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Skin Barrier Defects in Atopic Dermatitis

  • ALLERGIC SKIN DISEASES (L FONACIER, SECTION EDITOR)
  • Published:
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Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder, and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of antimicrobial peptides and proteases, are also discussed.

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Abbreviations

AD:

atopic dermatitis

AMPs:

antimicrobial peptides

CLDN:

claudin

DNCB:

2,4-dinitrochlorobenzene

KLK:

kallikrein

NMF:

natural moisturizing factors

PAR:

protease-activated receptor

TEWL:

transepidermal water loss

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health. J Invest Dermatol. 2011;131:67–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol. 2013;132:1132–8.

    PubMed  Google Scholar 

  3. Novak N, Bieber T, Leung DY. Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol. 2003;1112:S128–39.

    Google Scholar 

  4. Sybert VP, Dale BA, Holbrook KA. Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules. J Invest Dermatol. 1985;84:191–4.

    CAS  PubMed  Google Scholar 

  5. Seguchi T, Cui CY, Kusuda S, Takahashi M, Aisu K, Tezuka T. Decreased expression of filaggrin in atopic skin. Arch Dermatol Res. 1996;288:442–6.

    CAS  PubMed  Google Scholar 

  6. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337–42.

    CAS  PubMed  Google Scholar 

  7. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–6.

    CAS  PubMed  Google Scholar 

  8. Sandilands A, O'Regan GM, Liao H, Zhao Y, Terron-Kwiatkowski A, Watson RM, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol. 2006;126:1770–5.

    CAS  PubMed  Google Scholar 

  9. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006;118:214–9.

    CAS  PubMed  Google Scholar 

  10. Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol. 2007;127:724–6.

    CAS  PubMed  Google Scholar 

  11. Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol. 2007;127:564–7.

    CAS  PubMed  Google Scholar 

  12. 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;121:872–7 e9.

    CAS  PubMed  Google Scholar 

  13. Brown SJ, Sandilands A, Zhao Y, Liao H, Relton CL, Meggitt SJ, et al. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Invest Dermatol. 2008;128:1591–4.

    CAS  PubMed  Google Scholar 

  14. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315–27. An excellent review article describing filaggrin mutations, including seminal work that led to their link with ichythosis vulgaris and atopic dermatitis.

    CAS  PubMed  Google Scholar 

  15. Chen H, Common JE, Haines RL, Balakrishnan A, Brown SJ, Goh CS, et al. Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations. Br J Dermatol. 2011;165:106–14.

    CAS  PubMed  Google Scholar 

  16. Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kezic S, et al. Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol. 2012;132:98–104.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Ziyab AH, Karmaus W, Holloway JW, Zhang H, Ewart S, Arshad SH. DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants. J Eur Acad Dermatol Venereol. 2013;27:e420–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Gruber R, Elias PM, Crumrine D, Lin TK, Brandner JM, Hachem JP, et al. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am J Pathol. 2011;178:2252–63.

    PubMed Central  PubMed  Google Scholar 

  19. Mildner M, Jin J, Eckhart L, Kezic S, Gruber F, Barresi C, et al. Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model. J Invest Dermatol. 2010;130:2286–94.

    CAS  PubMed  Google Scholar 

  20. Vavrova K, Henkes D, Struver K, Sochorova M, Skolova B, Witting MY, et al. Filaggrin Deficiency Leads to Impaired Lipid Profile and Altered Acidification Pathways in a 3D Skin Construct. J Invest Dermatol. 2013 [Epub ahead of print].

  21. Kezic S, Kemperman PM, Koster ES, de Jongh CM, Thio HB, Campbell LE, et al. Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum. J Invest Dermatol. 2008;128:2117–9.

    CAS  PubMed  Google Scholar 

  22. Nemoto-Hasebe I, Akiyama M, Nomura T, Sandilands A, McLean WH, Shimizu H. Clinical severity correlates with impaired barrier in filaggrin-related eczema. J Invest Dermatol. 2009;129:682–9.

