestål C.L.
      • Belfrage E.
      • Bäck O.
      • Schmidtchen A.
      • Sonesson A.
      Skin barrier impairment correlates with cutaneous Staphylococcus aureus colonization and sensitization to skin-associated microbial antigens in adult patients with atopic dermatitis.
      ), although the directionality of this interaction is unknown. S. aureus utilizes a variety of secreted factors to disrupt the barrier, including proteases that degrade intercellular connections and pore-forming toxins to induce dermonecrosis (
      • Williams M.R.
      • Costa S.K.
      • Zaramela L.S.
      • Khalil S.
      • Todd D.A.
      • Winter H.L.
      • et al.
      Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis.
      ). S. aureus also induces the activity of host proteases, which exacerbate barrier dysfunction by degrading structural proteins such as FLG and desmoglein-1 (
      • Williams M.R.
      • Nakatsuji T.
      • Sanford J.A.
      • Vrbanac A.F.
      • Gallo R.L.
      Staphylococcus aureus induces increased serine protease activity in keratinocytes.
      ).

      Barrier dysfunction and immune dysregulation

      Barrier dysfunction induces immune dysregulation

      Defective barrier function also plays a role in the immune dysregulation seen in AD (Figure 1b). Classical AD immune responses are elevated in patients with FLG LOF mutations, with increased Th2 polarization, increased IgE levels, and enhanced responses to epicutaneous allergen challenge (
      • Brough H.A.
      • Simpson A.
      • Makinson K.
      • Hankinson J.
      • Brown S.
      • Douiri A.
      • et al.
      Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations.
      ). In mice, FLG deficiency induced similar polarization (
      • Fallon 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.
      ;
      • Scharschmidt 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.
      ). For example, increased levels of TSLP are seen in skin equivalent cultures with FLG deficiency, which resulted in increased Th2 polarization (
      • Wallmeyer L.
      • Dietert K.
      • Sochorová M.
      • Gruber A.D.
      • Kleuser B.
      • Vávrová K.
      • et al.
      TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents.
      ). FLG inhibits phospholipase A2 (PLA2), which participates in the generation of neolipid antigens that bind CD1a, resulting in a decrease in T-cell proliferation and ultimately a decrease in Th2 immune responses (
      • Jarrett R.
      • Salio M.
      • Lloyd-Lavery A.
      • Subramaniam S.
      • Bourgeois E.
      • Archer C.
      • et al.
      Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite–derived phospholipase.
      ). Conversely, patients with mutations in FLG lack the inhibition of PLA2-dependent neolipid generation, resulting in significant increases in both total CD1a-reactive T cells and the percentage of those cells expressing IL-13 compared with patients without FLG mutations (
      • Jarrett R.
      • Salio M.
      • Lloyd-Lavery A.
      • Subramaniam S.
      • Bourgeois E.
      • Archer C.
      • et al.
      Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite–derived phospholipase.
      ). Excessive protease activity in FLG-deficient (ft/ft) mice may also play a role in TSLP production, with the inhibition of the protease-activated receptor 2 inhibiting this response (
      • Moniaga C.S.
      • Jeong S.K.
      • Egawa G.
      • Nakajima S.
      • Hara-Chikuma M.
      • Jeon J.E.
      • et al.
      Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.
      ). The excessive protease activity in Netherton syndrome (aforementioned) also resulted in elevated skin TSLP and Th2 responses (
      • Briot A.
      • Deraison C.
      • Lacroix M.
      • Bonnart C.
      • Robin A.
      • Besson C.
      • et al.
      Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.
      ). In addition to FLG, other barrier deficiencies can induce immune dysregulation. Claudin-1, a tight junction protein, has been shown to be inversely correlated with Th2 polarization, although the directionality is unclear (
      • De Benedetto A.
      • Rafaels N.M.
      • McGirt L.Y.
      • Ivanov A.I.
      • Georas S.N.
      • Cheadle C.
      • et al.
      Tight junction defects in patients with atopic dermatitis.
      ). Tape stripping of mouse skin is an experimental approach to artificially mimic skin barrier dysfunction from scratching behavior, which provides a model for the itch‒scratch cycle in AD and results in the induction of TSLP and polarizes dendritic cells to elicit Th2 responses in draining lymph nodes (
      • Angelova-Fischer I.
      • Fernandez I.M.
      • Donnadieu M.H.
      • Bulfone-Paus S.
      • Zillikens D.
      • Fischer T.W.
      • et al.
      Injury to the stratum corneum induces in vivo expression of human thymic stromal lymphopoietin in the epidermis.
      ;
      • Kondo H.
      • Ichikawa Y.
      • Imokawa G.
      Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response.
      ;
      • Oyoshi M.K.
      • Larson R.P.
      • Ziegler S.F.
      • Geha R.S.
      Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression.
      ).
      Beyond the traditional Th2 paradigm, barrier dysfunction also induces other T-cell subsets seen in AD. Children with LOF FLG mutations have been shown to have increased peripheral Th17 responses, whereas FLG-deficient (ft/ft) mice have been shown to have increased Th17 cells and IL-17‒producing γδ T cells (
      • Bonefeld C.M.
      • Petersen T.H.
      • Bandier J.
      • Agerbeck C.
      • Linneberg A.
      • Ross-Hansen K.
      • et al.
      Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.
      ;
      • Jee M.H.
      • Johansen J.D.
      • Buus T.B.
      • Petersen T.H.
      • Gadsbøll A.S.Ø.
      • Woetmann A.
      • et al.
      Increased production of IL-17A-producing γδ T cells in the thymus of filaggrin-deficient mice.
      ;
      • Oyoshi M.K.
      • Murphy G.F.
      • Geha R.S.
      Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.
      ). Adults with LOF FLG mutations also have decreased numbers of Tregs with impaired function and decreased IL-10 production (
      • Moosbrugger-Martinz V.
      • Gruber R.
      • Ladstätter K.
      • Bellutti M.
      • Blunder S.
      • Schmuth M.
      • et al.
      Filaggrin null mutations are associated with altered circulating Tregs in atopic dermatitis.
      ).

      Immune dysregulation alters skin barrier function

      Immune dysregulation can also have profound effects on skin barrier function. Treatment of KCs with IL-4 and IL-13 decreases the expression of FLG and other epidermal structural barrier proteins, including involucrin and loricrin (
      • Howell M.D.
      • Kim B.E.
      • Gao P.
      • Grant A.V.
      • Boguniewicz M.
      • DeBenedetto A.
      • et al.
      Cytokine modulation of atopic dermatitis filaggrin skin expression.
      ;
      • Kim B.E.
      • Leung D.Y.M.
      • Boguniewicz M.
      • Howell M.D.
      Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6.
      ). FLG processing is also decreased by the downregulation of caspase-14, which processes FLG to pro-FLG (
      • Hvid M.
      • Johansen C.
      • Deleuran B.
      • Kemp K.
      • Deleuran M.
      • Vestergaard C.
      Regulation of caspase 14 expression in keratinocytes by inflammatory cytokines--a possible link between reduced skin barrier function and inflammation?.
      ). Treatment of KCs with IL-4 upregulates the production of proteases that contribute to desquamation, resulting in decreased barrier function as measured by TEWL (
      • Hatano Y.
      • Adachi Y.
      • Elias P.M.
      • Crumrine D.
      • Sakai T.
      • Kurahashi R.
      • et al.
      The Th2 cytokine, interleukin-4, abrogates the cohesion of normal stratum corneum in mice: implications for pathogenesis of atopic dermatitis.
      ). In addition, Th2-polarized skin has decreased levels of sphingomyelinase, an enzyme that depletes the sphingomyelin used by S. aureus α-toxin to cause KC lysis and skin barrier impairment (
      • Brauweiler A.M.
      • Bin L.
      • Kim B.E.
      • Oyoshi M.K.
      • Geha R.S.
      • Goleva E.
      • et al.
      Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin–induced keratinocyte death.
      ). The effect of inflammation on barrier function can also synergize with genetic defects. In FLG-deficient skin equivalent cultures, there is upregulation of involucrin, loricrin, and β-defensin-2, all of which are decreased in the presence of Th2 cytokines (
      • Hönzke S.
      • Wallmeyer L.
      • Ostrowski A.
      • Radbruch M.
      • Mundhenk L.
      • Schäfer-Korting M.
      • et al.
      Influence of Th2 cytokines on the cornified envelope, tight junction proteins, and β-defensins in filaggrin-deficient skin equivalents.
      ). In addition to Th2 cytokines, other cytokines implicated in the pathogenesis of AD have been shown to downregulate FLG and other factors involved in skin barrier function, including IL-17 (
      • Gutowska-Owsiak D.
      • Schaupp A.L.
      • Salimi M.
      • Selvakumar T.A.
      • McPherson T.
      • Taylor S.
      • et al.
      IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion.
      ), IL-31 (
      • Cornelissen C.
      • Marquardt Y.
      • Czaja K.
      • Wenzel J.
      • Frank J.
      • Lüscher-Firzlaff J.
      • et al.
      IL-31 regulates differentiation and filaggrin expression in human organotypic skin models.
      ), and IL-22 (
      • Gutowska-Owsiak D.
      • Schaupp A.L.
      • Salimi M.
      • Taylor S.
      • Ogg G.S.
      Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes.
      ).

