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

https://doi.org/10.1016/j.jaci.2008.04.022Get rights and content

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.

Section snippets

Skin biopsies

Subjects included 10 patients with AD diagnosed according to the Hanifin and Rajka14 criteria, and 10 healthy individuals with no history of skin disease. None of the patients had previously received oral corticosteroids or cyclosporin, and topical corticosteroids were not allowed for more than 1 week before enrollment. This study was approved by the institutional review board at National Jewish Medical and Research Center in Denver, and all patients gave written informed consent before

Epidermal keratinocytes in skin of patients with AD are defective in destruction of S aureus

In studies examining the interaction of fluorescently labeled S aureus with the epidermal keratinocytes in biopsies of normal skin, we noted that the bacterial structures rapidly became disorganized, the nuclei disappeared, and the cell envelopes became condensed. With increasing time, the covalently attached fluorescent label that was initially associated with the S aureus became diffuse and distributed throughout the cytoplasm of the keratinocytes.13 After 1 hour of exposure of S aureus to

Discussion

The skin of individuals with AD is frequently colonized and infected by S aureus, whereas these bacteria are rarely found on the skin of normal subjects.21, 22 In the current study, we have demonstrated directly that the epidermal keratinocytes in samples of AD skin are deficient in their ability to destroy S aureus that comes into contact with them. It is known that antimicrobial peptides play an important role in controlling colonization and growth of microbes at epithelial surfaces,23, 24

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    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.

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