    CAS  PubMed  Google Scholar 

  23. Kezic S, O'Regan GM, Lutter R, Jakasa I, Koster ES, Saunders S, et al. Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J Allergy Clin Immunol. 2012;129:1031–9 e1.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Moniaga CS, Jeong SK, Egawa G, Nakajima S, Hara-Chikuma M, Jeon JE, et al. Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice. Am J Pathol. 2013;182:841–51.

    CAS  PubMed  Google Scholar 

  25. Hoste E, Kemperman P, Devos M, Denecker G, Kezic S, Yau N, et al. Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin. J Invest Dermatol. 2011;131:2233–41.

    CAS  PubMed  Google Scholar 

  26. Kezic S, O'Regan GM, Yau N, Sandilands A, Chen H, Campbell LE, et al. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy. 2011;66:934–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. O'Regan GM, Kemperman PM, Sandilands A, Chen H, Campbell LE, Kroboth K, et al. Raman profiles of the stratum corneum define 3 filaggrin genotype-determined atopic dermatitis endophenotypes. J Allergy Clin Immunol. 2010;126:574–80.

    PubMed Central  PubMed  Google Scholar 

  28. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP, Mangan NE, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41:602–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H, et al. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol. 2012;129:1538–46.

    CAS  PubMed  Google Scholar 

  30. Scharschmidt TC, Man MQ, Hatano Y, Crumrine D, Gunathilake R, Sundberg JP, 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. 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;124:485–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. van Drongelen V, Alloul-Ramdhani M, Danso MO, Mieremet A, Mulder A, van Smeden J, et al. Knock-down of filaggrin does not affect lipid organization and composition in stratum corneum of reconstructed human skin equivalents. Exp Dermatol. 2013;22:807–12.

    PubMed  Google Scholar 

  33. Newell L, Polak ME, Perera J, Owen C, Boyd P, Pickard C, et al. Sensitization via healthy skin programs Th2 responses in individuals with atopic dermatitis. J Invest Dermatol. 2013;133:2372–80.

    CAS  PubMed  Google Scholar 

  34. Schuttelaar ML, Kerkhof M, Jonkman MF, Koppelman GH, Brunekreef B, de Jongste JC, et al. Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure. Allergy. 2009;64:1758–65.

    CAS  PubMed  Google Scholar 

  35. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80.

    CAS  PubMed  Google Scholar 

  36. Ito Y, Satoh T, Takayama K, Miyagishi C, Walls AF, Yokozeki H. Basophil recruitment and activation in inflammatory skin diseases. Allergy. 2011;66:1107–13.

    CAS  PubMed  Google Scholar 

  37. Gschwandtner M, Mildner M, Mlitz V, Gruber F, Eckhart L, Werfel T, et al. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model. Allergy. 2013;68:37–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. 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;21:104–10.

    CAS  PubMed  Google Scholar 

  39. 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;165:492–8.

    CAS  PubMed  Google Scholar 

  40. 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. 2009;124(3 Suppl 2):R7–12.

    CAS  PubMed  Google Scholar 

  41. Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction? J Invest Dermatol. 2011;131:150–7.

    CAS  PubMed  Google Scholar 

  42. 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;133:2678–85.

    CAS  PubMed  Google Scholar 

  43. Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Luscher-Firzlaff J, et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2012;129:426–33.

    CAS  PubMed  Google Scholar 

  44. Lesiak A, Kuna P, Zakrzewski M, van Geel M, Bladergroen RS, Przybylowska K, et al. Combined occurrence of filaggrin mutations and IL-10 or IL-13 polymorphisms predisposes to atopic dermatitis. Exp Dermatol. 2011;20:491–5.

    CAS  PubMed  Google Scholar 

  45. Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM, et al. Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization. J Allergy Clin Immunol. 2011;127:186–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Pellerin L, Henry J, Hsu CY, Balica S, Jean-Decoster C, Mechin MC, et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol. 2013;131:1094–102.

    CAS  PubMed  Google Scholar 

  47. Margolis DJ, Gupta J, Apter AJ, Ganguly T, Hoffstad O, Papadopoulos M, et al. Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol. 2013 [Epub ahead of print].