      Dysbiosis and immune dysregulation

      Skin microbiome alters immune responses in AD

      The pathogenesis of AD involves key interactions between immune responses and microbial communities (Figure 1c). The skin microbiome of patients with AD has considerable variability, with various microorganisms associated with exacerbating or alleviating the skin inflammation (
      • Byrd A.L.
      • Deming C.
      • Cassidy S.K.B.
      • Harrison O.J.
      • Ng W.I.
      • Conlan S.
      • et al.
      Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis.
      ). Colonization with S. aureus is associated with both Th2 polarization and IgE levels in patients with AD (
      • Simpson E.L.
      • Villarreal M.
      • Jepson B.
      • Rafaels N.
      • David G.
      • Hanifin J.
      • et al.
      Patients with atopic dermatitis colonized with Staphylococcus aureus have a distinct phenotype and endotype.
      ). A variety of S. aureus‒derived components have been implicated in Th2 polarization, including S. aureus enterotoxin B, protein A, δ-toxin, and diacylated lipopeptides (
      • Forbes-Blom E.
      • Camberis M.
      • Prout M.
      • Tang S.C.
      • Le Gros G.L.
      Staphylococcal-derived superantigen enhances peanut induced Th2 responses in the skin.
      ;
      • Nakamura Y.
      • Oscherwitz J.
      • Cease K.B.
      • Chan S.M.
      • Muñoz-Planillo R.
      • Hasegawa M.
      • et al.
      Staphylococcus δ-toxin induces allergic skin disease by activating mast cells.
      ;
      • Terada M.
      • Tsutsui H.
      • Imai Y.
      • Yasuda K.
      • Mizutani H.
      • Yamanishi K.
      • et al.
      Contribution of IL-18 to atopic-dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice.
      ). Penetration of the epidermis by S. aureus‒derived proteases is crucial for this induction of Th2 immunity (
      • Nakatsuji T.
      • Chen T.H.
      • Two A.M.
      • Chun K.A.
      • Narala S.
      • Geha R.S.
      • et al.
      Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression.
      ). In addition to S. aureus, Corynebacterium bovis induces Th2 polarization in a mouse model of AD (
      • Kobayashi T.
      • Glatz M.
      • Horiuchi K.
      • Kawasaki H.
      • Akiyama H.
      • Kaplan D.H.
      • et al.
      Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis.
      ). Conversely, the secretome of S. epidermidis blocks CD4 proliferation and induces Tregs (
      • Laborel-Préneron E.
      • Bianchi P.
      • Boralevi F.
      • Lehours P.
      • Fraysse F.
      • Morice-Picard F.
      • et al.
      Effects of the Staphylococcus aureus and Staphylococcus epidermidis secretomes isolated from the skin microbiota of atopic children on CD4+ T cell activation.
      ). Commensal skin microbiota also produce tryptophan metabolites that block Th2 induction through the aryl hydrocarbon receptor (
      • Yu J.
      • Luo Y.
      • Zhu Z.
      • Zhou Y.
      • Sun L.
      • Gao J.
      • et al.
      A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.
      ).
      Patients with AD have been identified with antigen-specific IgE directed against S. aureus components, which correlates with increased disease severity (
      • Sonesson A.
      • Bartosik J.
      • Christiansen J.
      • Roscher I.
      • Nilsson F.
      • Schmidtchen A.
      • et al.
      Sensitization to skin-associated microorganisms in adult patients with atopic dermatitis is of importance for disease severity.
      ). Specifically, IgE directed against S. aureus exotoxins can activate mast cells, basophils, and other cells bearing high-affinity IgE receptor to exacerbate the immune response (
      • Leung D.Y.
      • Harbeck R.
      • Bina P.
      • Reiser R.F.
      • Yang E.
      • Norris D.A.
      • et al.
      Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens.
      ).
      In addition to inducing the canonical Th2/IgE responses, dysbiosis can promote other cell subsets implicated in AD pathogenesis. S. aureus exotoxins can induce IL-22 production from human PBMC-derived T cells, with increased production observed from patients with AD when compared with healthy controls or patients with psoriasis (
      • Niebuhr M.
      • Mainardy J.
      • Heratizadeh A.
      • Satzger I.
      • Werfel T.
      Staphylococcal exotoxins induce interleukin 22 in human th22 cells.
      ,
      • Niebuhr M.
      • Scharonow H.
      • Gathmann M.
      • Mamerow D.
      • Werfel T.
      Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis.
      ). Epicutaneous application of S. aureus induces AD-like skin inflammation in an IL-17‒dependent manner (
      • Liu H.
      • Archer N.K.
      • Dillen C.A.
      • Wang Y.
      • Ashbaugh A.G.
      • Ortines R.V.
      • et al.
      Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-Mediated T cell responses.
      ;
      • Nakamura Y.
      • Oscherwitz J.
      • Cease K.B.
      • Chan S.M.
      • Muñoz-Planillo R.
      • Hasegawa M.
      • et al.
      Staphylococcus δ-toxin induces allergic skin disease by activating mast cells.
      ). In addition to bacteria, commensal yeast (Malassezia spp.) can induce Th17-dependent skin inflammation on tape-stripped skin (
      • Sparber F.
      • De Gregorio C.
      • Steckholzer S.
      • Ferreira F.M.
      • Dolowschiak T.
      • Ruchti F.
      • et al.
      The skin commensal yeast Malassezia triggers a type 17 response that coordinates anti-fungal immunity and exacerbates skin inflammation.
      )

      Immune dysregulation alters the skin microbiome

      Immune alterations can also influence the skin microbiome in AD. S. aureus binds more avidly to the Th2-polarized skin of AD owing to increased accessibility of surface proteins fibronectin and fibrinogen, compared with the skin in psoriasis or healthy controls (
      • Cho S.H.
      • Strickland I.
      • Tomkinson A.
      • Fehringer A.P.
      • Gelfand E.W.
      • Leung D.Y.M.
      Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
      ). Finally, the expression of HDPs with anti-staphylococcal activity by cultured human KCs, including human β-defensin (HBD) 2, HBD3, and cathelicidin (LL-37), is inhibited by Th2 cytokines (
      • Albanesi C.
      • Fairchild H.R.
      • Madonna S.
      • Scarponi C.
      • Pità O.D.
      • Leung D.Y.M.
      • et al.
      IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor cytokine signaling (SOCS)-1, and SOCS-3.
      ;
      • Howell 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.
      ). Similar decreases in HDP expression were seen with AD skin explants and could be reversed with anti–IL-4‒, anti–IL-10‒, and anti–IL-13‒neutralizing antibodies (
      • Howell M.D.
      • Kim B.E.
      • Gao P.
      • Grant A.V.
      • Boguniewicz M.
      • DeBenedetto A.
      • et al.
      Cytokine modulation of atopic dermatitis filaggrin skin expression.
      ,
      • Howell M.D.
      • Boguniewicz M.
      • Pastore S.
      • Novak N.
      • Bieber T.
      • Girolomoni G.
      • et al.
      Mechanism of HBD-3 deficiency in atopic dermatitis.
      ). The skin of patients with the Th2-predominant AD showed decreased levels of HDPs when compared with the skin of healthy controls or the skin of patients with psoriasis (
      • Nomura I.
      • Goleva E.
      • Howell M.D.
      • Hamid Q.A.
      • Ong P.Y.
      • Hall C.F.
      • et al.
      Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
      ;
      • Ong P.Y.
      • Ohtake T.
      • Brandt C.
      • Strickland I.
      • Boguniewicz M.
      • Ganz T.
      • et al.
      Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
      ).

      Barrier dysfunction, dysbiosis, and immune dysregulation

      Despite the interactions among barrier dysfunction, dysbiosis, and immune dysregulation, relatively few studies have made the connection between all the contributing factors in a single model. We recently found in a mouse model of AD-like skin inflammation mimicking tissue injury from scratching that (i) FLG-deficient (ft/ft) mice exhibited homeostatic dysbiosis and IL-1α dysregulation in skin compared with wild-type mice and (ii) injury-induced skin inflammation was driven by dysbiosis-mediated release of KC-derived IL-1α (
      • Archer N.K.
      • Jo J.H.
      • Lee S.K.
      • Kim D.
      • Smith B.
      • Ortines R.V.
      • et al.
      Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.
      ). Therefore, we discovered a mechanism in which the barrier dysfunction caused by FLG deficiency resulted in dysbiosis that along with skin injury led to IL-1α‒mediated immune dysregulation and chronic AD-like skin inflammation (Figure 1d). The interconnectedness of these contributing factors demonstrates the importance of understanding the complex interactions in the pathogenesis of AD.

