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.
Background Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea. Objective We sought to evaluate the effects of azelaic acid (AzA) on ...these elements of the innate immune system. Methods Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel. Results AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment. Limitations Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA. Conclusions These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.
Background A subset of subjects with atopic dermatitis (AD) are susceptible to serious infections with herpes simplex virus, called eczema herpeticum, or vaccina virus, called eczema vaccinatum. ...Objective This National Institute of Allergy and Infectious Diseases–funded multicenter study was performed to establish a database of clinical information and biologic samples on subjects with AD with and without a history of eczema herpeticum (ADEH+ and ADEH− subjects, respectively) and healthy control subjects. Careful phenotyping of AD subsets might suggest mechanisms responsible for disseminated viral infections and help identify at-risk individuals. Methods We analyzed the data from 901 subjects (ADEH+ subjects, n = 134; ADEH− subjects, n = 419; healthy control subjects, n = 348) enrolled between May 11, 2006, and September 16, 2008, at 7 US medical centers. Results ADEH+ subjects had more severe disease based on scoring systems (Eczema Area and Severity Index and Rajka-Langeland score), body surface area affected, and biomarkers (circulating eosinophil counts and serum IgE, thymus and activation-regulated chemokine, and cutaneous T cell–attracting chemokine) than ADEH− subjects ( P < .001). ADEH+ subjects were also more likely to have a history of food allergy (69% vs 40%, P < .001) or asthma (64% vs 44%, P < .001) and were more commonly sensitized to many common allergens ( P < .001). Cutaneous infections with Staphylococcus aureus or molluscum contagiosum virus were more common in ADEH+ subjects (78% and 8%, respectively) than in ADEH− subjects (29% and 2%, respectively; P < .001). Conclusion Subjects with AD in whom eczema herpeticum develops have more severe TH 2-polarized disease with greater allergen sensitization and more commonly have a history of food allergy, asthma, or both. They are also much more likely to experience cutaneous infections with S aureus or molluscum contagiosum.
Background Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin ( FLG ), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations ...have not been reported in African ancestry populations. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections. Objective We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. Methods Two common loss-of-function mutations plus 9 FLG single nucleotide polymorphisms were genotyped in 278 European American patients with AD, of whom 112 had ADEH, and 157 nonatopic controls. Replication was performed on 339 African American subjects. Results Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects ( P = 1.46 × 10−5 , 3.87 × 10−5 , respectively), but the frequency of the R501X mutation was 3 times higher (25% vs 9%) for ADEH than for AD without eczema herpeticum (EH) (odds ratio OR, 3.4; 1.7-6.8; P = .0002). Associations with ADEH were stronger with the combined null mutations (OR, 10.1; 4.7-22.1; P = 1.99 × 10−11 ). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African American subjects, but present among patients with AD (3.2%; P = .035) and common among patients with ADEH (9.4%; P = .0049). However, the 2282del4 mutation was absent among African American patients with ADEH and rare (<1%) among healthy individuals. Conclusion The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition.
Quality controls were performed as described previously.6 The Cochran-Armitage trend test was used to test for association between each SNP and disease status by using PLINK.7 AÂ linear regression ...analysis was performed to test for associations between individual genetic markers and log-adjusted total serum IgE (tIgE) concentrations and log-adjusted Eczema Area and Severity Index (EASI) scores, and a multiple logistic regression model was used to test for SNP-SNP interactions among cases only between TSLP and its receptors by using SAS version 9.1 software (SAS Institute, Inc, Cary, NC).
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.
To the Editor: Atopic dermatitis (AD) is a chronic skin condition that affects 10% to 20% of children and 1% to 3% of adults.1 Individuals with atopic dermatitis are at an increased risk for ...cutaneous infections with Staphylococcus aureus, herpes simplex, and the small pox or vaccinia virus.2 Recently, it has been shown that defects in the innate immune system, such as the capacity to increase the production of broad spectrum antimicrobial peptides like cathelicidin, may account for this increase in infections.3,4 Important insight into the mechanism responsible for the production of antimicrobial peptides came with the discovery of the vitamin D response element in the cathelicidin promoter and the finding that the conversion of 25-hydroxyvitamin D to the active 1,25 dihydroxyvitamin D by CYP27B1 can occur in keratinocytes and monocytes and is under the control of Toll-like receptor 2.4-6 Thus, with infection or wounding, activation of Toll-like receptor 2 results in expression of CYP27B1, causing conversion of 25-hydroxyvitamin D to the active 1,25 dihydroxyvitamin D, and subsequent induction of cathelicidin.5,6 Our study sought to examine whether supplementation with oral cholecalciferol could provide the CYP27B1 enzyme enough substrate to overcome this relative deficiency in induction of cathelicidin in atopic patients. Because this increase is primarily seen in lesional skin, it is hypothesized that only with the supplementation with oral vitamin D can AD lesional skin be allowed to increase cathelicidin to its normal level seen postinjury.
Background The basis for increased susceptibility of patients with atopic dermatitis (AD) to develop disseminated viral skin infections such as eczema herpeticum (AD with a history of eczema ...herpeticum, ADEH+ ) is poorly understood. Objective We sought to determine whether subjects with AD prone to disseminated viral skin infections have defects in their IFN responses. Methods GeneChip profiling was used to identify differences in gene expression of PBMCs from patients with ADEH+ compared with patients with AD without a history of eczema herpeticum (ADEH– ) and nonatopic controls. Key differences in protein expression were verified by enzyme-linked immunosorbent spot assay and/or ELISA. Clinical relevance was further demonstrated by a mouse model of disseminated viral skin infection and genetic association analysis for genetic variants in IFNG and IFNGR1 and ADEH among 435 cases and controls. Results We demonstrate by global gene expression analysis selective transcriptomic changes within the IFN superfamily of PBMCs from subjects with ADEH+ reflecting low IFN-γ and IFN-γ receptor gene expression. IFN-γ protein production was also significantly lower in patients with ADEH+ (n = 24) compared with patients with ADEH– (n = 20) and nonatopic controls (n = 20). IFN-γ receptor knockout mice developed disseminated viral skin infection after epicutaneous challenge with vaccinia virus. Genetic variants in IFNG and IFNGR1 single nucleotide polymorphisms (SNPs) were significantly associated with ADEH (112 cases, 166 controls) and IFN-γ production: a 2-SNP (A-G) IFNGR1 haplotype (rs10457655 and rs7749390) showed the strongest association with a reduced risk of ADEH+ (13.2% ADEH+ vs 25.5% ADEH– ; P = .00057). Conclusion Patients with ADEH+ have reduced IFN-γ production, and IFNG and IFNGR1 SNPs are significantly associated with ADEH+ and may contribute to an impaired immune response to herpes simplex virus.
Background Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral ...infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. Objective We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. Methods In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. Results YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4+ T-cell responses was observed. Conclusions YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.
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