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

Published: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)
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      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