Allergy Asthma Immunol Res.  2018 May;10(3):207-215. 10.4168/aair.2018.10.3.207.

Significance of Skin Barrier Dysfunction in Atopic Dermatitis

• Kim BE
• Leung DY

• KMID: 2409055
• DOI: http://doi.org/10.4168/aair.2018.10.3.207

Abstract

The epidermis contains epithelial cells, immune cells, and microbes which provides a physical and functional barrier to the protection of human skin. It plays critical roles in preventing environmental allergen penetration into the human body and responsing to microbial pathogens. Atopic dermatitis (AD) is the most common, complex chronic inflammatory skin disease. Skin barrier dysfunction is the initial step in the development of AD. Multiple factors, including immune dysregulation, filaggrin mutations, deficiency of antimicrobial peptides, and skin dysbiosis contribute to skin barrier defects. In the initial phase of AD, treatment with moisturizers improves skin barrier function and prevents the development of AD. With the progression of AD, effective topical and systemic therapies are needed to reduce immune pathway activation and general inflammation. Targeted microbiome therapy is also being developed to correct skin dysbiosis associated with AD. Improved identification and characterization of AD phenotypes and endotypes are required to optimize the precision medicine approach to AD.

Keyword

Atopic dermatitis; epidermal barrier; antimicrobial peptide; microbiome; moisturizer

MeSH Terms

Dermatitis, Atopic*
Dysbiosis
Epidermis
Epithelial Cells
Human Body
Humans
Inflammation
Microbiota
Peptides
Phenotype
Precision Medicine
Skin Diseases
Skin*
Peptides

Figure

• 

  Fig. 1 Impaired skin barrier enhances allergen penetration and activates the innate immune system. Multiple factors, including immune dysregulation, defects in terminal epithelial differentiation such as lack of filaggrin (FLG), deficiency of antimicrobial peptides (AMPs), altered composition of stratum corneum intercellular lipids, and altered skin microbiome cause skin barrier defects. Source: Czarnowicki et al. J Allergy Clin Immunol 2017;139:1723–34.

• 

  Fig. 2 Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibit significantly reduced filaggrin. Primary human keratinocytes were cultured for 5 days in 0.06 or 1.3 mmol/L CaCl2 in the presence of IL-4 plus IL-13 or interferon (IFN)-gamma. *P<0.05; ***P<0.001 between the exposure groups. Source: Howell et al. J Allergy Clin Immunol 2007;120:150–5.

Reference

1. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017; 139:S65–S76. PMID: 28390479.

2. Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schäppi G, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: where are we, and where should we go? J Allergy Clin Immunol. 2017; 139:S58–S64. PMID: 28390478.

3. Leung DY, Guttman-Yassky E. Assessing the current treatment of atopic dermatitis: unmet needs. J Allergy Clin Immunol. 2017; 139:S47–S48. PMID: 28390476.

4. Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. J Allergy Clin Immunol. 2017; 139:1723–1734. PMID: 28583445.

5. Ahn K. The prevalence of atopic dermatitis in Korean children. Allergy Asthma Immunol Res. 2016; 8:1–2. PMID: 26540495.

6. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006; 155:145–151. PMID: 16792766.

7. Rao DR, Sordillo JE, Kopel LS, Gaffin JM, Sheehan WJ, Hoffman E, et al. Association between allergic sensitization and exhaled nitric oxide in children in the School Inner-city Asthma Study. Ann Allergy Asthma Immunol. 2015; 114:256–257.e1. PMID: 25595887.

8. Boguniewicz M, Abramovits W, Paller A, Whitaker-Worth DL, Prendergast M, Cheng JW, et al. A multiple-domain framework of clinical, economic, and patient-reported outcomes for evaluating benefits of intervention in atopic dermatitis. J Drugs Dermatol. 2007; 6:416–423. PMID: 17668539.

9. Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. Pediatr Dermatol. 2008; 25:1–6.

10. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014; 134:769–779. PMID: 25282559.