      Therapeutics: Taking Complex Interactions into Account

      The complex interactions of barrier dysfunction, microbial dysbiosis, and immune dysregulation are important considerations in the development and use of therapeutics for AD (Figure 2). Targeting barrier dysfunction has long been a major aspect of clinical therapy, with topical emollients being the first-line initial treatment for AD (
      • Eichenfield L.F.
      • Ahluwalia J.
      • Waldman A.
      • Borok J.
      • Udkoff J.
      • Boguniewicz M.
      Current guidelines for the evaluation and management of atopic dermatitis: a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines.
      ). Topical emollient treatment can improve the dysbiosis present in AD, decreasing the prevalence of S. aureus and restoring the normally diverse skin microbiome that is also observed in the unaffected skin of patients with AD (
      • Seite S.
      • Flores G.E.
      • Henley J.B.
      • Martin R.
      • Zelenkova H.
      • Aguilar L.
      • et al.
      Microbiome of affected and unaffected skin of patients with atopic dermatitis before and after emollient treatment.
      ). Barrier-directed topical therapies are often combined with topical corticosteroids or calcineurin inhibitors, helping to address the immune dysfunction in AD. However, these immunomodulatory compounds can compromise skin barrier function, an effect that must be balanced with their ability to suppress inflammation (
      • Kao J.S.
      • Fluhr J.W.
      • Man M.Q.
      • Fowler A.J.
      • Hachem J.P.
      • Crumrine D.
      • et al.
      Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities.
      ;
      • Kim M.
      • Jung M.
      • Hong S.P.
      • Jeon H.
      • Kim M.J.
      • Cho M.Y.
      • et al.
      Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function.
      )
      Figure thumbnail gr2
      Figure 2The role of therapeutics in regulating interactions in AD pathogenesis. Therapeutic strategies can disrupt (e.g., dupilumab, bacterial transplant, and emollients) or strengthen (e.g., steroids and cyclosporine) the interactions between dysbiosis, barrier dysfunction, and immune dysregulation in AD pathogenesis, whereas the consequences of other therapeutics in these interactions are unknown (e.g., antimicrobials, mepolizumab, etc). AD, atopic dermatitis.
      Numerous therapies attempting to target the microbial alterations in AD have been attempted, none have yet been included in clinical treatment guidelines of AD, especially in the absence of clinical findings consistent impetiginization (ie, cutaneous bacterial superinfection) (
      • Eichenfield L.F.
      • Ahluwalia J.
      • Waldman A.
      • Borok J.
      • Udkoff J.
      • Boguniewicz M.
      Current guidelines for the evaluation and management of atopic dermatitis: a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines.
      ). Trials of topical antibiotics in AD have been performed, but results have been mixed, and the use of antibiotics raises concern for the development of antibiotic resistance (
      • Błażewicz I.
      • Jaśkiewicz M.
      • Bauer M.
      • Piechowicz L.
      • Nowicki R.J.
      • Kamysz W.
      • et al.
      Decolonization of Staphylococcus aureus in patients with atopic dermatitis: a reason for increasing resistance to antibiotics?.
      ;
      • Breuer K.
      • HAussler S.
      • Kapp A.
      • Werfel T.
      Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis.
      ;
      • Broberg A.
      • Faergemann J.
      Topical antimycotic treatment of atopic dermatitis in the head/neck area. A double-blind randomised study.
      ;
      • Hung S.H.
      • Lin Y.T.
      • Chu C.Y.
      • Lee C.C.
      • Liang T.C.
      • Yang Y.H.
      • et al.
      Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics.
      ). Dilute bleach baths have been suggested by several studies, but in comparative studies, they were found to not be more effective than water baths alone (
      • Hon K.L.
      • Tsang Y.C.K.
      • Lee V.W.Y.
      • Pong N.H.
      • Ha G.
      • Lee S.T.
      • et al.
      Efficacy of sodium hypochlorite (bleach) baths to reduce Staphylococcus aureus colonization in childhood onset moderate-to-severe eczema: a randomized, placebo-controlled cross-over trial.
      ;
      • Huang J.T.
      • Abrams M.
      • Tlougan B.
      • Rademaker A.
      • Paller A.S.
      Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity.
      ). In addition to reducing pathogenic bacteria, treatments addressing the role of commensals have been evaluated. Commensal bacteria can produce antimicrobial peptides, decreasing the colonization of S. aureus, improving barrier function, and decreasing immune activation (
      • Myles I.A.
      • Williams K.W.
      • Reckhow J.D.
      • Jammeh M.L.
      • Pincus N.B.
      • Sastalla I.
      • et al.
      Transplantation of human skin microbiota in models of atopic dermatitis.
      ;
      • Nakatsuji T.
      • Chen T.H.
      • Narala S.
      • Chun K.A.
      • Two A.M.
      • Yun T.
      • et al.
      Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis.
      ). Coagulase-negative staphylococci produce autoinducing peptides that inhibit the S. aureus accessory gene regulator system involved in quorum sensing, which resulted in reduced cytolytic toxin and virulence factor production (
      • Williams M.R.
      • Costa S.K.
      • Zaramela L.S.
      • Khalil S.
      • Todd D.A.
      • Winter H.L.
      • et al.
      Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis.
      ). Transplant with Roseamonas mucosa, a bacteria derived from the skin of healthy volunteers, showed a benefit in reducing disease severity and S. aureus burden (
      • Myles I.A.
      • Earland N.J.
      • Anderson E.D.
      • Moore I.N.
      • Kieh M.D.
      • Williams K.W.
      • et al.
      First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis.
      ).
      Therapies targeting the immune dysregulation often involve broad, systemic immunosuppression, including the use of methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine, although these drugs are usually reserved for severe, refractory cases owing to their adverse side effect profiles (
      • Megna M.
      • Napolitano M.
      • Patruno C.
      • Villani A.
      • Balato A.
      • Monfrecola G.
      • et al.
      Systemic treatment of adult atopic dermatitis: a review.
      ). Therapies directed toward specific dysregulated immune pathways have also become important in the treatment of severe AD. Dupilumab is a fully human mAb targeting the shared receptor subunit for IL-4 and IL-13. Dupilumab is approved in the U.S. for the treatment of adults and children (above the age of 6 years old) with poorly controlled AD (
      • Gooderham M.J.
      • Hong H.C.H.
      • Eshtiaghi P.
      • Papp K.A.
      Dupilumab: a review of its use in the treatment of atopic dermatitis.
      ;
      • Licari A.
      • Castagnoli R.
      • Marseglia A.
      • Olivero F.
      • Votto M.
      • Ciprandi G.
      • et al.
      Dupilumab to treat Type 2 inflammatory diseases in children and adolescents.
      ). In phase 3 trials, patients with AD treated with dupilumab achieved 36–38% improvement in the primary endpoint of the investigator global assessment (compared with 8–10% of the placebo group), and nearly 50% of patients with AD treated with dupilumab achieved at least 75% on the Eczema Area and Severity Index-75 (compared with ∼15% of the placebo group) as a secondary endpoint (
      • Simpson E.L.
      • Bieber T.
      • Guttman-Yassky E.
      • Beck L.A.
      • Blauvelt A.
      • Cork M.J.
      • et al.
      Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.
      ). The treatment has been shown to improve bacterial dysbiosis, reducing the prevalence of S. aureus and increasing microbial diversity (
      • Callewaert C.
      • Nakatsuji T.
      • Knight R.
      • Kosciolek T.
      • Vrbanac A.
      • Kotol P.
      • et al.
      IL-4Rα blockade by dupilumab decreases Staphylococcus aureus colonization and increases microbial diversity in atopic dermatitis.
      ). Dupilumab treatment also resulted in improved barrier function measures, including increased expression of FLG, loricrin, and claudins (
      • Guttman-Yassky E.
      • Bissonnette R.
      • Ungar B.
      • Suárez-Fariñas M.
      • Ardeleanu M.
      • Esaki H.
      • et al.
      Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
      ). However, the sizable population of partial or nonresponsive patients treated with dupilumab may be partially explained by the heterogeneous nature of this disease and suggests a need for a personalized therapeutic approach (
      • Hendricks A.J.
      • Lio P.A.
      • Shi V.Y.
      Management recommendations for dupilumab partial and non-durable responders in atopic dermatitis.
      ).
      Antibodies targeting additional cytokines have been attempted with varying degrees of success. For example, mepolizumab (anti–IL-5 mAb) is currently in phase 3 clinical trials after demonstrating improvements in pruritus, whereas nemolizumab (anti–IL-31R mAb) also showed a significant benefit in pruritus in patients with AD but little or no efficacy on the skin inflammation (
      • Hajdarbegovic E.
      • Balak D.M.W.
      Anti-interleukin-31 receptor A antibody for atopic dermatitis.
      ;
      • Oldhoff J.M.
      • Darsow U.
      • Werfel T.
      • Katzer K.
      • Wulf A.
      • Laifaoui J.
      • et al.
      Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis.
      ). Tralokinumab and Lebrikizumab, both anti–IL-13 mAbs, although targeting different epitopes, have also shown efficacy in moderate-to-severe AD in phase 2 studies and are both currently undergoing phase 3 trials (
      • Guttman-Yassky E.
      • Blauvelt A.
      • Eichenfield L.F.
      • Paller A.S.
      • Armstrong A.W.
      • Drew J.
      • et al.
      Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial.
      ;
      • Wollenberg A.
      • Howell M.D.
      • Guttman-Yassky E.
      • Silverberg J.I.
      • Kell C.
      • Ranade K.
      • et al.
      Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.
      ). Fezakinumab, an anti–IL-22 mAb showed modest but significant efficacy in reducing skin inflammation in patients with moderate-to-severe AD; however, the improvement persisted beyond the final treatment dose (
      • Guttman-Yassky E.
      • Brunner P.M.
      • Neumann A.U.
      • Khattri S.
      • Pavel A.B.
      • Malik K.
      • et al.
      Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial.
      ) Secukinumab (anti–IL-17A mAb) and MOR106 (anti–IL-17C mAb) both lacked efficacy against the skin inflammation in AD in phase 2 clinical trials (
      • Galapagos N.V.
      A Phase II, randomized, double-blind, placebo-controlled repeated-dose study to evaluate the efficacy, safety, tolerability,and PK/PD of intravenously administered MOR106 in adult subjects with moderate to severe atopic dermatitis.
      ;
      • Ungar B.
      • Pavel A.B.
      • Li R.
      • Kimmel G.
      • Nia J.
      • Hashim P.
      • et al.
      Phase 2 randomized, double-blind study of IL-17-targeting with secukinumab in atopic dermatitis [e-pub ahead of print].
      ). Furthermore, anti-IgE responses have been targeted in AD, but they either lacked efficacy or only had a modest effect in reducing skin inflammation in AD (
      • Gomez G.
      • Jogie-Brahim S.
      • Shima M.
      • Schwartz L.B.
      Omalizumab reverses the phenotypic and functional effects of IgE-enhanced Fc epsilonRI on human skin mast cells.
      ;
      • Krathen R.A.
      • Hsu S.
      Failure of omalizumab for treatment of severe adult atopic dermatitis.
      ;
      • Thaiwat S.
      • Sangasapaviliya A.
      Omalizumab treatment in severe adult atopic dermatitis.
      ;
      • Wang H.H.
      • Li Y.C.
      • Huang Y.C.
      Efficacy of omalizumab in patients with atopic dermatitis: a systematic review and meta-analysis.
      ). Conversely, several clinical trials have shown potential for exacerbation of AD, including recombinant IL-4 therapy that increased Th2 polarization in psoriasis and the use of anti-TNF therapies that induced sporadic and worsening AD-like lesions (
      • Flendrie M.
      • Vissers W.H.
      • Creemers M.C.
      • de Jong E.M.
      • van de Kerkhof P.C.
      • van Riel P.L.
      Dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective study.
      ;
      • Nakamura M.
      • Lee K.
      • Singh R.
      • Zhu T.H.
      • Farahnik B.
      • Abrouk M.
      • et al.
      Eczema as an adverse effect of anti-TNFα therapy in psoriasis and other Th1-mediated diseases: a review.
      ;
      • Rahier J.
      • Buche S.
      • Peyrin–Biroulet L.
      • Bouhnik Y.
      • Duclos B.
      • Louis E.
      • et al.
      Severe skin lesions cause patients with inflammatory bowel disease to discontinue anti–tumor necrosis factor therapy.
      ). However, additional studies are needed to understand how treatment efficacy is influenced by the variations in AD disease among patients.

