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Table of Contents
Vol. 3, No. 2, 2011
Issue release date: February 2011
Editor's Choice -- Free Access
J Innate Immun 2011;3:131–141
(DOI:10.1159/000323963)

Modifications of the Innate Immune System in Atopic Dermatitis

Maintz L. · Novak N.
Department of Dermatology and Allergy, University of Bonn, Bonn, Germany
email Corresponding Author

Abstract

Atopic dermatitis (AD) is a frequent chronic inflammatory skin disease which is often complicated by recurrent microbial superinfections. Genetically based modifications which might have an impact on the innate immune system, such as impairment of the skin barrier, modifications of pattern recognition receptors, deficiency of antimicrobial peptides, antiviral natural killer cells and plasmacytoid dendritic cells, facilitate the entry of allergens and infectious microbes into the skin, where they encounter immunocompetent cells. The micromilieu in the skin of AD patients further potentiates dysfunctions of the innate immune system, leading to a vicious circle promoting the disease. This article provides an overview of modifications of the innate immune system in AD.


 goto top of outline Key Words

  • Allergy
  • Antimicrobial peptides
  • Pathogen-associated molecular patterns
  • Toll-like receptor

 goto top of outline Abstract

Atopic dermatitis (AD) is a frequent chronic inflammatory skin disease which is often complicated by recurrent microbial superinfections. Genetically based modifications which might have an impact on the innate immune system, such as impairment of the skin barrier, modifications of pattern recognition receptors, deficiency of antimicrobial peptides, antiviral natural killer cells and plasmacytoid dendritic cells, facilitate the entry of allergens and infectious microbes into the skin, where they encounter immunocompetent cells. The micromilieu in the skin of AD patients further potentiates dysfunctions of the innate immune system, leading to a vicious circle promoting the disease. This article provides an overview of modifications of the innate immune system in AD.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Hon KL, Wong KY, Leung TF, Chow CM, Ng PC: Comparison of skin hydration evaluation sites and correlations among skin hydration, transepidermal water loss, SCORAD index, Nottingham Eczema Severity Score, and quality of life in patients with atopic dermatitis. Am J Clin Dermatol 2008;9:45–50.
  2. 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.
  3. Jensen JM, Folster-Holst R, Baranowsky A, Schunck M, Winoto-Morbach S, Neumann C, et al: Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J Invest Dermatol 2004;122:1423–1431.
  4. Rodriguez 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.
  5. de Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA: Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol 2009;129:14–30.
  6. 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, 493e1.
  7. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, de Benedetto A, et al: Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007;120:150–155.
  8. 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.
  9. Hatano Y, Terashi H, Arakawa S, Katagiri K: Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis. J Invest Dermatol 2005;124:786–792.
  10. Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz M, Werfel T, Herz U, et al: The Toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 2004;113:565–567.
  11. Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G: Association of the Toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 2009;64:1608–1615.
  12. Weidinger S, Novak N, Klopp N, Baurecht H, Wagenpfeil S, Rümmler L, et al: Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema. J Allergy Clin Immunol 2006;118:277–279.
  13. Terhorst D, Kalali BN, Weidinger S, Illig T, Novak N, Ring J, et al: Monocyte-derived dendritic cells from highly atopic individuals are not impaired in their pro-inflammatory response to Toll-like receptor ligands. Clin Exp Allergy 2007;37:381–390.
  14. 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.
  15. Niebuhr M, Lutat C, Sigel S, Werfel T: Impaired TLR-2 expression and TLR-2-mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy 2009;64:1580–1587.
  16. Mrabet-Dahbi S, Dalpke AH, Niebuhr M, Frey M, Draing C, Brand S, et al: The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 2008;121:1013–1019.
  17. Novak N, Yu CF, Bussmann C, Maintz L, Peng WM, Hart J, et al: Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007;62:766–772.
  18. Beygo J, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S: No evidence of an association between polymorphisms in the IRAK-M gene and atopic dermatitis in a German cohort. Mol Cell Probes 2009;23:16–19.
  19. Weidinger S, Klopp N, Rümmler L, Wagenpfeil S, Novak N, Baurecht HJ, et al: Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 2005;116:177–184.