11. Mahdavinia M, Rasmussen HE, Engen P, Van den Berg JP, Davis E, Engen K, et al. Atopic dermatitis and food sensitization in South African toddlers: role of fiber and gut microbiota. Ann Allergy Asthma Immunol. 2017; 118:742–743.e3. PMID: 28583264.

12. Visitsunthorn N, Chatpornvorarux S, Pacharn P, Jirapongsananuruk O. Atopy patch test in children with atopic dermatitis. Ann Allergy Asthma Immunol. 2016; 117:668–673. PMID: 27979025.

13. Roerdink EM, Flokstra-de Blok BM, Blok JL, Schuttelaar ML, Niggemann B, Werfel T, et al. Association of food allergy and atopic dermatitis exacerbations. Ann Allergy Asthma Immunol. 2016; 116:334–338. PMID: 26947239.

14. Pyun BY. Natural history and risk factors of atopic dermatitis in children. Allergy Asthma Immunol Res. 2015; 7:101–105. PMID: 25729616.

15. Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011; 3:67–73. PMID: 21461244.

16. Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, 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. PMID: 28228596.

17. Smith AR, Knaysi G, Wilson JM, Wisniewski JA. The skin as a route of allergen exposure: part I. Immune components and mechanisms. Curr Allergy Asthma Rep. 2017; 17:6. PMID: 28185161.

18. van Smeden J, Bouwstra JA. Stratum corneum lipids: their role for the skin barrier function in healthy subjects and atopic dermatitis patients. Curr Probl Dermatol. 2016; 49:8–26. PMID: 26844894.

19. Busse D, Kudella P, Grüning NM, Gisselmann G, Ständer S, Luger T, et al. A synthetic sandalwood odorant induces wound-healing processes in human keratinocytes via the olfactory receptor OR2AT4. J Invest Dermatol. 2014; 134:2823–2832. PMID: 24999593.

20. Erkoçoğlu M, Kocabaş CN. Role of IgA and IgM in severity of atopic dermatitis. Ann Allergy Asthma Immunol. 2015; 114:433.

21. Kim BE, Leung DY. Epidermal barrier in atopic dermatitis. Allergy Asthma Immunol Res. 2012; 4:12–16. PMID: 22211165.

22. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005; 6:328–340. PMID: 15803139.

23. Kalinin A, Marekov LN, Steinert PM. Assembly of the epidermal cornified cell envelope. J Cell Sci. 2001; 114:3069–3070. PMID: 11590230.

24. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable barrier. Exp Dermatol. 2008; 17:1063–1072. PMID: 19043850.

25. Potten CS. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int Rev Cytol. 1981; 69:271–318. PMID: 6163744.

26. Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol. 2002; 156:1099–1111. PMID: 11889141.

27. Wan H, Winton HL, Soeller C, Taylor GW, Gruenert DC, Thompson PJ, et al. The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy. 2001; 31:279–294. PMID: 11251630.

28. Schneeberger EE, Lynch RD. Structure, function, and regulation of cellular tight junctions. Am J Physiol. 1992; 262:L647–L661. PMID: 1616050.

29. Jonca N, Guerrin M, Hadjiolova K, Caubet C, Gallinaro H, Simon M, et al. Corneodesmosin, a component of epidermal corneocyte desmosomes, displays homophilic adhesive properties. J Biol Chem. 2002; 277:5024–5029. PMID: 11739386.

30. Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009; 30:131–141. PMID: 19217824.

31. Nakatsuji T, Gallo RL. Antimicrobial peptides: old molecules with new ideas. J Invest Dermatol. 2012; 132:887–895. PMID: 22158560.

32. Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE, et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006; 24:341–348. PMID: 16546102.

33. Niyonsaba F, Nagaoka I, Ogawa H, Okumura K. Multifunctional antimicrobial proteins and peptides: natural activators of immune systems. Curr Pharm Des. 2009; 15:2393–2413. PMID: 19601839.