      Conclusions

      The interactions between barrier dysfunction, dysbiosis, and immune dysregulation are crucial factors in the pathogenesis of AD. Further research is necessary into the roles and directionality of these interactions to better understand and treat this inflammatory skin disease. An improved understanding will help to usher in an era of directed, multifactorial treatments to this complex and heterogeneous disease.

      Conflict of Interest

      LSM is a full-time employee at Janssen Research and Development and may own Johnson & Johnson stock and stock options. LSM has received grant support from AstraZeneca, MedImmune (a subsidiary of AstraZeneca), Pfizer, Boehringer Ingelheim, Regeneron Pharmaceuticals, and Moderna Therapeutics; is a shareholder of Noveome Biotherapeutics; was a paid consultant for Almirall and Janssen Research and Development; and was on the scientific advisory board of Integrated Biotherapeutics, which are all developing therapeutics against infections (including Staphylococcus aureus and other pathogens) and/or inflammatory conditions. NKA has received grant support from Pfizer.

      Acknowledgments

      This work was funded in part by grants R01AR073665 (LSM and NKA), R01AR069502 (LSM and NKA) and R13AR009431-55 (Principal Investigator: Molly F. Kulesz-Martin) from the U.S. National Institutes of Health .

      Disclaimer

      The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. National Institutes of Health.

      Author Contributions

      Conceptualization: GJP, NKA; Funding Acquisition: NKA, LSM. Writing - Original Draft Preparation: GJP, NKA; Writing - Review and Editing: GJP, NKA, LSM

