Background In atopic subjects food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays a critical role in this response, and genetic ...polymorphisms in its components have been linked to allergy. Objective We sought to test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. Methods F709 mice, in which the IL-4Rα immunoreceptor tyrosine–based inhibitory motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses, including antibody production and TH 2 responses, were assessed. Results F709 mice, but not wild-type control animals, sensitized by means of gavage with OVA and either cholera toxin or staphylococcal enterotoxin B, displayed mast cell activation and systemic anaphylaxis on enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic TH 2 responses, and intestinal mast cell hyperplasia compared with wild-type mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high-affinity receptor for IgE (FcϵRI). Conclusion Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE dependent.
Background Atopic dermatitis (AD) is characterized by local and systemic TH 2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of TH 2 cytokines has been ...suggested as therapy for AD. Objectives We sought to examine the effect of the absence of IL-4 and IL-13 on the TH 17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. Methods 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. Results OVA-sensitized DKO mice exhibited impaired TH 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-γ 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 TH 2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. Conclusion Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated TH 17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.
Background Patients with atopic dermatitis (AD) exposed to the vaccinia virus (VV) smallpox vaccine have an increased risk of developing eczema vaccinatum. Objective To investigate the effects of ...local allergic skin inflammation on vaccinia immunity. Methods BALB/c mice were epicutaneously sensitized with ovalbumin (OVA) to induce allergic skin inflammation or with saline control, then inoculated with an attenuated VV strain by skin scarification or intraperitoneally. After 8 days, serum IgG anti-VV and cytokine secretion by splenocytes were measured. Results Mice inoculated with VV at sites of epicutaneous sensitization with OVA, but not control mice inoculated at saline exposed sites, developed satellite pox lesions and had impaired secretion of TH 1 cytokines in response to VV, decreased VV specific serum IgG2a , increased VV specific serum IgG1 , and impaired upregulation of IFN-α, but not the cathelicidin-related antimicrobial peptide, at the infection site. The VV immune response of OVA-sensitized mice inoculated with VV at distant skin sites or intraperitoneally was normal. Conclusion Local immune dysregulation at sites of allergic skin inflammation underlies the impaired TH 1 immune response to VV introduced at these sites and the increased susceptibility to develop satellite pox lesions, a characteristic of eczema vaccinatum in patients with AD. Clinical implications In a mouse model of AD, inoculation of VV at inflamed skin sites is associated with increased numbers of satellite pox lesions and an abnormal immune response to the virus. This may contribute to the susceptibility of patients with AD to virus dissemination after smallpox vaccination.
Background Atopic dermatitis (AD) is an inflammatory skin disorder occurring in genetically predisposed individuals with a systemic TH 2 bias. Atopic dermatitis patients exposed to the smallpox ...vaccine, vaccinia virus (VV), occasionally develop eczema vaccinatum (EV), an overwhelming and potentially lethal systemic infection with VV. Objective To establish a murine model of EV and examine the effects of skin inflammation on VV immunity. Methods The skin of RelB−/− mice, like that of chronic AD lesions in humans, exhibits thickening, eosinophilic infiltration, hyperkeratosis, and acanthosis. RelB−/− and wild-type (WT) control mice were infected with VV via skin scarification. Viral spread, cytokine levels, IgG2a responses and VV-specific T cells were measured. Results Cutaneously VV-infected RelB−/− , but not WT mice, exhibited weight loss, markedly impaired systemic clearance of the virus and increased contiguous propagation from the inoculation site. This was associated with a dramatically impaired generation of IFN-γ–producing CD8+ vaccinia-specific T cells along with decreased secretion of IFN-γ by VV-stimulated splenocytes. The TH 2 cytokines—IL-4, IL-5, IL-13, and IL-10—on the other hand, were overproduced. When infected intraperitoneally, RelB−/− mice generated robust T cell responses with good IFN-γ production. Conclusion Allergic inflammation in RelB−/− mice is associated with dysregulated immunity to VV encountered via the skin. We speculate that susceptibility of AD patients to overwhelming vaccinia virus infection is similarly related to ineffective T cell responses. Clinical implications The susceptibility of patients with AD to EV following cutaneous contact with VV is related to ineffective antiviral immune responses.
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