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Hand eczema is a highly prevalent skin disease and one of the most common work-related disorders. In up to two-thirds of individuals affected by hand eczema, the disease becomes chronic and results in substantial personal and occupational disability. Manifestations of chronic hand eczema vary in severity and appearance over time, and people with eczema typically experience itch, pain, and a burning sensation. The pathophysiology of chronic hand eczema is multifactorial. Major risk factors are current or past atopic dermatitis and excessive or prolonged exposure to irritants or allergens. Based on the suspected main causes, chronic hand eczema is commonly classified into irritant, allergic, and atopic hand eczema. Diagnosis and assessment can be complex, and management is often challenging. Strategies include structured education, avoidance of trigger factors, primary to tertiary prevention, topical anti-inflammatory treatment with glucocorticosteroids, calcineurin inhibitors, or januskinase inhibitors, phototherapy, systemic retinoids, and off-label use of immunosuppressive drugs. Topical and systemic immunomodulatory therapies approved for atopic dermatitis could be used in severe atopic hand eczema and some of them are under clinical development for chronic hand eczema. Additional research is needed to better understand chronic hand eczema subtypes and underlying mechanisms, and the comparative effectiveness and safety of therapies. This Review combines established knowledge with ongoing changes in our understanding of the disease and their implications for prevention, management, and future research., Competing Interests: Declaration of interests SW declares institutional research grants from LEO Pharma, Pfizer, and Sanofi; consulting fees from AbbVie, Almirall, Boehringer, GlaxoSmithKline, Leo Pharma, Eli Lilly, Pfizer, Regeneron, and Sanofi; honoraria for lectures from AbbVie, Almirall, Galderma, Leo Pharma, Eli Lilly, Pfizer, Regeneron, and Sanofi; and fees for being on the advisory board for AbbVie, Almirall, Leo Pharma, Eli Lilly, Pfizer, and Sanofi. NN declares institutional research grants from Sanofi, Abbvie, Biogen, Bristol Myers Squibb, Galderma, Janssen-Cilag, Moonlake, and UCB; consultation and lecture fees from AbbVie, Alk Abello, Allergopharma Almirall, Bencard Allergy Therapeutics, Blueprint, GlaxoSmithKline, HAL Allergy, Leo Pharma, Leti Pharma, Eli Lilly, Novartis, Pfizer, Regeneron, Sanofi, Stallergenes, Geer, and Streamed Up; and advisory and data safety board fees from AbbVie, Alk Abello, HAL Allergy, Leo Pharma, Novartis, Stallergenes Geer, Sanofi, and Regeneron., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Type 2 immune-mediated diseases give a clear answer to the issue of nature (genetics) versus nurture (environment). Both genetics and environment play vital complementary roles in the development of atopic dermatitis (AD). As a key component of the atopic march, AD demonstrates the interactive nature of genetic and environmental contributions to atopy. From sequence variants in the epithelial barrier gene encoding FLG to the hygiene hypothesis, AD combines a broad array of contributions into a single syndrome. This review will focus on the genetic contribution to AD and where genetics facilitates the elicitation or enhancement of AD pathogenesis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the proven effectiveness of psychotherapy for psychiatric disorders, adverse events or unwanted effects may occur. Unwanted effects, however, are rarely assessed. In self-help interventions, which usually are not supported by a therapist, such effects have received even less attention even though special caution is needed regarding unwanted effects such as those related to misapplication. For the present study, we present the newly developed Positive and Negative Effects of Psychotherapy Scale for Internet-Based Intervention (PANEPS-I) and examine possible unwanted effects of an internet-based self-help intervention in individuals with body-focused repetitive behaviors (BFRBs), aggregating three different techniques: habit reversal training (HRT), decoupling (DC), and decoupling in sensu (DC-is). Some HRT users have expressed concern that the suppression of the problematic behavior could lead to rebound effects, but this has not been examined rigorously. Following baseline assessment, 141 participants with at least one BFRB were randomly assigned to two intervention groups that differed only with respect to the delivery mode (video, manual); the content was the same. After 6 weeks, a post-assessment was conducted. Unwanted effects were assessed using the PANEPS-I. A total of 70% of the participants (both treatment groups combined) reported at least one positive effect of the intervention. Negative effects were reported by 14-92% of participants, depending