      References

        • Albanesi C.
        • Fairchild H.R.
        • Madonna S.
        • Scarponi C.
        • Pità O.D.
        • Leung D.Y.M.
        • et al.
        IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor cytokine signaling (SOCS)-1, and SOCS-3.
        J Immunol. 2007; 179: 984-992
        • Angelova-Fischer I.
        • Fernandez I.M.
        • Donnadieu M.H.
        • Bulfone-Paus S.
        • Zillikens D.
        • Fischer T.W.
        • et al.
        Injury to the stratum corneum induces in vivo expression of human thymic stromal lymphopoietin in the epidermis.
        J Invest Dermatol. 2010; 130: 2505-2507
        • Archer N.K.
        • Jo J.H.
        • Lee S.K.
        • Kim D.
        • Smith B.
        • Ortines R.V.
        • et al.
        Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.
        J Allergy Clin Immunol. 2019; 143: 1426-1443.e6
        • Asher M.I.
        • Montefort S.
        • Björkstén B.
        • Lai C.K.W.
        • Strachan D.P.
        • Weiland S.K.
        • et al.
        Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys.
        Lancet. 2006; 368 ([published correction appears in Lancet 2007;370:1128]): 733-743
        • Bhattacharya N.
        • Sato W.J.
        • Kelly A.
        • Ganguli-Indra G.
        • Indra A.K.
        Epidermal lipids: key mediators of atopic dermatitis pathogenesis.
        Trends Mol Med. 2019; 25: 551-562
        • Baurecht H.
        • Hotze M.
        • Brand S.
        • Büning C.
        • Cormican P.
        • Corvin A.
        • et al.
        Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.
        Am J Hum Genet. 2015; 96 ([published correction appears in Am J Hum Genet 2015;97:933]): 104-120
        • Baurecht H.
        • Rühlemann M.C.
        • Rodríguez E.
        • Thielking F.
        • Harder I.
        • Erkens A.S.
        • et al.
        Epidermal lipid composition, barrier integrity, and eczematous inflammation are associated with skin microbiome configuration.
        J Allergy Clin Immunol. 2018; 141: 1668-1676.e16
        • Berker M.
        • Frank L.J.
        • Geßner A.L.
        • Grassl N.
        • Holtermann A.V.
        • Höppner S.
        • et al.
        Allergies - A T cells perspective in the era beyond the TH1/TH2 paradigm.
        Clin Immunol. 2017; 174: 73-83
        • Błażewicz I.
        • Jaśkiewicz M.
        • Bauer M.
        • Piechowicz L.
        • Nowicki R.J.
        • Kamysz W.
        • et al.
        Decolonization of Staphylococcus aureus in patients with atopic dermatitis: a reason for increasing resistance to antibiotics?.
        Postepy Dermatol Alergol. 2017; 34: 553-560
        • Bonefeld C.M.
        • Petersen T.H.
        • Bandier J.
        • Agerbeck C.
        • Linneberg A.
        • Ross-Hansen K.
        • et al.
        Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.
        Br J Dermatol. 2016; 175: 706-712
        • Brandt E.B.
        • Sivaprasad U.
        Th2 cytokines and atopic dermatitis.
        J Clin Cell Immunol. 2011; 2: 110
        • Brauweiler A.M.
        • Bin L.
        • Kim B.E.
        • Oyoshi M.K.
        • Geha R.S.
        • Goleva E.
        • et al.
        Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin–induced keratinocyte death.
        J Allergy Clin Immunol. 2013; 131: 421-427.e1
        • Breuer K.
        • HAussler S.
        • Kapp A.
        • Werfel T.
        Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis.
        Br J Dermatol. 2002; 147: 55-61
        • Briot A.
        • Deraison C.
        • Lacroix M.
        • Bonnart C.
        • Robin A.
        • Besson C.
        • et al.
        Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.
        J Exp Med. 2009; 206: 1135-1147
        • Broberg A.
        • Faergemann J.
        Topical antimycotic treatment of atopic dermatitis in the head/neck area. A double-blind randomised study.
        Acta Derm Venereol. 1995; 75: 46-49
        • Brough H.A.
        • Simpson A.
        • Makinson K.
        • Hankinson J.
        • Brown S.
        • Douiri A.
        • et al.
        Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations.
        J Allergy Clin Immunol. 2014; 134: 867-875.e1
        • Brown S.J.
        • McLean W.H.
        One remarkable molecule: filaggrin.
        J Invest Dermatol. 2012; 132: 751-762
        • Brunner P.M.
        • Guttman-Yassky E.
        Racial differences in atopic dermatitis.
        Ann Allergy Asthma Immunol. 2019; 122: 449-455
        • Brunner P.M.
        • He H.
        • Pavel A.B.
        • Czarnowicki T.
        • Lefferdink R.
        • Erickson T.
        • et al.
        The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
        J Am Acad Dermatol. 2019; 81: 510-519
        • Byrd A.L.
        • Belkaid Y.
        • Segre J.A.
        The human skin microbiome.
        Nat Rev Microbiol. 2018; 16: 143-155
        • Byrd A.L.
        • Deming C.
        • Cassidy S.K.B.
        • Harrison O.J.
        • Ng W.I.
        • Conlan S.
        • et al.
        Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis.
        Sci Transl Med. 2017; 9: eaal4651
        • Callewaert C.
        • Nakatsuji T.
        • Knight R.
        • Kosciolek T.
        • Vrbanac A.
        • Kotol P.
        • et al.
        IL-4Rα blockade by dupilumab decreases Staphylococcus aureus colonization and increases microbial diversity in atopic dermatitis.
        J Invest Dermatol. 2020; 140: 191-202.e7
        • Chavanas S.
        • Bodemer C.
        • Rochat A.
        • Hamel-Teillac D.
        • Ali M.
        • Irvine A.D.
        • et al.
        Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.
        Nat Genet. 2000; 25: 141-142
        • Chen H.
        • Common J.E.A.
        • Haines R.L.
        • Balakrishnan A.
        • Brown S.J.
        • Goh C.S.M.
        • et al.
        Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations.
        Br J Dermatol. 2011; 165: 106-114
        • Cho S.H.
        • Strickland I.
        • Tomkinson A.
        • Fehringer A.P.
        • Gelfand E.W.
        • Leung D.Y.M.
        Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model.
        J Invest Dermatol. 2001; 116: 658-663
        • Chung J.
        • Simpson E.L.
        The socioeconomics of atopic dermatitis.
        Ann Allergy Asthma. Immunol. 2019; 122: 360-366
        • Ciprandi G.
        • De Amici M.
        • Giunta V.
        • Marseglia A.
        • Marseglia G.
        Serum interleukin-9 levels are associated with clinical severity in children with atopic dermatitis.
        Pediatr Dermatol. 2013; 30: 222-225
        • Clausen M.L.
        • Edslev S.M.
        • Andersen P.S.
        • Clemmensen K.
        • Krogfelt K.A.
        • Agner T.
        Staphylococcus aureus colonization in atopic eczema and its association with filaggrin gene mutations.
        Br J Dermatol. 2017; 177: 1394-1400
        • Cornelissen C.
        • Marquardt Y.
        • Czaja K.
        • Wenzel J.
        • Frank J.
        • Lüscher-Firzlaff J.
        • et al.
        IL-31 regulates differentiation and filaggrin expression in human organotypic skin models.
        J Allergy Clin Immunol. 2012; 129: 426-433.e4338
        • Czarnowicki T.
        • He H.
        • Krueger J.G.
        • Guttman-Yassky E.
        Atopic dermatitis endotypes and implications for targeted therapeutics.
        J Allergy Clin Immunol. 2019; 143: 1-11
        • De Benedetto A.
        • Kubo A.
        • Beck L.A.
        Skin barrier disruption: a requirement for allergen sensitization?.
        J Invest Dermatol. 2012; 132: 949-963
        • De Benedetto A.
        • Rafaels N.M.
        • McGirt L.Y.
        • Ivanov A.I.
        • Georas S.N.
        • Cheadle C.
        • et al.
        Tight junction defects in patients with atopic dermatitis.
        J Allergy Clin Immunol. 2011; 127: 773-786.e1–7
        • de Veer S.J.
        • Furio L.
        • Harris J.M.
        • Hovnanian A.
        Proteases: common culprits in human skin disorders.
        Trends Mol Med. 2014; 20: 166-178
        • Dharmage S.C.
        • Lowe A.J.
        • Matheson M.C.
        • Burgess J.A.
        • Allen K.J.
        • Abramson M.J.
        Atopic dermatitis and the atopic march revisited.
        Allergy. 2014; 69: 17-27
        • Divekar R.
        • Kita H.
        Recent advances in epithelium-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin) and allergic inflammation.
        Curr Opin Allergy Clin Immunol. 2015; 15: 98-103
        • Eichenfield L.F.
        • Ahluwalia J.
        • Waldman A.
        • Borok J.
        • Udkoff J.
        • Boguniewicz M.
        Current guidelines for the evaluation and management of atopic dermatitis: a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines.
        J Allergy Clin Immunol. 2017; 139: S49-S57
        • Elias P.M.
        Skin barrier function.
        Curr Allergy Asthma Rep. 2008; 8: 299-305
        • Elias P.M.
        • Friend D.S.
        The permeability barrier in mammalian epidermis.
        J Cell Biol. 1975; 65: 180-191
        • Engebretsen K.A.
        • Johansen J.D.
        • Kezic S.
        • Linneberg A.
        • Thyssen J.P.
        The effect of environmental humidity and temperature on skin barrier function and dermatitis.
        J Eur Acad Dermatol Venereol. 2016; 30: 223-249
        • Esaki 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: 1639-1651
        • Fallon 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: 602-608
        • Findley 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: 367-370
        • Flendrie M.
        • Vissers W.H.
        • Creemers M.C.
        • de Jong E.M.
        • van de Kerkhof P.C.
        • van Riel P.L.
        Dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective study.
        Arthritis Res Ther. 2005; 7: R666-R676
