He R, Kim HY, Yoon J et al.Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13. J Allergy Clin Immunol 124:761-770

Division of Immunology, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass., USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 10/2009; 124(4):761-70.e1. DOI: 10.1016/j.jaci.2009.07.040
Source: PubMed


Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD.
We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD.
Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined.
OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice.
Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.

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Available from: Andrew J Macginnitie, Oct 06, 2014
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    • "It thus is possible that patients become sensitized towards Der p 11 and other mite body-associated allergens by skin contact. In this context it has been found that epicutaneous sensitization to protein antigens indeed can induce allergic sensitization and even may enhance subsequent respiratory allergy towards the same antigen (Beck and Leung, 2000; He et al., 2009; Spergel et al., 1998). In an experimental dog model of acute atopic dermatitis, epicutaneous application of HDM extracts destroyed the skin barrier function by reduction of stratum corneum ceramides (Stahl et al., 2012). "
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    ABSTRACT: House dust mites belong to the most potent indoor allergen sources worldwide and are associated with allergic manifestations in the respiratory tract and the skin. Here we studied the importance of the high molecular weight allergen, Der p 11, in HDM allergy. Sequence analysis showed that Der p 11 has high homology to paramyosins from mites, ticks and other invertebrates. A synthetic gene coding for Der p 11 was expressed in Escherichia coli and rDer p 11 purified to homogeneity as folded, alpha helical protein as determined by circular dichroism spectroscopy. Using antibodies raised against rDer p 11 and immunogold electron microscopy, the allergen was localized in the muscle beneath the skin of mite bodies but not in faeces. IgE reactivity of rDer p 11 was tested with sera from HDM allergic patients from Europe and Africa in RAST-based dot-blot assays. Interestingly, we found that Der p 11 is a major allergen for patients suffering from atopic dermatitis (AD), whereas it is only a minor allergen for patients suffering from respiratory forms of HDM allergy. Thus, rDer p 11 might be a useful serological marker allergen for the identification of a subgroup of HDM allergic patients suffering from HDM-associated AD.Journal of Investigative Dermatology accepted article preview online, 07 July 2014; doi:10.1038/jid.2014.271.
    Full-text · Article · Jul 2014 · Journal of Investigative Dermatology
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    • "In addition to IL-17A, the Th2 cytokine IL-4 is capable of regulating the expression of the GC receptor and may impact GC responsiveness [59]. Since the presence of a Th2 response can dampen IL-17A production (Figure 2A and E [52]), we reasoned that the relative absence of the Th2 response in the Th17 adoptive transfer model compared with that generated during NO2-promoted allergic airway disease (Figure 4B-C versus 4F-G) may explain the differences in sensitivity to treatment with Dex and anakinra during in vitro restimulation. Therefore, we administered anti-IL-4 or IgG isotype control antibody prior to NO2 sensitization and antigen challenge, as in Figure 2. In vivo administration was followed by the pharmacologic treatment of lung cells restimulated in the presence of OVA antigen with either anakinra, Dex, or the combination of anakinra and Dex. "
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    ABSTRACT: Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "Recently, the conceptual focus on understanding AD has increasingly shifted to including a primary defect in the epithelial barrier as an initial event in the atopic march. Many studies in animal models demonstrate that epidermal barrier dysfunction can be caused by repeated sensitization to allergens to the skin, which leads to phenotypes of atopic dermatitis, systemic sensitization, increased risk of allergic rhinitis, lung inflammation and AHR910. "
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    ABSTRACT: Although atopic dermatitis (AD) is the initial step of the "atopic march", a progression from AD to asthma, the underlying mechanism remains unknown. Selective expression of IL-13 in the skin of mice caused an AD phenotype resembling human AD, and the disorder was associated with enhanced production of thymic stromal lymphopoietin (TSLP) in the AD skin with a systemic Th2 immunity. Here we show that IL-13 transgenic mice with AD had significantly enhanced lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR) when sensitized and challenged by allergen. In addition, the level of TSLP was significantly higher in acute AD than in chronic AD. Furthermore, elimination of TSLP signaling significantly diminished the allergic asthma responses, immune cell production of Th2 cytokines (IL-4, IL-13), and serum IgE. These studies indicate that IL-13 induces AD and atopic march via a TSLP dependent mechanism.
    Full-text · Article · Jul 2011 · Scientific Reports
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