on the effect. The highest agreement rates were found for "no positive goal orientation" (52.5%), "did not address personal problems" (48.8%), "time/performance pressure" (20.9%), shame (16.3%), and concerns about data privacy (14.3%). Participants in the manual intervention group reported unethical procedures (e.g., data privacy concerns) more often (Cohen's d = .44) than those in the video intervention group. Responders reported more positive effects and nonresponders more malpractice (|d| = .80, .54, respectively). HRT users (self-report) showed no significant differences compared to nonusers regarding negative effects. Stepwise hierarchical regression analyses indicated a dose-response relationship for reported positive effects and malpractice. Side effects may occur in any kind of intervention. Usage of HRT did not lead to more reported negative effects compared to nonusage. To improve the quality and effectiveness and ensure the safety of the user, especially those using digital self-help interventions, it is important to regularly assess unintended effects since there is no supervision of the patient in unguided self-help interventions., (Copyright © 2023 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)

The role of NLRP1 inflammasome activation and subsequent production of IL-1 family cytokines in the development of atopic dermatitis (AD) is not clearly understood. Staphylococcus aureus is known to be associated with increased mRNA levels of IL1 family cytokines in the skin and more severe AD. In this study, the altered expression of IL-1 family cytokines and inflammasome-related genes was confirmed, and a positive relationship between mRNA levels of inflammasome sensor NLRP1 and IL1B or IL18 was determined. Enhanced expression of the NLRP1 and PYCARD proteins and increased caspase-1 activity were detected in the skin of patients with AD. The genetic association of IL18R1 and IL18RAP with AD was confirmed, and the involvement of various immune cell types was predicted using published GWAS and expression quantitative trait loci datasets. In keratinocytes, the inoculation with S. aureus led to the increased secretion of IL-1β and IL-18, whereas small interfering RNA silencing of NLRP1 inhibited the production of these cytokines. Our results suggest that skin colonization with S. aureus may cause the activation of the NLRP1 inflammasome in keratinocytes, which leads to the secretion of IL-1β and IL-18 and thereby may contribute to the pathogenesis of AD, particularly in the presence of genetic variations in the IL-18 pathway., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis is the most common inflammatory skin disease and is characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in atopic dermatitis pathogenesis, but the alterations in the proteome that occur in the full epidermis have not been defined. Using a pressure-cycling technology and data-independent acquisition approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and nonlesional patient skin. Results were validated by targeted proteomics using parallel reaction monitoring mass spectrometry and immunofluorescence staining. Proteins that were differentially abundant in the epidermis of patients with atopic dermatitis versus in healthy control reflect the strong inflammation in lesional skin and the defect in keratinocyte differentiation and epidermal stratification that already characterizes nonlesional skin. Most importantly, they reveal impaired activation of the NRF2-antioxidant pathway and reduced abundance of mitochondrial proteins involved in key metabolic pathways in the affected epidermis. Analysis of primary human keratinocytes with small interfering RNA‒mediated NRF2 knockdown revealed that the impaired NRF2 activation and mitochondrial abnormalities are partially interlinked. These results provide insight into the molecular alterations in the epidermis of patients with atopic dermatitis and identify potential targets for pharmaceutical intervention., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive., Objective: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD., Methods: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (AD Mut ) (n = 15), along with matched wild-type (AD Wt ) patients and healthy controls. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed., Results: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of AD Wt demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional AD Wt or AD Mut skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified., Conclusions: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss advances in our understanding of the disease and their implications for prevention, management, and future research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Analysis of the human skin proteome is key to understand molecular mechanisms maintaining health or leading to diseases of this important organ. For minimal invasive sampling of skin proteomes, the use of self-adhesive tape strips has been successfully applied. However, the methods previously presented were evaluated on different types of skin samples (e.g. healthy, diseased) and used a variety of cell lysis/protein extraction methods, which renders a systematic comparison and thus the identification of the most efficient protocols difficult. Here, we present a study comparing five different approaches for cell lysis and protein extraction from single tape strip biopsies. Extraction using a detergent mix or 1% SDS proved to be most efficient. Further, we replaced protein precipitation by single-pot, solid-phase-enhanced sample preparation (SP3), which strongly enhanced the number of identified proteins. This fully LC-MS compatible methodology provides a fast and reproducible approach for minimal invasive sampling of human skin proteomes. BIOLOGICAL SIGNIFICANCE: Fast and reproducible minimal invasive sampling of human skin proteomes is a major prerequisite for clinical proteomics studies aiming to decipher molecular mechanisms involved in the homeostasis as well as in the development of diseases. By optimization of tape strip sampling, e.g. the introduction of SP3 sample cleanup prior to LC-MS analysis, the presented protocol leads to yet not reported numbers of protein identifications from healthy human skin. Further, due to its efficiency it allows analysis from minimal sample amounts, e.g. from single tape strips, while established protocols relied on pooling of multiple tape strips. This provides the opportunity to perform spatially (lateral) resolved proteome analyses from different depths of the skin by analysis of consecutive strips., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) affects up to 20% of children and adults worldwide. To gain a deeper understanding of the pathophysiology of AD, we conducted a large-scale transcriptomic study of AD with deeply sequenced RNA-sequencing samples using long (126-bp) paired-end reads. In addition to the comparisons against previous transcriptomic studies, we conducted in-depth analysis to obtain a high-resolution view of the global architecture of the AD transcriptome and contrasted it with that of psoriasis from the same cohort. By using 147 RNA samples in total, we found striking correlation between dysregulated genes in lesional psoriasis and lesional AD skin with 81% of AD dysregulated genes being shared with psoriasis. However, we described disease-specific molecular and cellular features, with AD skin showing dominance of IL-13 pathways, but with near undetectable IL-4 expression. We also demonstrated greater disease heterogeneity and larger proportion of dysregulated long noncoding RNAs in AD, and illustrated the translational impact, including skin-type classification and drug-target prediction. This study is by far the largest study comparing the AD and psoriasis transcriptomes using RNA sequencing and demonstrating the shared inflammatory components, as well as specific discordant cytokine signatures of these two skin diseases., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In this study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in the lesional skin of patients with psoriasis. The expression of miR-146a was approximately twofold higher than that of miR-146b in healthy human skin, and it was more strongly induced by stimulation of proinflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of patients with psoriasis, among which FERMT1 was verified as a direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in the miR-146a encoding gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a -/- and skin fibroblasts from miR-146a -/- and miR-146b -/- mice stimulated with psoriasis-associated cytokines as compared with wild-type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease. Therefore, we investigate associations and potential underlying pathways of AD and cardiovascular disease in large cohort studies: the AOK PLUS cohort (n = 1.2 Mio), the GINIplus/LISAplus birth cohorts (n = 2,286), and the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 2,990). In addition, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of patients with AD in AOK PLUS showed slightly increased risk for incident angina pectoris (adjusted risk ratio 1.17 [95% confidence interval 1.12-1.23]), hypertension (1.04 [1.02-1.06]), and peripheral arterial disease (1.15 [1.11-1.19]) but not for myocardial infarction (1.05 [0.99-1.12]) and stroke (1.02 [0.98-1.07]). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and cardiovascular disease. This study indicates only a marginally increased risk for angina pectoris, hypertension, and peripheral arterial disease and no increased risk for myocardial infarction or stroke in patients with AD. Relevant associations of AD with cardiovascular risk factors reported in US populations could not be confirmed. Likewise, patients with AD did not have increased genetic risk factors for cardiovascular disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4 + CD25 - T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4 + CD25 - T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical trials often continue to be undertaken even though the effectiveness of the intervention under consideration has already been demonstrated. In addition, vehicle- or placebo-controlled studies predominate over head-to-head comparisons, although the latter would be more informative for clinicians in guiding patient management. This creates research waste, and both investigators and funders are to blame. Wilkes et al. used a network analysis approach to show duplication of effort in trials assessing topical calcineurin inhibitors and corticosteroids as treatment options for atopic eczema. Unfortunately, this is just the tip of the research waste iceberg., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (also known as atopic eczema) is a chronic inflammatory skin disease that is characterised by intense itching and recurrent eczematous lesions. Although it most often starts in infancy and affects two of ten children, it is also highly prevalent in adults. It is the leading non-fatal health burden attributable to skin diseases, inflicts a substantial psychosocial burden on patients and their relatives, and increases the risk of food allergy, asthma, allergic rhinitis, other immune-mediated inflammatory diseases, and mental health disorders. Originally regarded as a childhood disorder mediated by an imbalance towards a T-helper-2 response and exaggerated IgE responses to allergens, it is now recognised as a lifelong disposition with variable clinical manifestations and expressivity, in which defects of the epidermal barrier are central. Present prevention and treatment focus on restoration of epidermal barrier function, which is best achieved through the use of emollients. Topical corticosteroids are still the first-line therapy for acute flares, but they are also used proactively along with topical calcineurin inhibitors to maintain remission. Non-specific immunosuppressive drugs are used in severe refractory cases, but targeted disease-modifying drugs are being developed. We need to improve understanding of the heterogeneity of the disease and its subtypes, the role of atopy and autoimmunity, the mechanisms behind disease-associated itch, and the comparative effectiveness and safety of therapies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4,185) and a prospective cohort of German Health Insurance beneficiaries (n=1,811,098). A potential genetic overlap was explored using genome-wide data from >22,000 coronary artery disease and >4,000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3,717 controls. After controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odds ratio (OR)=2.36; 95% confidence interval CI=1.26-4.41) and myocardial infarction (MI, OR=2.26; 95% CI=1.03-4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk (RR)=1.11; 95% CI=1.08-1.14) and MI (RR=1.14; 95% CI=1.06-1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the major histocompatibility complex, there was no evidence of genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases the risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct.

Epigenetic alterations are increasingly recognized as mechanisms for disease-associated changes in genome function and important risk factors for complex diseases. The epigenome differs between cell types and so far has been characterized in few human tissues only. In order to identify disease-associated DNA methylation differences for atopic dermatitis (AD), we investigated DNA from whole blood, T cells, B cells, as well as lesional and non-lesional epidermis from AD patients and healthy controls. To elicit functional links, we examined epidermal mRNA expression profiles. No genome-wide significant DNA methylation differences between AD cases and controls were observed in whole blood, T cells, and B cells, and, in general, intra-individual differences in DNA methylation were larger than interindividual differences. However, striking methylation differences were observed between lesional epidermis from patients and healthy control epidermis for various CpG sites, which partly correlated with altered transcript levels of genes predominantly relevant for epidermal differentiation and innate immune response. Significant DNA methylation differences were discordant in skin and blood samples, suggesting that blood is not an ideal surrogate for skin tissue. Our pilot study provides preliminary evidence for functionally relevant DNA methylation differences associated with AD, particularly in the epidermis, and represents a starting point for future investigations of epigenetic mechanisms in AD.

