Summary Atopic Dermatitis (AD) is characterized by allergic skin inflammation. A hallmark of AD is a dry itchy skin, due at least in part, to defects in skin genes that are important for maintaning skin barrier function. The pathogenesis of AD remains incompletely understood. Since the description of the Nc/Nga mouse as a spontaneously occurring model of AD, a number of mouse models of AD have been developed. They can be categorized into three groups: 1) Models induced by epicutaneous application of sensitizers; 2) Transgenic mice that either over-express or lack selective molecules; 3) Mice that spontaneously develop AD-like skin lesions. These models have resulted in a better understanding of the pathogenesis of AD. This review discusses these models and emphasizes the role of mechanical skin injury and skin barrier dysfunction in eliciting allergic skin inflammation.

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR ؊/؊ mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR ؊/؊ mice in response to OVA was normal. Skin dendritic cells from TSLPR ؊/؊ mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4 ؉ T cells from TSLPR ؊/؊ mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.

Background Filaggrin is important for skin barrier function and is mutated in 15-20% of patients with atopic dermatitis. Objective To examine whether filaggrin deficiency predisposes to skin inflammation and epicutaneous (EC) sensitization with protein antigen. Methods Skin histology in filaggrin-deficient ft/ft mice and WT controls was assessed by H&E staining and immunohistochemistry. Cytokine mRNA expression was examined by quantitative RT-PCR. Serum antibody levels and splenocyte secretion of cytokines were measured by ELISA. Results ft/ft mice developed eczematous skin lesions after age 28 weeks and a progressive increase in serum IgE and IgG1 levels. Normal appearing skin from 8-week-old ft/ft mice had epidermal thickening and increased dermal infiltration with CD4+ cells and expression of mRNA for IL-17, IL-6 and IL-23, but not IL-4, IL-13 or IFN-γ. Lesional skin of 32-week-old ft/ft mice exhibited qualitatively similar, but more pronounced, changes, and elevated IL-4 mRNA levels. EC application of ovalbumin (OVA) to shaved skin of 8-week-old ft/ft mice, but not WT mice, resulted in increased epidermal thickening, dermal infiltration by CD4+ cells, but not eosinophils, and expression of IL-17, IL-6, IL-23, IL-4 and IFN-γ, but not IL-5 or IL-13, mRNA. Splenocytes from EC sensitized ft/ft mice, but not controls, secreted cytokines in response to OVA stimulation and their sera, but not those of controls, contained OVA specific IgE and IgG1 antibodies. Conclusions Filaggrin deficient mice exhibit Th17-dominated skin inflammation, eczematous changes with age, and are permissive to EC sensitization with protein antigen.

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Atopic dermatitis (AD) is characterized by intense scratching and a Th2 dominated systemic and local immune response to cutaneously introduced antigens. Because scratching inflicts mechanical injury to the skin, we examined the effect of mechanical injury inflicted by tape stripping on the capacity of skin dendritic cells (DCs) to polarize T cells towards a Th2 phenotype. DCs isolated from skin 6 hrs after tape stripping elicited significantly higher production of IL-4 and IL-13, and significantly lower production of interferon-γ (IFN-γ) by OVA stimulated CD4+ DO.11.10 cells, than DCs isolated from unmanipulated skin, and expressed significantly more mRNA for the Th2 skewing molecules IL-10 and the Notch ligands Jagged1 and Jagged2, but significantly less mRNA for the Th1 skewing cytokine IL-12. CD11c+FITC+ cells isolated from draining lymph nodes (DLN) of shaved and tape stripped mouse skin 24 hrs after painting with FITC polarized T cells towards Th2 significantly more than CD11c+FITC+ cells isolated from DLN of shaved non tape stripped skin, and expressed significantly more IL-10, Jagged1 and Jagged2 mRNA, but significantly less IL-12 mRNA. Tape stripping significantly increased TSLP levels in the skin. Studies in TSLPR−/− mice demonstrated that TSLP played an essential role in the Th2 polarization effect of tape stripping on skin DCs. These results suggest that mechanical injury inflicted by scratching in patients with AD polarizes skin DCs to elicit a Th2 response by upregulating local expression of TSLP.

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Summary Scratching triggers skin flares in atopic dermatitis (AD). We demonstrate that scratching of human skin, and tape stripping of mouse skin, causes neutrophil influx. This influx in mice was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1−/− mice, and required expression of BLT1 on both T cells and non-T cells. Co-transfer of WT neutrophils, but not neutrophils deficient in BLT1 or the LTB4 synthesizing enzyme LTA4H, restored the ability of WT CD4+ effector T cells to transfer allergic skin inflammation to Ltb4r1−/− recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation.

Background Sensitization to food antigen may occur through cutaneous exposure. Objective Test the hypothesis that epicutaneous (EC) sensitization with food antigen predisposes to IgE-mediated anaphylaxis upon oral allergen challenge. Methods BALB/c mice were EC sensitized by repeated application of ovalbumin (OVA) to tape-stripped skin over 7 weeks, or orally immunized with OVA and cholera toxin (CT) weekly for 8 weeks, then orally challenged with OVA. Body temperature was monitored and serum mouse mast cell protease 1 (mMCP-1) level was determined following challenge. Tissue mast cells (MCs) were examined by chloroacetate esterase (CAE) staining. Serum OVA-specific IgE and IgG1 antibodies, and cytokines in supernatants of OVA-stimulated splenocytes, were measured by ELISA. Serum interleukin-4 (IL-4) levels were measured using an in vivo cytokine capture assay (IVCCA). Results EC sensitized mice exhibited expansion of connective tissue MC in the jejunum, increased serum IL-4 levels, and systemic anaphylaxis following oral challenge, as evidenced by decreased body temperature and increased serum mMCP-1 level. Intestinal MC expansion and anaphylaxis were IgE-dependent, as they did not occur in EC sensitized IgE−/− mice. Mice orally immunized with OVA+CT failed to increase serum IL-4 levels, expand their intestinal MCs, or develop anaphylaxis following oral challenge, despite OVA-specific IgE levels and splenocyte cytokine production in response to OVA stimulation, which were comparable to those of EC sensitized mice. Conclusion EC sensitized mice, but not mice orally immunized with antigen+CT, develop expansion of intestinal MCs and IgE-mediated anaphylaxis following single oral antigen challenge. IgE is necessary but not sufficient for food anaphylaxis, and MC expansion in the gut may play an important role in the development of anaphylaxis. Clinical Implications The skin may be an important route of sensitization to food antigens. Avoidance of cutaneous sensitization may prevent the development of food anaphylaxis.