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IL-17 in atopic eczema: Linking allergen-specific adaptive and microbial-triggered innate immune response

https://doi.org/10.1016/j.jaci.2008.10.031Get rights and content

Background

Patients with atopic eczema (AE) regularly experience colonization with Staphylococcus aureus that is directly correlated with the severity of eczema. Recent studies show that an impaired IL-17 immune response results in diseases associated with chronic skin infections.

Objective

We sought to elucidate the effect of IL-17 on antimicrobial immune responses in AE skin.

Methods

T cells infiltrating atopy patch test (APT) reactions were characterized for IL-17 secretion to varying stimuli. IL-17–dependent induction of the antimicrobial peptide human β-defensin 2 (HBD-2) in keratinocytes was investigated.

Results

Approximately 10% of APT-infiltrating T cells secreted IL-17 after phorbol 12-myristate 13-acetate (PMA)/ionomycin stimulation. Among these, 33% belonged to the newly characterized subtype TH2/IL-17. Despite the capacity to secrete IL-17, specific T-cell clones released only low amounts of IL-17 on cognate allergen stimulation, whereas IL-4, IFN-γ, or both were efficiently induced. IL-17 secretion was not enhanced by IL-23, IL-1β, or IL-6 but was enhanced by the S aureus–derived superantigen staphylococcal enterotoxin B. Both healthy and AE keratinocytes upregulated HBD-2 in response to IL-17, but coexpressed IL-4/IL-13 partially inhibited this effect. In vivo, additional application of staphylococcal enterotoxin B induced IL-17 in APT reactions, whereas IL-4, IFN-γ, and IL-10 were marginally regulated. Induced IL-17 upregulated HBD-2 in human keratinocytes in vivo.

Conclusion

IL-17–capable T cells, in particular TH2/IL-17 cells, infiltrate acute AE reactions. Although IL-17 secretion by specific T cells is tightly regulated, it can be triggered by bacteria-derived superantigens. The ineffective IL-17–dependent upregulation of HBD-2 in patients with AE is due to a partial inhibition by the type 2 microenvironment, which could partially explain why patients with AE do not clear S aureus.

Section snippets

Patients

Patients with AE according to the criteria of Hanifin and Rajka (n = 3) and a positive skin prick test response to Dermatophagoides pteronyssinus, RAST class of 3 or greater to Der p 1, and positive APT reaction to D pteronyssinus were included in the study. Before blood or skin samples were obtained, each participant provided informed consent. The study was approved by the ethics committee of the Istituto Dermopatico Dell'Immacolata.

Cytokines and antibodies

The following antibodies were used in flow cytometric

IL-17–producing T lymphocytes infiltrate the skin during APT reactions: Newly characterized TH2/IL-17 subset

Three patients with AE with a documented hypersensitivity to D pteronyssinus were challenged with APTs to D pteronyssinus. Biopsy specimens were taken from the resulting eczematous reactions, and infiltrating T cells were isolated and characterized by means of intracellular cytokine staining with flow cytometric techniques. In line with the hypothesis of a type 2 domination in early AE, the majority of skin-derived T cells activated in vitro by PMA plus ionomycin expressed high levels of IL-4 (

Discussion

Increasing evidence suggests a central role of IL-17 in encompassing host defense against microorganisms at surface barriers. In patients with AE, disease severity positively correlates with skin colonization of S aureus. This observation led us to investigate IL-17 in the pathogenesis of AE.

In this study we demonstrate that distinct subpopulations of IL-17–secreting T cells infiltrate acute skin lesions, where they trigger keratinocytes to produce the antimicrobial peptide HBD-2. However, this

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    K. Eyerich was supported by a grant of the “Bayerische Forschungsstiftung” (BFS). This work was supported by a grant of the European Community (UE-LSHB-CT-2005-018681) and by the Italian minister of health.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

    These authors contributed equally to this work.

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