  48. Esparza-Gordillo J, Weidinger S, Folster-Holst R, Bauerfeind A, Ruschendorf F, Patone G, et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet. 2009;41:596–601.

    CAS  PubMed  Google Scholar 

  49. O'Regan GM, Campbell LE, Cordell HJ, Irvine AD, McLean WH, Brown SJ. Chromosome 11q13.5 variant associated with childhood eczema: an effect supplementary to filaggrin mutations. J Allergy Clin Immunol. 2010;125:170–4.

    PubMed Central  PubMed  Google Scholar 

  50. Guttman-Yassky E, Suarez-Farinas M, Chiricozzi A, Nograles KE, Shemer A, Fuentes-Duculan J, et al. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol. 2009;124:1235–44 e58.

    CAS  PubMed  Google Scholar 

  51. Igawa S, Kishibe M, Honma M, Murakami M, Mizuno Y, Suga Y, et al. Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). J Dermatol Sci. 2013;72:54–60.

    PubMed  Google Scholar 

  52. Jarzab J, Filipowska B, Zebracka J, Kowalska M, Bozek A, Rachowska R, et al. Locus 1q21 Gene expression changes in atopic dermatitis skin lesions: deregulation of small proline-rich region 1A. Int Arch Allergy Immunol. 2010;151:28–37.

    CAS  PubMed  Google Scholar 

  53. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Sevilla LM, Nachat R, Groot KR, Klement JF, Uitto J, Djian P, et al. Mice deficient in involucrin, envoplakin, and periplakin have a defective epidermal barrier. J Cell Biol. 2007;179:1599–612.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Fartasch M, Diepgen TL. The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids? Acta Derm Venereol Suppl (Stockh). 1992;176:26–31.

    CAS  Google Scholar 

  56. Werner Y, Lindberg M, Forslind B. Membrane-coating granules in "dry" non-eczematous skin of patients with atopic dermatitis. A quantitative electron microscopic study. Acta Derm Venereol. 1987;67:385–90.

    CAS  PubMed  Google Scholar 

  57. Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol. 1991;96:523–6.

    CAS  PubMed  Google Scholar 

  58. 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;130:2511–4.

    CAS  PubMed  Google Scholar 

  59. Di Nardo A, Wertz P, Giannetti A, Seidenari S. Ceramide and cholesterol composition of the skin of patients with atopic dermatitis. Acta Derm Venereol. 1998;78:27–30.

    PubMed  Google Scholar 

  60. Janssens M, van Smeden J, Gooris GS, Bras W, Portale G, Caspers PJ, 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;53:2755–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Park YH, Jang WH, Seo JA, Park M, Lee TR, Kim DK, et al. Decrease of ceramides with very long-chain fatty acids and downregulation of elongases in a murine atopic dermatitis model. J Invest Dermatol. 2012;132:476–9.

    CAS  PubMed  Google Scholar 

  62. Janssens M, Mulder AA, van Smeden J, Pilgram GS, Wolterbeek R, Lavrijsen AP, et al. Electron diffraction study of lipids in non-lesional stratum corneum of atopic eczema patients. Biochim Biophys Acta. 1828;2013:1814–21.

    Google Scholar 

  63. Hara J, Higuchi K, Okamoto R, Kawashima M, Imokawa G. High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis. J Invest Dermatol. 2000;115:406–13.

    CAS  PubMed  Google Scholar 

  64. Kusuda S, Cui CY, Takahashi M, Tezuka T. Localization of sphingomyelinase in lesional skin of atopic dermatitis patients. J Invest Dermatol. 1998;111:733–8.

    CAS  PubMed  Google Scholar 

  65. Imokawa G. A possible mechanism underlying the ceramide deficiency in atopic dermatitis: expression of a deacylase enzyme that cleaves the N-acyl linkage of sphingomyelin and glucosylceramide. J Dermatol Sci. 2009;55:1–9.