Relationships between chronic diseases have emerged as major clinical, public health and research issues. Consequently, clinical and epidemiological research on comorbidities of skin diseases is increasingly recognized as an important tool to understand their etiologies more fully and to capture their morbidities and burdens. In this issue, Flohr and colleagues report a cross-sectional analysis on the complex associations among atopic dermatitis, filaggrin loss-of-function mutations, skin barrier function, and food sensitization in exclusively breastfed infants. When interpreting this and other association studies, various alternative models of comorbidity should be considered as suggested by Neale and Kendler.

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisms (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18 × 10(-8), odds ratio (OR)=1.27, 95% confidence interval (CI)=1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NFκBIA.

Atopic dermatitis (AD) and psoriasis are common skin diseases characterized by cutaneous inflammation and disturbed epidermal differentiation. Genome-wide analyses have shown overlapping susceptibility loci, such as the epidermal differentiation complex on chromosome 1q21. Recently, a deletion on 1q21 (LCE3C_LCE3B-del), comprising LCE3B and LCE3C, two members of the late cornified envelope (LCE) gene cluster, was found to be associated with psoriasis. Although the mechanistic role of LCE proteins in psoriasis has not been identified, these proteins are putatively involved in skin barrier formation and repair. Considering the potential genetic overlap between the two diseases and the recent finding that mutations in the skin barrier protein filaggrin are associated with AD, we investigated a possible association between LCE3C_LCE3B-del and AD. Evaluation of four different cohorts of European ancestry, containing a total of 1075 AD patients and 1658 controls, did not provide evidence for such an association. Subgroup analysis did not reveal an association with concomitant asthma. Our data suggest that the potential roles of skin barrier defects in the pathogenesis of AD and psoriasis are based on distinct genetic causes.

Allergic contact dermatitis is one of the most frequent dermatological problems affecting 7% of the general population. Impaired skin barrier function facilitates the penetration of contact allergens and irritants into the epidermal layer and is regarded as an important cofactor promoting the process of allergic contact sensitization. Filaggrin is crucial for the maintenance of the skin barrier function. Loss-of-function mutations within the filaggrin (FLG) gene are associated with skin barrier diseases such as ichthyosis vulgaris and atopic eczema (AE). To assess the impact of FLG on allergic contact sensitization and plausible intermediate traits, the two prevalent FLG mutations R501X and 2282del4 were typed in 1,502 individuals of the KORA C population-based cohort with extensive dermatologic phenotyping. Associations of FLG mutations with AE could be replicated. Strong associations were seen with dry skin, palmar hyperlinearity, and keratosis pilaris. In addition, an association with contact sensitization to nickel and contact sensitization to nickel combined with intolerance to fashion jewelry, but not with other contact allergens, was observed. From these data, we conclude that a genetically determined FLG deficiency manifests as dry skin and features of ichthyosis vulgaris. In addition, FLG deficiency may also represent a risk factor for contact sensitization to allergens.

Although seasonal variations are well known in many patients with eczema, no systematic population-based panel study evaluating seasonality and quantifying the influence of factors like climate and pollen on symptom variations has been conducted so far. Thirty-nine children with eczema, who had been identified in 1996 in a cross-sectional study on 1673 6-y-olds in Augsburg (Germany), participated in the study. Between March and September 1999, they daily recorded itch, extent, and possibly triggering factors on quantitative scales. Daily temperature, humidity, radiation, and pollen concentration were measured. Mixed linear models, taking the time series structure and confounding into account, were used for analysis. Seasonal patterns were significantly different between children: twenty-one had symptoms mainly in winter. They were affected by changes in outdoor temperature: itch was reduced by 22% (95% confidence interval (CI): 16%-27%) and extent by 65% (CI: 54%-72%) per 15 degrees C temperature increase. Eighteen children exhibited more symptoms in summer and especially during days with high grass-pollen exposure when itch was 16% higher (CI: 8%-24%) and extent 19% (CI: 2%-39%). This effect was stronger for children sensitized against pollen. Consideration of the individual type of eczema may help to arrange appropriate preventive and therapeutic measures.