  20. Macaluso F, Nothnagel M, Parwez Q, Petrasch-Parwez E, Bechara FG, Epplen JT, et al: Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 2007;16:692–698.
  21. Kabesch M, Peters W, Carr D, Leupold W, Weiland SK, von Mutius E: Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 2003;111:813–817.
  22. Weidinger S, Klopp N, Rümmler L, Wagenpfeil S, Baurecht HJ, Gauger A, et al: Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults. Clin Exp Allergy 2005;35:866–872.
  23. Carrera MC, Moura P, Crovella S, de Souza PR, de Alencar LC, Sarinho E: High polymorphism of the MBL2 gene in patients with atopic dermatitis. Ann Allergy Asthma Immunol 2010;105:39–42.
  24. Hashimoto S, Nakamura K, Oyama N, Kaneko F, Fujita T, Tsunemi Y, et al: Mannose-binding lectin (MBL) single nucleotide polymorphism is not associated with atopic dermatitis in Japanese patients. J Dermatol 2005;32:1038–1040.
  25. Howell MD: The role of human beta defensins and cathelicidins in atopic dermatitis. Curr Opin Allergy Clin Immunol 2007;7:413–417.
  26. 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.
  27. 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;130:1355–1364.
  28. 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;122:62–68.
  29. Eyerich K, Pennino D, Scarponi C, Foerster S, Nasorri F, Behrendt H, et al: IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response. J Allergy Clin Immunol 2009;123:59–66.
  30. Peng WM, Jenneck C, Bussmann C, Bogdanow M, Hart J, Leung DY, et al: Risk factors of atopic dermatitis patients for eczema herpeticum. J Invest Dermatol 2007;127:1261–1263.
  31. Buchau AS, MacLeod DT, Morizane S, Kotol PF, Hata T, Gallo RL: Bcl-3 acts as an innate immune modulator by controlling antimicrobial responses in keratinocytes. J Invest Dermatol 2009;129:2148–2155.
  32. Hata TR, Kotol P, Jackson M, Nguyen M, Paik A, Udall D, et al: Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol 2008;122:829–831.
  33. 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;174:8003–8010.
  34. Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G: Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 2002;119:433–439.
  35. Sayama K, Komatsuzawa H, Yamasaki K, Shirakata Y, Hanakawa Y, Ouhara K, et al: New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of beta-defensins, LL37, and TLR2. Eur J Immunol 2005;35:1886–1895.
  36. Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, et al: Cutting edge: proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol 2007;178:3373–3377.
  37. Wu WH, Park CO, Oh SH, Kim HJ, Kwon YS, Bae BG, et al: Thymic stromal lymphopoietin-activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis. J Allergy Clin Immunol 2010;126:290–299, 299e1–4.
  38. He R, Oyoshi MK, Garibyan L, Kumar L, Ziegler SF, Geha RS: TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc Natl Acad Sci USA 2008;105:11875–11880.
  39. Homey B, Steinhoff M, Ruzicka T, Leung DY: Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 2006;118:178–189.
  40. Ezzat MH, Sallam MA, Shaheen KY: Serum mucosa-associated epithelial chemokine (MEC/CCL28) in atopic dermatitis: a specific marker for severity. Int J Dermatol 2009;48:822–829.
  41. Gros E, Bussmann C, Bieber T, Förster I, Novak N: Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis. J Allergy Clin Immunol 2009;124:753–760e1.
  42. Strid J, Strobel S: Skin barrier dysfunction and systemic sensitization to allergens through the skin. Curr Drug Targets Inflamm Allergy 2005;4:531–541.
  43. Cho SH, Strickland I, Boguniewicz M, Leung DY: Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 2001;108:269–274.
  44. Matsubara M, Harada D, Manabe H, Hasegawa K: Staphylococcus aureus peptidoglycan stimulates granulocyte macrophage colony-stimulating factor production from human epidermal keratinocytes via mitogen-activated protein kinases. FEBS Lett 2004;566:195–200.
  45. Langer K, Breuer K, Kapp A, Werfel T: Staphylococcus aureus-derived enterotoxins enhance house dust mite-induced patch test reactions in atopic dermatitis. Exp Dermatol 2007;16:124–129.
  46. Bieber T: Atopic dermatitis. N Engl J Med 2008;358:1483–1494.
  47. Breuer K, Wittmann M, Kempe K, Kapp A, Mai U, Dittrich-Breiholz O, et al: Alpha-Toxin is produced by skin-colonizing Staphylococcus aureus and induces a T helper type 1 response in atopic dermatitis. Clin Exp Allergy 2005;35:1088–1095.
  48. Katsuta M, Takigawa Y, Kimishima M, Inaoka M, Takahashi R, Shiohara T: NK cells and gamma delta+ T cells are phenotypically and functionally defective due to preferential apoptosis in patients with atopic dermatitis. J Immunol 2006;176:7736–7744.
  49. Novak N, Allam JP, Hagemann T, Jenneck C, Laffer S, Valenta R, et al: Characterization of FcεRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2004;114:364–370.
  50. Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma E, Moderer M, et al: Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 2002;119:1096–1102.
  51. Novak N: New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 2009;64:265–275.