        • Fleury O.M.
        • McAleer M.A.
        • Feuillie C.
        • Formosa-Dague C.
        • Sansevere E.
        • Bennett D.E.
        • et al.
        Clumping factor B promotes adherence of Staphylococcus aureus to corneocytes in atopic dermatitis.
        Infect Immun. 2017; 85 (e00994-16)
        • Forbes-Blom E.
        • Camberis M.
        • Prout M.
        • Tang S.C.
        • Le Gros G.L.
        Staphylococcal-derived superantigen enhances peanut induced Th2 responses in the skin.
        Clin Exp Allergy. 2012; 42: 305-314
        • Furue M.
        • Chiba T.
        • Tsuji G.
        • Ulzii D.
        • Kido-Nakahara M.
        • Nakahara T.
        • et al.
        Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies.
        Allergol Int. 2017; 66: 398-403
        • Fyhrquist N.
        • Lehtimäki S.
        • Lahl K.
        • Savinko T.
        • Lappeteläinen A.M.
        • Sparwasser T.
        • et al.
        Foxp3+ cells control Th2 responses in a murine model of atopic dermatitis.
        J Invest Dermatol. 2012; 132: 1672-1680
        • Galapagos N.V.
        A Phase II, randomized, double-blind, placebo-controlled repeated-dose study to evaluate the efficacy, safety, tolerability,and PK/PD of intravenously administered MOR106 in adult subjects with moderate to severe atopic dermatitis.
        (accessed 31 July 2020)
        • Gallo R.L.
        Human skin is the largest epithelial surface for interaction with microbes.
        J Invest Dermatol. 2017; 137: 1213-1214
        • Gavrilova T.
        Immune dysregulation in the pathogenesis of atopic dermatitis.
        Dermatitis. 2018; 29: 57-62
        • Gittler J.K.
        • Shemer A.
        • Suárez-Fariñas M.
        • Fuentes-Duculan J.
        • Gulewicz K.J.
        • Wang C.Q.F.
        • 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: 1344-1354
        • Gomez G.
        • Jogie-Brahim S.
        • Shima M.
        • Schwartz L.B.
        Omalizumab reverses the phenotypic and functional effects of IgE-enhanced Fc epsilonRI on human skin mast cells.
        J Immunol. 2007; 179: 1353-1361
        • Gooderham M.J.
        • Hong H.C.H.
        • Eshtiaghi P.
        • Papp K.A.
        Dupilumab: a review of its use in the treatment of atopic dermatitis.
        J Am Acad Dermatol. 2018; 78: S28-S36
        • Greene R.S.
        • Downing D.T.
        • Pochi P.E.
        • Strauss J.S.
        Anatomical variation in the amount and composition of human skin surface lipid.
        J Invest Dermatol. 1970; 54: 240-247
        • Grice 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: 1190-1192
        • Gustafsson D.
        • Sjöberg O.
        • Foucard T.
        Development of allergies and asthma in infants and young children with atopic dermatitis--a prospective follow-up to 7 years of age.
        Allergy. 2000; 55: 240-245
        • Gutowska-Owsiak D.
        • Schaupp A.L.
        • Salimi M.
        • Selvakumar T.A.
        • McPherson T.
        • Taylor S.
        • et al.
        IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion.
        Exp Dermatol. 2012; 21: 104-110
        • Gutowska-Owsiak D.
        • Schaupp A.L.
        • Salimi M.
        • Taylor S.
        • Ogg G.S.
        Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes.
        Br J Dermatol. 2011; 165: 492-498
        • Guttman-Yassky E.
        • Bissonnette R.
        • Ungar B.
        • Suárez-Fariñas M.
        • Ardeleanu M.
        • Esaki H.
        • et al.
        Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
        J Allergy Clin Immunol. 2019; 143: 155-172
        • Guttman-Yassky E.
        • Blauvelt A.
        • Eichenfield L.F.
        • Paller A.S.
        • Armstrong A.W.
        • Drew J.
        • et al.
        Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial.
        JAMA Dermatol. 2020; 156: 411-420
        • Guttman-Yassky E.
        • Brunner P.M.
        • Neumann A.U.
        • Khattri S.
        • Pavel A.B.
        • Malik K.
        • et al.
        Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial.
        J Am Acad Dermatol. 2018; 78: 872-881.e6
        • Guzik T.J.
        • Bzowska M.
        • Kasprowicz A.
        • Czerniawska-Mysik G.
        • Wójcik K.
        • Szmyd D.
        • et al.
        Persistent skin colonization with Staphylococcus aureus in atopic dermatitis: relationship to clinical and immunological parameters.
        Clin Exp Allergy. 2005; 35: 448-455
        • Hachem J.P.
        • Houben E.
        • Crumrine D.
        • Man M.Q.
        • Schurer N.
        • Roelandt T.
        • et al.
        Serine protease signaling of epidermal permeability barrier homeostasis.
        J Invest Dermatol. 2006; 126: 2074-2086
        • Hajdarbegovic E.
        • Balak D.M.W.
        Anti-interleukin-31 receptor A antibody for atopic dermatitis.
        N Engl J Med. 2017; 376: 2092
        • Hatano Y.
        • Adachi Y.
        • Elias P.M.
        • Crumrine D.
        • Sakai T.
        • Kurahashi R.
        • et al.
        The Th2 cytokine, interleukin-4, abrogates the cohesion of normal stratum corneum in mice: implications for pathogenesis of atopic dermatitis.
        Exp Dermatol. 2013; 22: 30-35
        • Heede N.G.
        • Thyssen J.P.
        • Thuesen B.H.
        • Linneberg A.
        • Szecsi P.B.
        • Stender S.
        • et al.
        Health-related quality of life in adult dermatitis patients stratified by filaggrin genotype.
        Contact Dermatitis. 2017; 76: 167-177
        • Hendricks A.J.
        • Lio P.A.
        • Shi V.Y.
        Management recommendations for dupilumab partial and non-durable responders in atopic dermatitis.
        Am J Clin Dermatol. 2019; 20: 565-569
        • Herberth G.
        • Heinrich J.
        • Röder S.
        • Figl A.
        • Weiss M.
        • Diez U.
        • et al.
        Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life.
        Pediatr Allergy Immunol. 2010; 21: 5-13
        • Higaki S.
        • Morohashi M.
        • Yamagishi T.
        • Hasegawa Y.
        Comparative study of staphylococci from the skin of atopic dermatitis patients and from healthy subjects.
        Int J Dermatol. 1999; 38: 265-269
        • Hon K.L.
        • Tsang Y.C.K.
        • Lee V.W.Y.
        • Pong N.H.
        • Ha G.
        • Lee S.T.
        • et al.
        Efficacy of sodium hypochlorite (bleach) baths to reduce Staphylococcus aureus colonization in childhood onset moderate-to-severe eczema: a randomized, placebo-controlled cross-over trial.
        J Dermatol Treat. 2016; 27: 156-162
        • Hönzke S.
        • Wallmeyer L.
        • Ostrowski A.
        • Radbruch M.
        • Mundhenk L.
        • Schäfer-Korting M.
        • et al.
        Influence of Th2 cytokines on the cornified envelope, tight junction proteins, and β-defensins in filaggrin-deficient skin equivalents.
        J Invest Dermatol. 2016; 136: 631-639
        • Hosogi M.
        • Schmelz M.
        • Miyachi Y.
        • Ikoma A.
        Bradykinin is a potent pruritogen in atopic dermatitis: a switch from pain to itch.
        Pain. 2006; 126: 16-23
        • Howell M.D.
        • Boguniewicz M.
        • Pastore S.
        • Novak N.
        • Bieber T.
        • Girolomoni G.
        • et al.
        Mechanism of HBD-3 deficiency in atopic dermatitis.
        Clin Immunol. 2006; 121: 332-338
        • Howell 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: 2248-2258
        • Howell 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. 2009; 124: R7-R12
        • Huang J.T.
        • Abrams M.
        • Tlougan B.
        • Rademaker A.
        • Paller A.S.
        Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity.
        Pediatrics. 2009; 123: e808-e814
        • Hung S.H.
        • Lin Y.T.
        • Chu C.Y.
        • Lee C.C.
        • Liang T.C.
        • Yang Y.H.
        • et al.
        Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics.
        Ann Allergy Asthma Immunol. 2007; 98: 51-56
        • Hussain M.
        • Borcard L.
        • Walsh K.P.
        • Rodriguez M.P.
        • Mueller C.
        • Kim B.S.
        • et al.
        Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy.
        J Allergy Clin Immunol. 2018; 141: 223-234.e5
        • Hvid M.
        • Johansen C.
        • Deleuran B.
        • Kemp K.
        • Deleuran M.
        • Vestergaard C.
        Regulation of caspase 14 expression in keratinocytes by inflammatory cytokines--a possible link between reduced skin barrier function and inflammation?.
        Exp Dermatol. 2011; 20: 633-636
        • Ishikawa J.
        • Narita H.
        • Kondo N.
        • Hotta M.
        • Takagi Y.
        • Masukawa Y.
        • et al.
        Changes in the ceramide profile of atopic dermatitis patients.
        J Invest Dermatol. 2010; 130: 2511-2514
        • Janssens M.
        • van Smeden J.
        • Gooris G.S.
        • Bras W.
        • Portale G.
        • Caspers P.J.
        • et al.
        Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients.
        J Lipid Res. 2012; 53: 2755-2766
        • Jarrett R.
        • Salio M.
        • Lloyd-Lavery A.
        • Subramaniam S.
        • Bourgeois E.
        • Archer C.
        • et al.
        Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite–derived phospholipase.
        Sci Transl Med. 2016; 8: 325ra18
        • Jee M.H.
        • Johansen J.D.
        • Buus T.B.
        • Petersen T.H.
        • Gadsbøll A.S.Ø.
        • Woetmann A.
        • et al.
        Increased production of IL-17A-producing γδ T cells in the thymus of filaggrin-deficient mice.
        Front Immunol. 2018; 9: 988
        • Jeong S.K.
        • Kim H.J.
        • Youm J.K.
        • Ahn S.K.
        • Choi E.H.
        • Sohn M.H.
        • et al.