    CAS  PubMed  Google Scholar 

  66. Sawada E, Yoshida N, Sugiura A, Imokawa G. Th1 cytokines accentuate but Th2 cytokines attenuate ceramide production in the stratum corneum of human epidermal equivalents: an implication for the disrupted barrier mechanism in atopic dermatitis. J Dermatol Sci. 2012;68:25–35.

    CAS  PubMed  Google Scholar 

  67. Tawada C, Kanoh H, Nakamura M, Mizutani Y, Fujisawa T, Banno Y, et al. Interferon-γ decreases ceramides with long-chain fatty acids: possible involvement in atopic dermatitis and psoriasis. J Invest Dermatol. 2013. [Epub ahead of print].

  68. Rebane A, Zimmermann M, Aab A, Baurecht H, Koreck A, Karelson M, et al. Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. J Allergy Clin Immunol. 2012;129:1297–306.

    CAS  PubMed  Google Scholar 

  69. Niessen CM. Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol. 2007;127:2525–32.

    CAS  PubMed  Google Scholar 

  70. Kirschner N, Brandner JM. Barriers and more: functions of tight junction proteins in the skin. Ann N Y Acad Sci. 2012;1257:158–66.

    CAS  PubMed  Google Scholar 

  71. Kubo A, Nagao K, Yokouchi M, Sasaki H, Amagai M. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J Exp Med. 2009;21(206):2937–46.

    Google Scholar 

  72. Reefer AJ, Satinover SM, Wilson BB, Woodfolk JA. The relevance of microbial allergens to the IgE antibody repertoire in atopic and nonatopic eczema. J Allergy Clin Immunol. 2007;120:156–63.

    CAS  PubMed  Google Scholar 

  73. Wisniewski JA, Agrawal R, Minnicozzi S, Xin W, Patrie J, Heymann PW, et al. Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis. Clin Exp Allergy. 2013;43:1160–70.

    CAS  PubMed  Google Scholar 

  74. Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest. 1999;104:123–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Ohnemus U, Kohrmeyer K, Houdek P, Rohde H, Wladykowski E, Vidal S, et al. Regulation of epidermal tight-junctions (TJ) during infection with exfoliative toxin-negative Staphylococcus strains. J Invest Dermatol. 2008;128:906–16.

    CAS  PubMed  Google Scholar 

  76. 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;127:773–86. This article provides both genetic and functional evidence of a role for claudin-1 in the impairment of tight junctions in humans with AD.

    PubMed Central  PubMed  Google Scholar 

  77. De Benedetto A, Slifka MK, Rafaels NM, Kuo IH, Georas SN, Boguniewicz M, et al. Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis. J Allergy Clin Immunol. 2011;128:242–6.

    PubMed Central  PubMed  Google Scholar 

  78. Braff MH, Bardan A, Nizet V, Gallo RL. Cutaneous defense mechanisms by antimicrobial peptides. J Invest Dermatol. 2005;125:9–13.

    CAS  PubMed  Google Scholar 

  79. 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;24:341–8.

    CAS  PubMed  Google Scholar 

  80. 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;347:1151–60.

    CAS  PubMed  Google Scholar 

  81. 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;171:3262–9.

    CAS  PubMed  Google Scholar 

  82. Rieg S, Steffen H, Seeber S, Humeny A, Kalbacher H, Dietz K, et al. Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo. J Immunol. 2005;174:8003–10.

    CAS  PubMed  Google Scholar 

  83. 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;117:836–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. 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 beta-defensin (HBD)-2, HBD-3 and cathelicidin in the skin of patients with atopic dermatitis. Br J Dermatol. 2010;163:659–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Ballardini N, Johansson C, Lilja G, Lindh M, Linde Y, Scheynius A, et al. Enhanced expression of the antimicrobial peptide LL-37 in lesional skin of adults with atopic eczema. Br J Dermatol. 2009;161:40–7.

    CAS  PubMed  Google Scholar 

  86. Asano S, Ichikawa Y, Kumagai T, Kawashima M, Imokawa G. Microanalysis of an antimicrobial peptide, beta-defensin-2, in the stratum corneum from patients with atopic dermatitis. Br J Dermatol. 2008;159:97–104.

