The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 62-68, July 2008

Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human β-defensin-3

  • Kevin O. Kisich, PhD

      Affiliations

    • Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo
    • Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
    • ,
  • Charles W. Carspecken, BS

      Affiliations

    • Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo
    • Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
    • ,
  • Stephanie Fiéve, BS

      Affiliations

    • Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo
    • ,
  • Mark Boguniewicz, MD

      Affiliations

    • Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo
    • Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
    • ,
  • Donald Y.M. Leung, MD, PhD

      Affiliations

    • Division of Allergy/Immunology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colo
    • Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo
    • Corresponding Author InformationReprint requests: Donald Y. M. Leung, MD, PhD, National Jewish Medical and Research Center, 1400 Jackson Street, Room K926i, Denver, CO 80206.

Received 5 March 2008; received in revised form 21 April 2008; accepted 23 April 2008. published online 06 June 2008.

Background

Individuals with atopic dermatitis (AD) have frequent colonization and infection with Staphylococcus aureus. Rapid elimination of S aureus depends on constitutive synthesis and mobilization of human β-defensin-3 (HBD-3).

Objective

To determine whether keratinocytes in AD, compared with normal, skin are less able to kill S aureus rapidly, and to assess the potential role that abnormally low mobilization of HBD-3 onto S aureus has in this process.

Methods

Skin samples from 10 normal individuals and 10 patients with AD were compared for synthesis and mobilization of HBD-3 onto surface-associated S aureus. Furthermore, keratinocytes from 10 individuals were studied for the effects of TH2 cytokines on the ability of the cells to synthesize and mobilize HBD-3, and to kill S aureus.

Results

Keratinocytes in skin biopsies from subjects with AD were defective in killing S aureus relative to normal individuals (P < .001). The constitutive levels of HBD-3 in the epidermal keratinocytes were similar between normal individuals and those with AD. However, the cells of patients with AD were unable to mobilize HBD-3 efficiently to kill S aureus. Physiologic Ca++ was essential for development of normal HBD-3 levels by cultured human keratinocytes. Mobilization of HBD-3 and the ability to kill S aureus were significantly (P < .05) inhibited by IL-4 and IL-13. Antagonism of IL-4/10/13 with antibodies significantly (P < .01) improved mobilization of HBD-3 onto the surface of S aureus by skin from patients with AD.

Conclusion

Patients with AD have problems with S aureus skin infection. This is a result of increased levels of TH2 cytokines, which inhibit keratinocyte mobilization of HBD-3.

Key words: Antimicrobial peptides, defensins, human, bacterial infections, skin, keratinocytes

Abbreviations used: AD, Atopic dermatitis, DAPI, 4′-6-Diamidino-2-phenylindole, dihydrochloride, HBD-3, Human β-defensin-3, KGM, Keratinocyte Growth Medium, MRSA, Methicillin-resistant Staphylococcus aureus

 

 Supported by AR41256 and N01-AI-40029 National Institutes of Health contract.

 Disclosure of potential conflict of interest: D. Y. M. Leung has served as a consultant for Novartis and Genentech, and has received research grants from the National Institutes of Health, Novartis, and Genentech. M. Boguniewicz has received research grants from Novartis and Sinclair. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(08)00767-7

doi:10.1016/j.jaci.2008.04.022

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 62-68, July 2008

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