        Mite and cockroach allergens activate protease-activated receptor 2 and delay epidermal permeability barrier recovery.
        J Invest Dermatol. 2008; 128: 1930-1939
        • Jinnestål C.L.
        • Belfrage E.
        • Bäck O.
        • Schmidtchen A.
        • Sonesson A.
        Skin barrier impairment correlates with cutaneous Staphylococcus aureus colonization and sensitization to skin-associated microbial antigens in adult patients with atopic dermatitis.
        Int J Dermatol. 2014; 53: 27-33
        • Kanda N.
        • Hoashi T.
        • Saeki H.
        The roles of sex hormones in the course of atopic dermatitis.
        Int J Mol Sci. 2019; 20: 4660
        • Kantor R.
        • Silverberg J.I.
        Environmental risk factors and their role in the management of atopic dermatitis.
        Expert Rev Clin Immunol. 2017; 13: 15-26
        • Kao J.S.
        • Fluhr J.W.
        • Man M.Q.
        • Fowler A.J.
        • Hachem J.P.
        • Crumrine D.
        • et al.
        Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities.
        J Invest Dermatol. 2003; 120: 456-464
        • Kezic S.
        • O’Regan G.M.
        • Yau N.
        • Sandilands A.
        • Chen H.
        • Campbell L.E.
        • et al.
        Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.
        Allergy. 2011; 66: 934-940
        • Kido-Nakahara M.
        • Furue M.
        • Ulzii D.
        • Nakahara T.
        Itch in atopic dermatitis.
        Immunol Allergy Clin North Am. 2017; 37: 113-122
        • Kim B.E.
        • Leung D.Y.M.
        • Boguniewicz M.
        • Howell M.D.
        Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6.
        Clin Immunol. 2008; 126: 332-337
        • Kim M.
        • Jung M.
        • Hong S.P.
        • Jeon H.
        • Kim M.J.
        • Cho M.Y.
        • et al.
        Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function.
        Exp Dermatol. 2010; 19: 501-510
        • Kobayashi T.
        • Glatz M.
        • Horiuchi K.
        • Kawasaki H.
        • Akiyama H.
        • Kaplan D.H.
        • et al.
        Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis.
        Immunity. 2015; 42: 756-766
        • Kondo H.
        • Ichikawa Y.
        • Imokawa G.
        Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response.
        Eur J Immunol. 1998; 28: 769-779
        • Kong H.H.
        • Oh J.
        • Deming C.
        • Conlan S.
        • Grice E.A.
        • Beatson M.A.
        • et al.
        Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis.
        Genome Res. 2012; 22: 850-859
        • Krathen R.A.
        • Hsu S.
        Failure of omalizumab for treatment of severe adult atopic dermatitis.
        J Am Acad Dermatol. 2005; 53: 338-340
        • Kuo I.H.
        • Yoshida T.
        • De Benedetto A.D.
        • Beck L.A.
        The cutaneous innate immune response in patients with atopic dermatitis.
        J Allergy Clin Immunol. 2013; 131: 266-278
        • Laborel-Préneron E.
        • Bianchi P.
        • Boralevi F.
        • Lehours P.
        • Fraysse F.
        • Morice-Picard F.
        • et al.
        Effects of the Staphylococcus aureus and Staphylococcus epidermidis secretomes isolated from the skin microbiota of atopic children on CD4+ T cell activation.
        PLoS One. 2015; 10 ([published correction appears in PLoS One 2015;10:e0144323]): e0141067
        • Leung D.Y.
        • Harbeck R.
        • Bina P.
        • Reiser R.F.
        • Yang E.
        • Norris D.A.
        • et al.
        Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens.
        J Clin Invest. 1993; 92: 1374-1380
        • Leung D.Y.M.
        Pathogenesis of atopic dermatitis.
        J Allergy Clin Immunol. 1999; 104: S99-S108
        • Licari A.
        • Castagnoli R.
        • Marseglia A.
        • Olivero F.
        • Votto M.
        • Ciprandi G.
        • et al.
        Dupilumab to treat Type 2 inflammatory diseases in children and adolescents.
        Paediatr Drugs. 2020; 22: 295-310
        • Liu H.
        • Archer N.K.
        • Dillen C.A.
        • Wang Y.
        • Ashbaugh A.G.
        • Ortines R.V.
        • et al.
        Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-Mediated T cell responses.
        Cell Host Microbe. 2017; 22: 653-666.e5
        • Ma L.
        • Xue H.B.
        • Guan X.H.
        • Shu C.M.
        • Zhang J.H.
        • Yu J.
        Possible pathogenic role of T helper type 9 cells and interleukin (IL)-9 in atopic dermatitis.
        Clin Exp Immunol. 2014; 175: 25-31
        • Macheleidt O.
        • Sandhoff K.
        • Kaiser H.W.
        Deficiency of epidermal protein-bound ω-hydroxyceramides in atopic dermatitis.
        J Invest Dermatol. 2002; 119: 166-173
        • Margolis D.J.
        • Apter A.J.
        • Gupta J.
        • Hoffstad O.
        • Papadopoulos M.
        • Campbell L.E.
        • et al.
        The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort.
        J Allergy Clin Immunol. 2012; 130: 912-917
        • Margolis D.J.
        • Mitra N.
        • Kim B.
        • Gupta J.
        • Hoffstad O.J.
        • Papadopoulos M.
        • et al.
        Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis.
        Hum Immunol. 2015; 76: 571-577
        • Mashiko S.
        • Mehta H.
        • Bissonnette R.
        • Sarfati M.
        Increased frequencies of basophils, type 2 innate lymphoid cells and Th2 cells in skin of patients with atopic dermatitis but not psoriasis.
        J Dermatol Sci. 2017; 88: 167-174
        • Megna M.
        • Napolitano M.
        • Patruno C.
        • Villani A.
        • Balato A.
        • Monfrecola G.
        • et al.
        Systemic treatment of adult atopic dermatitis: a review.
        Dermatol Ther. 2017; 7: 1-23
        • Mollanazar N.K.
        • Smith P.K.
        • Yosipovitch G.
        Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
        Clin Rev Allergy Immunol. 2016; 51: 263-292
        • Moniaga C.S.
        • Jeong S.K.
        • Egawa G.
        • Nakajima S.
        • Hara-Chikuma M.
        • Jeon J.E.
        • et al.
        Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.
        Am J Pathol. 2013; 182: 841-851
        • Moosbrugger-Martinz V.
        • Gruber R.
        • Ladstätter K.
        • Bellutti M.
        • Blunder S.
        • Schmuth M.
        • et al.
        Filaggrin null mutations are associated with altered circulating Tregs in atopic dermatitis.
        J Cell Mol Med. 2019; 23: 1288-1299
        • Myles I.A.
        • Earland N.J.
        • Anderson E.D.
        • Moore I.N.
        • Kieh M.D.
        • Williams K.W.
        • et al.
        First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis.
        JCI Insight. 2018; 3: e120608
        • Myles I.A.
        • Williams K.W.
        • Reckhow J.D.
        • Jammeh M.L.
        • Pincus N.B.
        • Sastalla I.
        • et al.
        Transplantation of human skin microbiota in models of atopic dermatitis.
        JCI Insight. 2016; 1: e86955
        • Nakajima S.
        • Nomura T.
        • Common J.
        • Kabashima K.
        Insights into atopic dermatitis gained from genetically defined mouse models.
        J Allergy Clin Immunol. 2019; 143: 13-25
        • Nakamura M.
        • Lee K.
        • Singh R.
        • Zhu T.H.
        • Farahnik B.
        • Abrouk M.
        • et al.
        Eczema as an adverse effect of anti-TNFα therapy in psoriasis and other Th1-mediated diseases: a review.
        J Dermatol Treat. 2017; 28: 237-241
        • Nakamura Y.
        • Oscherwitz J.
        • Cease K.B.
        • Chan S.M.
        • Muñoz-Planillo R.
        • Hasegawa M.
        • et al.
        Staphylococcus δ-toxin induces allergic skin disease by activating mast cells.
        Nature. 2013; 503: 397-401
        • Nakatsuji T.
        • Chen T.H.
        • Narala S.
        • Chun K.A.
        • Two A.M.
        • Yun T.
        • et al.
        Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis.
        Sci Transl Med. 2017; 9: eaah4680
        • Nakatsuji T.
        • Chen T.H.
        • Two A.M.
        • Chun K.A.
        • Narala S.
        • Geha R.S.
        • et al.
        Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression.
        J Invest Dermatol. 2016; 136: 2192-2200
        • Nanda A.
        Concomitance of psoriasis and atopic dermatitis.
        Dermatology. 1995; 191: 72
        • Nemes Z.
        • Steinert P.M.
        Bricks and mortar of the epidermal barrier.
        Exp Mol Med. 1999; 31: 5-19
        • Niebuhr M.
        • Mainardy J.
        • Heratizadeh A.
        • Satzger I.
        • Werfel T.
        Staphylococcal exotoxins induce interleukin 22 in human th22 cells.
        Int Arch Allergy Immunol. 2014; 165: 35-39
        • Niebuhr M.
        • Scharonow H.
        • Gathmann M.
        • Mamerow D.
        • Werfel T.
        Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis.
        J Allergy Clin Immunol. 2010; 126: 1176-1183.e4
        • Nomura I.
        • Goleva E.
        • Howell M.D.
        • Hamid Q.A.
        • Ong P.Y.
        • Hall C.F.
        • et al.
        Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
        J Immunol. 2003; 171: 3262-3269
        • Oldhoff J.M.
        • Darsow U.
        • Werfel T.
        • Katzer K.
        • Wulf A.
        • Laifaoui J.
        • et al.
        Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis.
        Allergy. 2005; 60: 693-696
        • Ong P.Y.
        • Ohtake T.
        • Brandt C.
        • Strickland I.
        • Boguniewicz M.
        • Ganz T.
        • et al.
        Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
        N Engl J Med. 2002; 347: 1151-1160
        • Oyoshi M.K.
        • Larson R.P.
        • Ziegler S.F.
        • Geha R.S.
        Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression.
