Background Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight ...junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. Objective We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Methods Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. Results We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with TH 2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Conclusion Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.
Orchestrating when and how the cutaneous innate immune system should respond to commensal or pathogenic microbes is a critical function of the epithelium. The cutaneous innate immune system is a key ...determinant of the physical, chemical, microbial, and immunologic barrier functions of the epidermis. A malfunction in this system can lead to an inadequate host response to a pathogen or a persistent inflammatory state. Atopic dermatitis is the most common inflammatory skin disorder and characterized by abnormalities in both skin barrier structures (stratum corneum and tight junctions), a robust TH 2 response to environmental antigens, defects in innate immunity, and an altered microbiome. Many of these abnormalities may occur as the consequence of epidermal dysfunction. The epidermis directly interfaces with the environment and, not surprisingly, expresses many pattern recognition receptors that make it a key player in cutaneous innate immune responses to skin infections and injury. This review will discuss the role epidermal innate receptors play in regulation of skin barriers and, where possible, discuss the relevance of these findings for patients with atopic dermatitis.
Background Disruption of the epithelial barrier might be a risk factor for allergen sensitization and asthma. Viral respiratory tract infections are strongly associated with asthma exacerbation, but ...the effects of respiratory viruses on airway epithelial barrier function are not well understood. Many viruses generate double-stranded RNA, which can lead to airway inflammation and initiate an antiviral immune response. Objectives We investigated the effects of the synthetic double-stranded RNA polyinosinic:polycytidylic acid (polyI:C) on the structure and function of the airway epithelial barrier in vitro. Methods 16HBE14o- human bronchial epithelial cells and primary airway epithelial cells at an air-liquid interface were grown to confluence on Transwell inserts and exposed to polyI:C. We studied epithelial barrier function by measuring transepithelial electrical resistance and paracellular flux of fluorescent markers and structure of epithelial apical junctions by means of immunofluorescence microscopy. Results PolyI:C induced a profound decrease in transepithelial electrical resistance and increase in paracellular permeability. Immunofluorescence microscopy revealed markedly reduced junctional localization of zonula occludens-1, occludin, E-cadherin, β-catenin, and disorganization of junction-associated actin filaments. PolyI:C induced protein kinase D (PKD) phosphorylation, and a PKD antagonist attenuated polyI:C-induced disassembly of apical junctions and barrier dysfunction. Conclusions PolyI:C has a powerful and previously unsuspected disruptive effect on the airway epithelial barrier. PolyI:C-dependent barrier disruption is mediated by disassembly of epithelial apical junctions, which is dependent on PKD signaling. These findings suggest a new mechanism potentially underlying the associations between viral respiratory tract infections, airway inflammation, and allergen sensitization.
To the Editor: Atopic dermatitis (AD) is the most common inflammatory skin disease, affecting up to 20% of children in the United States, and is characterized by an increased susceptibility to ...cutaneous infections.1,2 One in 10 subjects with AD has difficulty clearing cutaneous infections with a host of viruses including herpes simplex, vaccinia, human papilloma, and/or molluscum contagiosum.1 This typically manifests as more extensive cutaneous and sometimes systemic disease and/or resistance to standard therapies.
The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing.
With the aim to ...analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan BU-based; n = 618; 79%; treosulfan TREO-based; n=162; 21%).
No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients (
< 0.001); more active diseases at the time of SCT (
< 0.001); a higher prevalence of patients with either hematopoietic cell transplantation-comorbidity index ≥3 (
< 0.001) or a good Karnofsky performance status (
= 0.025); increased use of peripheral blood stem cells as graft sources (
< 0.001); and greater use of reduced intensity conditioning regimens (
= 0.013) and of haploidentical donors (
< 0.001). Moreover, the 2-y cumulative incidence of relapse with myeloablative doses of BU was significantly lower than that registered with reduced intensity conditioning (21% versus 31%;
= 0.0003). This was not observed in the TREO-based group.
Despite a higher number of risk factors in the TREO group, no significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival according to the type of alkylator, suggesting that TREO has no advantage over BU in terms of efficacy and toxicity in acute myeloid leukemia and myelodysplastic syndrome.
Contribution of FLG mutations to S. aureus colonization in mild, moderate and severe AD was assessed by including interaction between EASI and FLG mutations in logistic regression models adjusting ...for total IgE, age, and sex.
Eczema Area and Severity Index (EASI), Rajka-Langeland severity score, past staphylococcal infection, past eczema herpeticum (EH) and laboratory test results were compared amongst the age of AD onset ...groups.
GSEA revealed 20 KEGG pathways (Familywise-error rate; P<0.04) with cytokine/cytokine receptor, T cell receptor signaling, and chemokine signaling being the most over-represented.
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