    CAS  PubMed  Google Scholar 

  87. Gambichler T, Skrygan M, Tomi NS, Othlinghaus N, Brockmeyer NH, Altmeyer P, et al. Differential mRNA expression of antimicrobial peptides and proteins in atopic dermatitis as compared to psoriasis vulgaris and healthy skin. Int Arch Allergy Immunol. 2008;147:17–24.

    CAS  PubMed  Google Scholar 

  88. Glaser R, Meyer-Hoffert U, Harder J, Cordes J, Wittersheim M, Kobliakova J, et al. The antimicrobial protein psoriasin (S100A7) is upregulated in atopic dermatitis and after experimental skin barrier disruption. J Invest Dermatol. 2009;129:641–9.

    PubMed  Google Scholar 

  89. Harder J, Dressel S, Wittersheim M, Cordes J, Meyer-Hoffert U, Mrowietz U, et al. Enhanced expression and secretion of antimicrobial peptides in atopic dermatitis and after superficial skin injury. J Invest Dermatol. 2010;130:1355–64.

    CAS  PubMed  Google Scholar 

  90. Kisich KO, Carspecken CW, Fieve S, Boguniewicz M, Leung DY. Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3. J Allergy Clin Immunol. 2008;122:62–8.

    CAS  PubMed  Google Scholar 

  91. Kim E, Lee JE, Namkung JH, Kim PS, Kim S, Shin ES, et al. Single nucleotide polymorphisms and the haplotype in the DEFB1 gene are associated with atopic dermatitis in a Korean population. J Dermatol Sci. 2009;54:25–30.

    CAS  PubMed  Google Scholar 

  92. Prado-Montes de Oca E, Garcia-Vargas A, Lozano-Inocencio R, Gallegos-Arreola MP, Sandoval-Ramirez L, Davalos-Rodriguez NO, et al. Association of beta-defensin 1 single nucleotide polymorphisms with atopic dermatitis. Int Arch Allergy Immunol. 2007;142:211–8.

    CAS  PubMed  Google Scholar 

  93. Howell MD, Boguniewicz M, Pastore S, Novak N, Bieber T, Girolomoni G, et al. Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol. 2006;121:332–8.

    CAS  PubMed  Google Scholar 

  94. Howell MD, Novak N, Bieber T, Pastore S, Girolomoni G, Boguniewicz M, et al. Interleukin-10 downregulates anti-microbial peptide expression in atopic dermatitis. J Invest Dermatol. 2005;125:738–45.

    CAS  PubMed  Google Scholar 

  95. Alase A, Seltmann J, Werfel T, Wittmann M. Interleukin-33 modulates the expression of human beta-defensin 2 in human primary keratinocytes and may influence the susceptibility to bacterial superinfection in acute atopic dermatitis. Br J Dermatol. 2012;167:1386–9.

    CAS  PubMed  Google Scholar 

  96. Komatsu N, Saijoh K, Kuk C, Liu AC, Khan S, Shirasaki F, et al. Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. Exp Dermatol. 2007;16:513–9.

    CAS  PubMed  Google Scholar 

  97. Komatsu N, Saijoh K, Toyama T, Ohka R, Otsuki N, Hussack G, et al. Multiple tissue kallikrein mRNA and protein expression in normal skin and skin diseases. Br J Dermatol. 2005;153:274–81.

    CAS  PubMed  Google Scholar 

  98. Voegeli R, Rawlings AV, Breternitz M, Doppler S, Schreier T, Fluhr JW. Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol. 2009;161:70–7.

    CAS  PubMed  Google Scholar 

  99. Vasilopoulos Y, Cork MJ, Murphy R, Williams HC, Robinson DA, Duff GW, et al. Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. J Invest Dermatol. 2004;123:62–6.

    CAS  PubMed  Google Scholar 

  100. Hubiche T, Ged C, Benard A, Leaute-Labreze C, McElreavey K, de Verneuil H, et al. Analysis of SPINK 5, KLK 7 and FLG genotypes in a French atopic dermatitis cohort. Acta Derm Venereol. 2007;87:499–505.