 goto top of outline Author Contacts

Prof. Dr. Natalija Novak
Department of Dermatology and Allergy
University of Bonn
Sigmund-Freud-Strasse 25, DE–53127 Bonn (Germany)
Tel. +49 228 2871 5370, E-Mail Natalija.Novak@ukb.uni-bonn.de


 goto top of outline Article Information

Received: December 8, 2010
Accepted after revision: January 3, 2011
Published online: January 21, 2011
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 1, Number of References : 51


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 3, No. 2, Year 2011 (Cover Date: February 2011)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Atopic dermatitis (AD) is a frequent chronic inflammatory skin disease which is often complicated by recurrent microbial superinfections. Genetically based modifications which might have an impact on the innate immune system, such as impairment of the skin barrier, modifications of pattern recognition receptors, deficiency of antimicrobial peptides, antiviral natural killer cells and plasmacytoid dendritic cells, facilitate the entry of allergens and infectious microbes into the skin, where they encounter immunocompetent cells. The micromilieu in the skin of AD patients further potentiates dysfunctions of the innate immune system, leading to a vicious circle promoting the disease. This article provides an overview of modifications of the innate immune system in AD.



 goto top of outline Author Contacts

Prof. Dr. Natalija Novak
Department of Dermatology and Allergy
University of Bonn
Sigmund-Freud-Strasse 25, DE–53127 Bonn (Germany)
Tel. +49 228 2871 5370, E-Mail Natalija.Novak@ukb.uni-bonn.de


 goto top of outline Article Information

Received: December 8, 2010
Accepted after revision: January 3, 2011
Published online: January 21, 2011
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 1, Number of References : 51