34. Kiatsurayanon C, Niyonsaba F, Smithrithee R, Akiyama T, Ushio H, Hara M, et al. Host defense (Antimicrobial) peptide, human β-defensin-3, improves the function of the epithelial tight-junction barrier in human keratinocytes. J Invest Dermatol. 2014; 134:2163–2173. PMID: 24633129.

35. Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T, et al. Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J Gene Med. 2009; 11:220–228. PMID: 19115333.

36. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol. 2011; 127:773–786.e1-7. PMID: 21163515.

37. Niyonsaba F, Ushio H, Nagaoka I, Okumura K, Ogawa H. The human beta-defensins (-1, -2, -3, -4) and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes. J Immunol. 2005; 175:1776–1784. PMID: 16034119.

38. Niyonsaba F, Ushio H, Nakano N, Ng W, Sayama K, Hashimoto K, et al. Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol. 2007; 127:594–604. PMID: 17068477.

39. Golec M. Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide. Ann Agric Environ Med. 2007; 14:1–4. PMID: 17655171.

40. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep. 2009; 9:265–272. PMID: 19656472.

41. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol. 2008; 121:1337–1343. PMID: 18329087.

42. Kezic S, Jakasa I. Filaggrin and skin barrier function. Curr Probl Dermatol. 2016; 49:1–7. PMID: 26844893.

43. Chng KR, Tay AS, Li C, Ng AH, Wang J, Suri BK, et al. Whole metagenome profiling reveals skin microbiome-dependent susceptibility to atopic dermatitis flare. Nat Microbiol. 2016; 1:16106. PMID: 27562258.

44. Oh J, Conlan S, Polley EC, Segre JA, Kong HH. Shifts in human skin and nares microbiota of healthy children and adults. Genome Med. 2012; 4:77. PMID: 23050952.

45. Oh J, Byrd AL, Deming C, Conlan S, Kong HH, NISC Comparative Sequencing Program, et al. Biogeography and individuality shape function in the human skin metagenome. Nature. 2014; 514:59–64. PMID: 25279917.

46. Capone KA, Dowd SE, Stamatas GN, Nikolovski J. Diversity of the human skin microbiome early in life. J Invest Dermatol. 2011; 131:2026–2032. PMID: 21697884.

47. Knaysi G, Smith AR, Wilson JM, Wisniewski JA. The skin as a route of allergen exposure: part II. Allergens and role of the microbiome and environmental exposures. Curr Allergy Asthma Rep. 2017; 17:7. PMID: 28210979.

48. Nakamizo S, Egawa G, Honda T, Nakajima S, Belkaid Y, Kabashima K. Commensal bacteria and cutaneous immunity. Semin Immunopathol. 2015; 37:73–80. PMID: 25326105.

49. Byrd AL, Deming C, Cassidy SK, Harrison OJ, Ng WI, Conlan S, et al. Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med. 2017; 9:eaal4651. PMID: 28679656.

50. Lee E, Lee SY, Kang MJ, Kim K, Won S, Kim BJ, et al. Clostridia in the gut and onset of atopic dermatitis via eosinophilic inflammation. Ann Allergy Asthma Immunol. 2016; 117:91–92.e1. PMID: 27179583.

51. Tang KT, Ku KC, Chen DY, Lin CH, Tsuang BJ, Chen YH. Adult atopic dermatitis and exposure to air pollutants-a nationwide population-based study. Ann Allergy Asthma Immunol. 2017; 118:351–355. PMID: 28126434.

52. Knox SM, Erwin EA, Mosser-Goldfarb JL, Scherzer R. Sensitization patterns among patients with atopic dermatitis evaluated in a large tertiary care pediatric center. Ann Allergy Asthma Immunol. 2017; 118:645–647. PMID: 28372896.

53. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest. 1998; 101:1614–1622. PMID: 9541491.

54. Nikolovski J, Stamatas GN, Kollias N, Wiegand BC. Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life. J Invest Dermatol. 2008; 128:1728–1736. PMID: 18200056.

55. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011; 365:1315–1327. PMID: 21991953.

56. Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, et al. Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age. Br J Dermatol. 2010; 163:1333–1336. PMID: 21137118.