        J Allergy Clin Immunol. 2010; 126: 976-984.e5
        • Oyoshi M.K.
        • Murphy G.F.
        • Geha R.S.
        Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen.
        J Allergy Clin Immunol. 2009; 124: 485-493.e1
        • Paller A.S.
        • Kong H.H.
        • Seed P.
        • Naik S.
        • Scharschmidt T.C.
        • Gallo R.L.
        • et al.
        The microbiome in patients with atopic dermatitis.
        J Allergy Clin Immunol. 2019; 143 ([published correction appears in J Allergy Clin Immunol 2019;143:1660]): 26-35
        • Palmer C.N.A.
        • Irvine A.D.
        • Terron-Kwiatkowski A.
        • Zhao Y.
        • Liao H.
        • Lee S.P.
        • et al.
        Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
        Nat Genet. 2006; 38: 441-446
        • Pappas A.
        Epidermal surface lipids.
        Dermatoendocrinol. 2009; 1: 72-76
        • Pascolini C.
        • Sinagra J.
        • Pecetta S.
        • Bordignon V.
        • De Santis A.
        • Cilli L.
        • et al.
        Molecular and immunological characterization of Staphylococcus aureus in pediatric atopic dermatitis: implications for prophylaxis and clinical management.
        Clin Dev Immunol. 2011; 2011: 718708
        • Paternoster L.
        • Standl M.
        • Waage J.
        • Baurecht H.
        • Hotze M.
        • Strachan D.P.
        • et al.
        Multi-ethnic genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.
        Nat Genet. 2015; 47: 1449-1456
        • Proksch E.
        • Fölster-Holst R.
        • Jensen J.M.
        Skin barrier function, epidermal proliferation and differentiation in eczema.
        J Dermatol Sci. 2006; 43: 159-169
        • Quiroz F.G.
        • Fiore V.F.
        • Levorse J.
        • Polak L.
        • Wong E.
        • Pasolli H.A.
        • et al.
        Liquid-liquid phase separation drives skin barrier formation.
        Science. 2020; 367: eaax9554
        • Rahier J.
        • Buche S.
        • Peyrin–Biroulet L.
        • Bouhnik Y.
        • Duclos B.
        • Louis E.
        • et al.
        Severe skin lesions cause patients with inflammatory bowel disease to discontinue anti–tumor necrosis factor therapy.
        Clin Gastroenterol Hepatol. 2010; 8: 1048-1055
        • Rawlings A.V.
        • Harding C.R.
        Moisturization and skin barrier function.
        Dermatol Ther. 2004; 17: 43-48
        • Saeki H.
        • Kuwata S.
        • Nakagawa H.
        • Etoh T.
        • Yanagisawa M.
        • Miyamoto M.
        • et al.
        Analysis of disease-associated amino acid epitopes on HLA class II molecules in atopic dermatitis.
        J Allergy Clin Immunol. 1995; 96: 1061-1068
        • Salimi M.
        • Barlow J.L.
        • Saunders S.P.
        • Xue L.
        • Gutowska-Owsiak D.
        • Wang X.
        • et al.
        A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis.
        J Exp Med. 2013; 210: 2939-2950
        • Scharschmidt 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: 496-506.e1
        • Schauber J.
        • Gallo R.L.
        Antimicrobial peptides and the skin immune defense system.
        J Allergy Clin Immunol. 2008; 122: 261-266
        • Seite S.
        • Flores G.E.
        • Henley J.B.
        • Martin R.
        • Zelenkova H.
        • Aguilar L.
        • et al.
        Microbiome of affected and unaffected skin of patients with atopic dermatitis before and after emollient treatment.
        J Drugs Dermatol. 2014; 13: 1365-1372
        • Shi B.
        • Leung D.Y.M.
        • Taylor P.A.
        • Li H.
        Methicillin-resistant Staphylococcus aureus colonization is associated with decreased skin commensal bacteria in atopic dermatitis.
        J Invest Dermatol. 2018; 138: 1668-1671
        • Simpson E.L.
        • Bieber T.
        • Guttman-Yassky E.
        • Beck L.A.
        • Blauvelt A.
        • Cork M.J.
        • et al.
        Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.
        N Engl J Med. 2016; 375: 2335-2348
        • Simpson E.L.
        • Villarreal M.
        • Jepson B.
        • Rafaels N.
        • David G.
        • Hanifin J.
        • et al.
        Patients with atopic dermatitis colonized with Staphylococcus aureus have a distinct phenotype and endotype.
        J Invest Dermatol. 2018; 138: 2224-2233
        • Soares P.
        • Fidler K.
        • Felton J.
        • Tavendale R.
        • Hövels A.
        • Bremner S.A.
        • et al.
        Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs.
        Br J Dermatol. 2018; 179: 717-723
        • Sonesson A.
        • Bartosik J.
        • Christiansen J.
        • Roscher I.
        • Nilsson F.
        • Schmidtchen A.
        • et al.
        Sensitization to skin-associated microorganisms in adult patients with atopic dermatitis is of importance for disease severity.
        Acta Derm Venereol. 2013; 93: 340-345
        • Sparber F.
        • De Gregorio C.
        • Steckholzer S.
        • Ferreira F.M.
        • Dolowschiak T.
        • Ruchti F.
        • et al.
        The skin commensal yeast Malassezia triggers a type 17 response that coordinates anti-fungal immunity and exacerbates skin inflammation.
        Cell Host Microbe. 2019; 25: 389-403.e6
        • Su C.
        • Yang T.
        • Wu Z.
        • Zhong J.
        • Huang Y.
        • Huang T.
        • et al.
        Differentiation of T-helper cells in distinct phases of atopic dermatitis involves Th1/Th2 and Th17/Treg.
        Eur J Inflamm. 2017; 15: 46-52
        • Sugaya M.
        The role of Th17-related cytokines in atopic dermatitis.
        Int J Mol Sci. 2020; 21: 1314
        • Takai T.
        • Ikeda S.
        Barrier Dysfunction caused by environmental proteases in the pathogenesis of allergic diseases.
        Allergol Int. 2011; 60: 25-35
        • Terada M.
        • Tsutsui H.
        • Imai Y.
        • Yasuda K.
        • Mizutani H.
        • Yamanishi K.
        • et al.
        Contribution of IL-18 to atopic-dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice.
        Proc Natl Acad Sci USA. 2006; 103: 8816-8821
        • Thaiwat S.
        • Sangasapaviliya A.
        Omalizumab treatment in severe adult atopic dermatitis.
        Asian Pac J Allergy Immunol. 2011; 29: 357-360
        • Ungar B.
        • Pavel A.B.
        • Li R.
        • Kimmel G.
        • Nia J.
        • Hashim P.
        • et al.
        Phase 2 randomized, double-blind study of IL-17-targeting with secukinumab in atopic dermatitis [e-pub ahead of print].
        J Allergy Clin Immunol. 2020; (accessed 31 July 2020)https://doi.org/10.1016/j.jaci.2020.04.055
        • van der Heijden F.L.
        • Wierenga E.A.
        • Bos J.D.
        • Kapsenberg M.L.
        High frequency of IL-4-producing CD4+ allergen-specific T lymphocytes in atopic dermatitis lesional skin.
        J Invest Dermatol. 1991; 97: 389-394
        • van Smeden J.
        • Janssens M.
        • Kaye E.C.J.
        • Caspers P.J.
        • Lavrijsen A.P.
        • Vreeken R.J.
        • et al.
        The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients.
        Exp Dermatol. 2014; 23: 45-52
        • Vestergaard C.
        • Yoneyama H.
        • Murai M.
        • Nakamura K.
        • Tamaki K.
        • Terashima Y.
        • et al.
        Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions.
        J Clin Invest. 1999; 104: 1097-1105
        • Wallmeyer L.
        • Dietert K.
        • Sochorová M.
        • Gruber A.D.
        • Kleuser B.
        • Vávrová K.
        • et al.
        TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents.
        Sci Rep. 2017; 7: 1-12
        • Wang H.H.
        • Li Y.C.
        • Huang Y.C.
        Efficacy of omalizumab in patients with atopic dermatitis: a systematic review and meta-analysis.
        J Allergy Clin Immunol. 2016; 138: 1719-1722.e1
        • Weidinger S.
        • Beck L.A.
        • Bieber T.
        • Kabashima K.
        • Irvine A.D.
        Atopic dermatitis.
        Nat Rev Dis Primers. 2018; 4: 1
        • Williams M.R.
        • Costa S.K.
        • Zaramela L.S.
        • Khalil S.
        • Todd D.A.
        • Winter H.L.
        • et al.
        Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis.
        Sci Transl Med. 2019; 11: eaat8329
        • Williams M.R.
        • Nakatsuji T.
        • Sanford J.A.
        • Vrbanac A.F.
        • Gallo R.L.
        Staphylococcus aureus induces increased serine protease activity in keratinocytes.
        J Invest Dermatol. 2017; 137: 377-384
        • Wollenberg A.
        • Howell M.D.
        • Guttman-Yassky E.
        • Silverberg J.I.
        • Kell C.
        • Ranade K.
        • et al.
        Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.
        J Allergy Clin Immunol. 2019; 143: 135-141
        • Yu J.
        • Luo Y.
        • Zhu Z.
        • Zhou Y.
        • Sun L.
        • Gao J.
        • et al.
        A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.
        J Allergy Clin Immunol. 2019; 143: 2108-2119.e12
        • Zaniboni M.C.
        • Samorano L.P.
        • Orfali R.L.
        • Aoki V.
        Skin barrier in atopic dermatitis: beyond filaggrin.
        An Bras Dermatol. 2016; 91: 472-478
        • Zeeuwen P.L.
        • Boekhorst J.
        • van den Bogaard E.H.
        • de Koning H.D.
        • van de Kerkhof P.M.
        • Saulnier D.M.
        • et al.
        Microbiome dynamics of human epidermis following skin barrier disruption.
        Genome Biol. 2012; 13: R101
        • Zeeuwen P.L.J.M.
        • Ederveen T.H.A.
        • van der Krieken D.A.
        • Niehues H.
        • Boekhorst J.
        • Kezic S.
        • et al.
        Gram-positive anaerobe cocci are underrepresented in the microbiome of filaggrin-deficient human skin.
        J Allergy Clin Immunol. 2017; 139: 1368-1371