 goto top of outline Publication Details

Journal of Innate Immunity

Vol. 3, No. 2, Year 2011 (Cover Date: February 2011)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Hon KL, Wong KY, Leung TF, Chow CM, Ng PC: Comparison of skin hydration evaluation sites and correlations among skin hydration, transepidermal water loss, SCORAD index, Nottingham Eczema Severity Score, and quality of life in patients with atopic dermatitis. Am J Clin Dermatol 2008;9:45–50.
  2. 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.
  3. Jensen JM, Folster-Holst R, Baranowsky A, Schunck M, Winoto-Morbach S, Neumann C, et al: Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J Invest Dermatol 2004;122:1423–1431.
  4. Rodriguez 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.
  5. de Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA: Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol 2009;129:14–30.
  6. 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, 493e1.
  7. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, de Benedetto A, et al: Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007;120:150–155.
  8. 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.
  9. Hatano Y, Terashi H, Arakawa S, Katagiri K: Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis. J Invest Dermatol 2005;124:786–792.
  10. Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz M, Werfel T, Herz U, et al: The Toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 2004;113:565–567.
  11. Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G: Association of the Toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 2009;64:1608–1615.
  12. Weidinger S, Novak N, Klopp N, Baurecht H, Wagenpfeil S, Rümmler L, et al: Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema. J Allergy Clin Immunol 2006;118:277–279.
  13. Terhorst D, Kalali BN, Weidinger S, Illig T, Novak N, Ring J, et al: Monocyte-derived dendritic cells from highly atopic individuals are not impaired in their pro-inflammatory response to Toll-like receptor ligands. Clin Exp Allergy 2007;37:381–390.
  14. 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.
  15. Niebuhr M, Lutat C, Sigel S, Werfel T: Impaired TLR-2 expression and TLR-2-mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy 2009;64:1580–1587.
  16. Mrabet-Dahbi S, Dalpke AH, Niebuhr M, Frey M, Draing C, Brand S, et al: The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 2008;121:1013–1019.
  17. Novak N, Yu CF, Bussmann C, Maintz L, Peng WM, Hart J, et al: Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007;62:766–772.
  18. Beygo J, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S: No evidence of an association between polymorphisms in the IRAK-M gene and atopic dermatitis in a German cohort. Mol Cell Probes 2009;23:16–19.
  19. Weidinger S, Klopp N, Rümmler L, Wagenpfeil S, Novak N, Baurecht HJ, et al: Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 2005;116:177–184.
  20. Macaluso F, Nothnagel M, Parwez Q, Petrasch-Parwez E, Bechara FG, Epplen JT, et al: Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 2007;16:692–698.
  21. Kabesch M, Peters W, Carr D, Leupold W, Weiland SK, von Mutius E: Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 2003;111:813–817.
  22. Weidinger S, Klopp N, Rümmler L, Wagenpfeil S, Baurecht HJ, Gauger A, et al: Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults. Clin Exp Allergy 2005;35:866–872.
  23. Carrera MC, Moura P, Crovella S, de Souza PR, de Alencar LC, Sarinho E: High polymorphism of the MBL2 gene in patients with atopic dermatitis. Ann Allergy Asthma Immunol 2010;105:39–42.
  24. Hashimoto S, Nakamura K, Oyama N, Kaneko F, Fujita T, Tsunemi Y, et al: Mannose-binding lectin (MBL) single nucleotide polymorphism is not associated with atopic dermatitis in Japanese patients. J Dermatol 2005;32:1038–1040.
  25. Howell MD: The role of human beta defensins and cathelicidins in atopic dermatitis. Curr Opin Allergy Clin Immunol 2007;7:413–417.
  26. 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.
  27. 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;130:1355–1364.
  28. 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;122:62–68.
  29. Eyerich K, Pennino D, Scarponi C, Foerster S, Nasorri F, Behrendt H, et al: IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response. J Allergy Clin Immunol 2009;123:59–66.
  30. Peng WM, Jenneck C, Bussmann C, Bogdanow M, Hart J, Leung DY, et al: Risk factors of atopic dermatitis patients for eczema herpeticum. J Invest Dermatol 2007;127:1261–1263.
  31. Buchau AS, MacLeod DT, Morizane S, Kotol PF, Hata T, Gallo RL: Bcl-3 acts as an innate immune modulator by controlling antimicrobial responses in keratinocytes. J Invest Dermatol 2009;129:2148–2155.
  32. Hata TR, Kotol P, Jackson M, Nguyen M, Paik A, Udall D, et al: Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol 2008;122:829–831.
  33. 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;174:8003–8010.
  34. Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G: Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 2002;119:433–439.
  35. Sayama K, Komatsuzawa H, Yamasaki K, Shirakata Y, Hanakawa Y, Ouhara K, et al: New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of beta-defensins, LL37, and TLR2. Eur J Immunol 2005;35:1886–1895.
  36. Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, et al: Cutting edge: proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol 2007;178:3373–3377.
  37. Wu WH, Park CO, Oh SH, Kim HJ, Kwon YS, Bae BG, et al: Thymic stromal lymphopoietin-activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis. J Allergy Clin Immunol 2010;126:290–299, 299e1–4.
  38. He R, Oyoshi MK, Garibyan L, Kumar L, Ziegler SF, Geha RS: TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc Natl Acad Sci USA 2008;105:11875–11880.
  39. Homey B, Steinhoff M, Ruzicka T, Leung DY: Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 2006;118:178–189.
  40. Ezzat MH, Sallam MA, Shaheen KY: Serum mucosa-associated epithelial chemokine (MEC/CCL28) in atopic dermatitis: a specific marker for severity. Int J Dermatol 2009;48:822–829.
  41. Gros E, Bussmann C, Bieber T, Förster I, Novak N: Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis. J Allergy Clin Immunol 2009;124:753–760e1.
  42. Strid J, Strobel S: Skin barrier dysfunction and systemic sensitization to allergens through the skin. Curr Drug Targets Inflamm Allergy 2005;4:531–541.
  43. Cho SH, Strickland I, Boguniewicz M, Leung DY: Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 2001;108:269–274.
  44. Matsubara M, Harada D, Manabe H, Hasegawa K: Staphylococcus aureus peptidoglycan stimulates granulocyte macrophage colony-stimulating factor production from human epidermal keratinocytes via mitogen-activated protein kinases. FEBS Lett 2004;566:195–200.
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