57. Kim BE, Bin L, Ye YM, Ramamoorthy P, Leung DY. IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication. J Invest Dermatol. 2013; 133:2678–2685. PMID: 23657503.

58. Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest. 1994; 94:870–876. PMID: 8040343.

59. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007; 120:150–155. PMID: 17512043.

60. Jang H, Matsuda A, Jung K, Karasawa K, Matsuda K, Oida K, et al. Skin pH is the master switch of kallikrein 5-mediated skin barrier destruction in a murine atopic dermatitis model. J Invest Dermatol. 2016; 136:127–135. PMID: 26763432.

61. Nicotera P, Melino G. Caspase-14 and epidermis maturation. Nat Cell Biol. 2007; 9:621–622. PMID: 17541415.

62. Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S, et al. Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol. 2007; 9:666–674. PMID: 17515931.

63. Oyoshi MK, Murphy GF, Geha RS. Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen. J Allergy Clin Immunol. 2009; 124:485–493. 493.e1PMID: 19665780.

64. Man MQ, Hatano Y, Lee SH, Man M, Chang S, Feingold KR, et al. Characterization of a hapten-induced, murine model with multiple features of atopic dermatitis: structural, immunologic, and biochemical changes following single versus multiple oxazolone challenges. J Invest Dermatol. 2008; 128:79–86. PMID: 17671515.

65. Scott IR, Harding CR. Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment. Dev Biol. 1986; 115:84–92. PMID: 3516761.

66. Gutowska-Owsiak D, Schaupp AL, Salimi M, Taylor S, Ogg GS. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes. Br J Dermatol. 2011; 165:492–498. PMID: 21564072.

67. Gutowska-Owsiak D, Schaupp AL, Salimi M, Selvakumar TA, 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. PMID: 22229441.

68. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008; 126:332–337. PMID: 18166499.

69. Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol. 2009; 123:1361–1370.e7. PMID: 19501237.

70. Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol. 2007; 127:722–724. PMID: 17008875.

71. Wan J, Mitra N, Hoffstad OJ, Margolis DJ. Influence of FLG mutations and TSLP polymorphisms on atopic dermatitis onset age. Ann Allergy Asthma Immunol. 2017; 118:737–738.e1. PMID: 28479194.

72. Yu HS, Kang MJ, Jung YH, Kim HY, Seo JH, Kim YJ, et al. Mutations in the filaggrin are predisposing factor in Korean children with atopic dermatitis. Allergy Asthma Immunol Res. 2013; 5:211–215. PMID: 23814674.

73. O'Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008; 122:689–693. PMID: 18774165.

74. Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol. 2008; 121:872–877.e9. PMID: 18325573.

75. Gruber R, Börnchen C, Rose K, Daubmann A, Volksdorf T, Wladykowski E, et al. Diverse regulation of claudin-1 and claudin-4 in atopic dermatitis. Am J Pathol. 2015; 185:2777–2789. PMID: 26319240.

76. Leclerc EA, Huchenq A, Mattiuzzo NR, Metzger D, Chambon P, Ghyselinck NB, et al. Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction. J Cell Sci. 2009; 122:2699–2709. PMID: 19596793.

77. Lee UH, Kim BE, Kim DJ, Cho YG, Ye YM, Leung DY. Atopic dermatitis is associated with reduced corneodesmosin expression: role of cytokine modulation and effects on viral penetration. Br J Dermatol. 2017; 176:537–540.

78. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, 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. PMID: 12960356.

79. Ong PY, 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. PMID: 12374875.

80. Hata TR, Kotol P, Boguniewicz M, Taylor P, Paik A, Jackson M, et al. History of eczema herpeticum is associated with the inability to induce human β-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis. Br J Dermatol. 2010; 163:659–661. PMID: 20545685.

81. Brauweiler AM, Goleva E, Leung DY. Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6). J Invest Dermatol. 2014; 134:2114–2121. PMID: 24468745.

