The mechanism that predisposes patients with atopic dermatitis (AD) to disseminated vaccinia viral (VV) skin infection after smallpox vaccination is unknown. We have demonstrated that expression of S100A11, a calcium-binding protein involved in keratinocyte differentiation, is downregulated in AD.
We investigated whether inhibiting expression of S100A11 increased VV replication in human keratinocytes and the mechanism by which S100A11 affects the innate immune response of keratinocytes.
Small interfering RNA duplexes were used to reduce gene expression of S100A11 in keratinocytes. VV replication was evaluated by real-time PCR and viral plaque assay. VV cytopathic effect was assessed by crystal violet staining. Affymetrix GeneChip assay was used to compare gene expression profiles. Real time PCR, Western blotting, and immunohistochemistry staining assay were used to evaluate gene expression in keratinocytes and AD skin biopsies.
Keratinocytes with deficient S100A11 expression supported increased VV replication and manifested augmented VV cytopathic effects. Gene microarray analysis revealed that the IL-10 receptor 2 chain (IL-10R2), which binds IFN-lambdas, was downregulated by 2.26-fold in S100A11-silenced keratinocytes. IL-10R2 expression was found to be decreased in skin biopsies from patients with acute AD (mean, 25.21 +/- 5.25; n = 20) compared with skin from normal healthy subjects (mean, 137.1 +/- 34.46; n = 19; P < .01). Furthermore, deficient S100A11 gene expression significantly impaired IL-29 (IFN-lambda1) responsiveness (2' 5'-oligoadenylate synthetase and Myxovirus [influenza virus] resistance induction) and its anti-VV effects in keratinocytes.
Inhibition of S100A11 gene expression impairs the ability of keratinocytes to control VV replication via downregulation of IFN-lambda receptor IL-10R2.
"A recent study suggested an impaired IL-28/IL-29 responsiveness of keratinocytes from these patients being a mechanism contributing to the increased susceptibility to viral infections. This hypothesis was deduced from the observation that S100A11 expression was reduced in the skin of atopic dermatitis patients and that experimental reduction of this molecule in normal keratinocytes in vitro decreased expression of the IL-28/IL-29 receptor subunit IL-10RB and reduced IL-29-induced expression of antiviral proteins in these cells (Bin and others 2009). However, the direct proof of impaired keratinocyte IL-28/IL-29 sensitivity in atopic dermatitis is still lacking. "
[Show abstract][Hide abstract] ABSTRACT: The skin forms an essential barrier between the inside of an organism and the environment. In addition to its function in insulation, temperature regulation, and sensation, it protects the body against physical trauma, pathogens, UV radiation, and excessive water loss. Many processes necessary for maintaining the skin integrity, including antimicrobial/antiviral defense, wound healing, and removal of tumors, are regulated by cytokines. Accumulating results lead us to assume that interleukin (IL)-28 and IL-29, 2 novel members of the IL-10-interferon cytokine family, are important regulators of some of these processes. In the skin, IL-28 and IL-29 can be produced by virus-infected cells, maturing dendritic cells (DCs), and regulatory T-cells, and they mainly influence keratinocytes and melanocytes. In keratinocytes, IL-28 and IL-29 induce growth inhibition. Simultaneously, these cytokines increase the cellular synthesis of proteins that directly hinder virus replication and enhance the readiness to present viral antigens to immune cells. Further, IL-28 and IL-29 upregulate expression of viral and microbial sensing cellular receptors, including toll-like receptor (TLR)3, TLR2, and melanoma differentiation associated gene 5, and strengthen the cellular response to these receptors' ligands. Thereby, in the noninfected skin IL-28 and IL-29 enhance the capacity of keratinocytes to react to viral and microbial products and at least indirectly upregulate their inflammatory potential and innate immunity. IL-28 and IL-29 can act synergistically with other mediators secreted during DC maturation (eg, IL-20). In summary, IL-28/IL-29 may play an important role in the skin in the clearance of viral and microbial infections and in the removal of tumors.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 08/2010; 30(8):617-28. DOI:10.1089/jir.2010.0064 · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review highlights some of the research advances in anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects and in allergic skin disease that were reported in the Journal in 2008. Key epidemiologic observations include a rise in anaphylaxis in a population-based study and lower rates of peanut allergy in Israel, where infants consume peanut early compared with the United Kingdom, where dietary introduction is generally delayed. Advances in food allergy diagnosis include IgE epitope mapping that discloses the likelihood and severity of allergy; studies correlating likelihood of clinical reactivity on the basis of food-specific IgE to sesame, peanut, milk, and tree nuts; and an observation that a low baseline angiotensin-converting enzyme level may be associated with having pharyngeal edema during a reaction. Molecular, immunologic, and genetic studies are discerning pathways that are key in development of food allergy, identifying new modalities to interrupt mast cell degranulation, and elucidating risks associated with penicillin allergy. Regarding treatment, clinical studies show a majority of children with milk and egg allergy tolerate these proteins in modest amounts when they are extensively heated in baked goods, and studies show promise for oral immunotherapy to treat milk allergy and sublingual immunotherapy for honey bee venom hypersensitivity. The importance of skin barrier dysfunction has continued to be highlighted in the pathophysiology of atopic dermatitis (AD). Research has also continued to identify immunologic defects that contribute to the propensity of patients with AD to develop viral and bacterial infection. New therapeutic approaches to AD, urticaria, and angioedema have been reported including use of probiotics, biologics, vitamin D, and skin barrier creams.
The Journal of allergy and clinical immunology 03/2009; 123(2):319-27. DOI:10.1016/j.jaci.2008.12.025 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review highlights some of the research advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insects, as well as advances in allergic skin disease that were reported in the Journal in 2009. Among key epidemiologic observations, several westernized countries report that more than 1% of children have peanut allergy, and there is some evidence that environmental exposure to peanut is a risk factor. The role of regulatory T cells, complement, platelet-activating factor, and effector cells in the development and expression of food allergy were explored in several murine models and human studies. Delayed anaphylaxis to mammalian meats appears to be related to IgE binding to the carbohydrate moiety galactose-alpha-1,3-galactose, which also has implications for hypersensitivity to murine mAb therapeutics containing this oligosaccharide. Oral immunotherapy studies continue to show promise for the treatment of food allergy, but determining whether the treatment causes tolerance (cure) or temporary desensitization remains to be explored. Increased baseline serum tryptase levels might inform the risk of venom anaphylaxis and might indicate a risk for mast cell disorders in persons who have experienced such episodes. Reduced structural and immune barrier function contribute to local and systemic allergen sensitization in patients with atopic dermatitis, as well as increased propensity of skin infections in these patients. The use of increased doses of nonsedating antihistamines and potential usefulness of omalizumab for chronic urticaria was highlighted. These exciting advances reported in the Journal can improve patient care today and provide insights on how we can improve the diagnosis and treatment of these allergic diseases in the future.
The Journal of allergy and clinical immunology 01/2010; 125(1):85-97. DOI:10.1016/j.jaci.2009.11.031 · 11.48 Impact Factor
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