    CAS  PubMed  Google Scholar 

  101. Buddenkotte J, Stroh C, Engels IH, Moormann C, Shpacovitch VM, Seeliger S, et al. Agonists of proteinase-activated receptor-2 stimulate upregulation of intercellular cell adhesion molecule-1 in primary human keratinocytes via activation of NF-kappa B. J Invest Dermatol. 2005;124:38–45.

    CAS  PubMed  Google Scholar 

  102. Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23:6176–80.

    CAS  PubMed  Google Scholar 

  103. Morizane S, Yamasaki K, Kajita A, Ikeda K, Zhan M, Aoyama Y, et al. TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis. J Allergy Clin Immunol. 2012;130:259-61 e1.

    Google Scholar 

  104. Cheng T, Tjabringa GS, van Vlijmen-Willems IM, Hitomi K, van Erp PE, Schalkwijk J, et al. The cystatin M/E-controlled pathway of skin barrier formation: expression of its key components in psoriasis and atopic dermatitis. Br J Dermatol. 2009;161:253–64.

    CAS  PubMed  Google Scholar 

  105. Kim N, Bae KB, Kim MO, Yu DH, Kim HJ, Yuh HS, et al. Overexpression of cathepsin S induces chronic atopic dermatitis in mice. J Invest Dermatol. 2012;132:1169–76.

    CAS  PubMed  Google Scholar 

  106. Tsukuba T, Okamoto K, Okamoto Y, Yanagawa M, Kohmura K, Yasuda Y, et al. Association of cathepsin E deficiency with development of atopic dermatitis. J Biochem. 2003;134:893–902.

    CAS  PubMed  Google Scholar 

  107. 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;20:633–6.

    CAS  PubMed  Google Scholar 

  108. Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25(2):141–2.

    CAS  PubMed  Google Scholar 

  109. 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(5):1135–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Briot A, Lacroix M, Robin A, Steinhoff M, Deraison C, Hovnanian A. Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. J Invest Dermatol. 2010;130:2736–42.

    CAS  PubMed  Google Scholar 

  111. Kusunoki T, Okafuji I, Yoshioka T, Saito M, Nishikomori R, Heike T, et al. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol. 2005;115:636–8.

    CAS  PubMed  Google Scholar 

  112. Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet. 2001;29:175–8.

    CAS  PubMed  Google Scholar 

  113. Folster-Holst R, Stoll M, Koch WA, Hampe J, Christophers E, Schreiber S. Lack of association of SPINK5 polymorphisms with nonsyndromic atopic dermatitis in the population of Northern Germany. Br J Dermatol. 2005;152:1365–7.

    CAS  PubMed  Google Scholar 

  114. Weidinger S, Baurecht H, Wagenpfeil S, Henderson J, Novak N, Sandilands A, et al. Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J Allergy Clin Immunol. 2008;122:560–8.

    CAS  PubMed  Google Scholar 

  115. Stout TE, McFarland T, Mitchell JC, Appukattan B, Stout TJ. Recombinant filaggrin is internalized and processed to correct filaggrin deficiency. J Invest Dermatol. 2014;134:423–9.

    CAS  PubMed  Google Scholar 

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Conflict of Interest

This work is supported by NIH grants R01 AR059058 and R01 AI052196.

Rachana Agrawal and Judith A. Woodfolk declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Department of Medicine, University of Virginia Health System, Allergy Division, PO Box 801355, Charlottesville, VA, 22908-1355, USA

    Rachana Agrawal & Judith A. Woodfolk

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  1. Rachana Agrawal
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  2. Judith A. Woodfolk
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Correspondence to Judith A. Woodfolk.

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This article is part of the Topical Collection on Allergic Skin Diseases

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Agrawal, R., Woodfolk, J.A. Skin Barrier Defects in Atopic Dermatitis. Curr Allergy Asthma Rep 14, 433 (2014). https://doi.org/10.1007/s11882-014-0433-9

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