82. Son ED, Kim HJ, Park T, Shin K, Bae IH, Lim KM, et al. Staphylococcus aureus inhibits terminal differentiation of normal human keratinocytes by stimulating interleukin-6 secretion. J Dermatol Sci. 2014; 74:64–71. PMID: 24398033.

83. Brauweiler AM, Hall CF, Goleva E, Leung DY. Staphylococcus aureus lipoteichoic acid inhibits keratinocyte differentiation through a p63-mediated pathway. J Invest Dermatol. 2017; 137:2030–2033. PMID: 28528912.

84. Howell MD, Wollenberg A, Gallo RL, Flaig M, Streib JE, Wong C, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006; 117:836–841. PMID: 16630942.

85. Leung DY. New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int. 2013; 62:151–161. PMID: 23712284.

86. Danso M, Boiten W, van Drongelen V, Gmelig Meijling K, Gooris G, El Ghalbzouri A, et al. Altered expression of epidermal lipid biosynthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition. J Dermatol Sci. 2017; 88:57–66. PMID: 28571749.

87. Kim D, Lee NR, Park SY, Jun M, Lee K, Kim S, et al. As in atopic dermatitis, nonlesional skin in allergic contact dermatitis displays abnormalities in barrier function and ceramide content. J Invest Dermatol. 2017; 137:748–750. PMID: 27826010.

88. Ito S, Ishikawa J, Naoe A, Yoshida H, Hachiya A, Fujimura T, et al. Ceramide synthase 4 is highly expressed in involved skin of patients with atopic dermatitis. J Eur Acad Dermatol Venereol. 2017; 31:135–141. PMID: 27358008.

89. Li S, Villarreal M, Stewart S, Choi J, Ganguli-Indra G, Babineau DC, et al. Altered composition of epidermal lipids correlates with Staphylococcus aureus colonization status in atopic dermatitis. Br J Dermatol. 2017; 177:e125–e127. PMID: 28244066.

90. Oh MJ, Nam JJ, Lee EO, Kim JW, Park CS. A synthetic C16 omegahydroxyphytoceramide improves skin barrier functions from diversely perturbed epidermal conditions. Arch Dermatol Res. 2016; 308:563–574. PMID: 27402316.

91. Lowe AJ, Su JC, Allen KJ, Abramson MJ, Cranswick N, Robertson CF, et al. A randomized trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitization: the PEBBLES pilot study. Br J Dermatol. 2017; Forthcoming.

92. Eyerich K, Eyerich S, Biedermann T. The multi-modal immune pathogenesis of atopic eczema. Trends Immunol. 2015; 36:788–801. PMID: 26602548.

93. Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama H, Kaplan DH, et al. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity. 2015; 42:756–766. PMID: 25902485.

94. Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, et al. Compartmentalized control of skin immunity by resident commensals. Science. 2012; 337:1115–1119. PMID: 22837383.

95. Zeeuwen PL, Boekhorst J, van den Bogaard EH, de Koning HD, van de Kerkhof PM, Saulnier DM, et al. Microbiome dynamics of human epidermis following skin barrier disruption. Genome Biol. 2012; 13:R101. PMID: 23153041.

96. Wollina U. Microbiome in atopic dermatitis. Clin Cosmet Investig Dermatol. 2017; 10:51–56.

97. Kennedy EA, Connolly J, Hourihane JO, Fallon PG, McLean WH, Murray D, et al. Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year. J Allergy Clin Immunol. 2017; 139:166–172. PMID: 27609659.

98. Ali SM, Yosipovitch G. Skin pH: from basic science to basic skin care. Acta Derm Venereol. 2013; 93:261–267. PMID: 23322028.

99. Rippke F, Schreiner V, Schwanitz HJ. The acidic milieu of the horny layer: new findings on the physiology and pathophysiology of skin pH. Am J Clin Dermatol. 2002; 3:261–272. PMID: 12010071.

100. Brauweiler AM, Goleva E, Leung DY. Interferon-γ protects from staphylococcal alpha toxin-induced keratinocyte death through apolipoprotein L1. J Invest Dermatol. 2016; 136:658–664. PMID: 27015454.

101. Czarnowicki T, Malajian D, Khattri S, Correa da Rosa J, Dutt R, Finney R, et al. Petrolatum: barrier repair and antimicrobial responses underlying this “inert” moisturizer. J Allergy Clin Immunol. 2016; 137:1091–1102.e7. PMID: 26431582.

102. Lee HJ, Lee SH. Epidermal permeability barrier defects and barrier repair therapy in atopic dermatitis. Allergy Asthma Immunol Res. 2014; 6:276–287. PMID: 24991450.

103. Eichenfield LF, 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. PMID: 28390477.

104. Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of emollient therapy for the primary prevention of atopic dermatitis. J Am Acad Dermatol. 2010; 63:587–593. PMID: 20692725.

105. Simpson EL, Chalmers JR, Hanifin JM, Thomas KS, Cork MJ, McLean WH, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014; 134:818–823. PMID: 25282563.

106. Cardona ID, Stillman L, Jain N. Does bathing frequency matter in pediatric atopic dermatitis? Ann Allergy Asthma Immunol. 2016; 117:9–13. PMID: 27371966.

107. Pabst RC, Starr KP, Qaiyumi S, Schwalbe RS, Gewolb IH. The effect of application of aquaphor on skin condition, fluid requirements, and bacterial colonization in very low birth weight infants. J Perinatol. 1999; 19:278–283. PMID: 10685239.

108. Glatz M, Polley E, Simpson E, Kong H. Emollient therapy alters skin barrier and microbes in infants at risk for developing atopic dermatitis. J Invest Dermatol. 2015; 135:S31.

109. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics. 2009; 123:e808–e814. PMID: 19403473.

110. Eriksson S, van der Plas MJ, Mörgelin M, Sonesson A. Antibacterial and antibiofilm effects of sodium hypochlorite against Staphylococcus aureus isolates derived from patients with atopic dermatitis. Br J Dermatol. 2017; 177:513–521. PMID: 28238217.

111. Myles IA, Williams KW, Reckhow JD, Jammeh ML, Pincus NB, Sastalla I, et al. Transplantation of human skin microbiota in models of atopic dermatitis. JCI Insight. 2016; 1:e86955. PMID: 27478874.

112. Hyung KE, Kim SJ, Jang YW, Lee DK, Hyun KH, Moon BS, et al. Therapeutic effects of orally administered CJLP55 for atopic dermatitis via the regulation of immune response. Korean J Physiol Pharmacol. 2017; 21:335–343. PMID: 28461776.

113. Notay M, Foolad N, Vaughn AR, Sivamani RK. Probiotics, prebiotics, and synbiotics for the treatment and prevention of adult dermatological diseases. Am J Clin Dermatol. 2017; 18:721–732. PMID: 28681230.

114. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016; 375:2335–2348. PMID: 27690741.

115. Thaçi D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016; 387:40–52. PMID: 26454361.

116. Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014; 371:130–139. PMID: 25006719.

117. Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014; 134:1293–1300. PMID: 25482871.

118. Rø AD, Simpson MR, Rø TB, Storrø O, Johnsen R, Videm V, et al. Reduced Th22 cell proportion and prevention of atopic dermatitis in infants following maternal probiotic supplementation. Clin Exp Allergy. 2017; 47:1014–1021. PMID: 28346719.

119. di Mauro G, Bernardini R, Barberi S, Capuano A, Correra A, De'Angelis GL, et al. Prevention of food and airway allergy: consensus of the Italian Society of Preventive and Social Paediatrics, the Italian Society of Paediatric Allergy and Immunology, and Italian Society of Pediatrics. World Allergy Organ J. 2016; 9:28. PMID: 27583103.

120. Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell LE, McLean WH, et al. Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol. 2015; 135:930–935.e1. PMID: 25618747.

121. Kim J, Kim BE, Lee J, Han Y, Jun HY, Kim H, et al. Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy. J Allergy Clin Immunol. 2016; 137:1282–1285.e4. PMID: 26879860.