Colonization of human skin with Staphylococcus aureus is a common feature in a variety of dermatologic diseases. In order to reproducibly investigate the adherence of Staphylococcus aureus to human epidermal cells, an in vitro assay was established using the biotin/streptavidine labeling system and the HaCaT cell line. This assay was used to define the role of several Staphylococcus aureus surface proteins with regard to their function in the staphylococcal adhesion process. Our studies included the standard laboratory strain Newman as well as its genetically constructed mutants DU5873, DU5852, DU5854, and DU5886 generated by allele replacement or transposon mutagenesis, which are deficient in the elaboration of staphylococcal protein A (spa), clumping factor (clfA), coagulase (coa), and the fibronectin-binding proteins A and B (fnbA/B), respectively. In comparison with strain Newman all mutants showed remarkably reduced adherence to the HaCaT keratinocyte cell line in our assay, yielding only between 43% and 60% of the adherence capacity of strain Newman after 60 min. Bacterial adherence could be re-established by introducing the cloned wild-type genes for the surface proteins on shuttle plasmids into the chromosomally defective mutants, thus suggesting a pathogenetic role of these proteins in the attachment of Staphylococcus aureus to human keratinocytes. Bacterial adherence was additionally enhanced by alkaline pH-values that are characteristic for skin conditions with epidermal barrier dysfunction. The use of Staphylococcus aureus mutant strains, deficient in the elaboration of defined proteins, allows specific investigation of colonization and virulence factors of this dermatologic relevant microorganism.

Serum and liver protein patterns were studied, respectively, in 5 patients (serum) and 1 patient (liver) with carbohydrate-deficient glycoprotein syndrome (CDGS) type I by high-resolution two-dimensional electrophoresis (2-DE) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The pattern of serum glycoproteins in all 5 patients presented abnormal trains of isoforms with decreased mass (delta molecular weight 3000) and all showed a cathodal shift. Two-dimensional electrophoresis and SDS-PAGE mass analysis of transferrin, alpha1 -antitrypsin, haptoglobin beta-chain, and alpha1-acid glycoprotein after neuraminidase and N-glycosidase F treatments demonstrated that the additional trains of the isoforms found in CDGS type I contain homologous species of isoforms. Some of them still showed charge differences, and all still contained glycans except for transferrin, with some unusual nonglycosylated isoforms. In addition, deficiencies in clusterin and serum amyloid P, not described so far, have been found in all 5 patients. The two-dimensional pattern of immunodetected precursors of serum proteins in liver cells from 1 patient with CDGS showed abnormal low-mass precursors and the absence of the precursors normally found in controls. These results suggest that these abnormal precursors accumulate during the early oligosaccharide processing of the nascent protein-bound oligosaccharides and that glycoprotein precursors undergo an altered intracellular transport while the post-translational processing along the normal pathway is still apparently functioning in patients with CDGS.

The uridine diphosphogalactose pyrophosphorylase activity has been determined in human adult and fetal tissues as well as blood of various ages by measurement of UDP-galactose production from gal-1-p and UTP. The highest activity was found from adult liver in which the specific activity was about 5% of the gal-1-p uridyltransferase activity. In general adult tissues had a somewhat higher activity than the corresponding fetal tissues except erythrocytes in which fetuses had a 5-10 times higher activity than adults. From normal blood the pyrophosphorylase activity in erythrocytes decreased with age, but in the case of galactosemia the decrease with age was not distinct. According to agarose gel isoelectrofocusing studies, at least two isozyme forms for UDP-galactose pyrophosphorylase exist with the activity bands between pH 6.0-6.15. The patterns of AGIF bands of pyrophosphorylase varied according to the age of the samples, suggesting the development of the isozyme forms of pyrophosphorylase to be age-dependent. Uridyltransferase, on the other hand, resolved into multiple bands between pH 5.1-5.6 on agarose gels and the patterns varied according to the variants but not to the age. Significance of the decrease in the pyrophosphorylase activity in erythrocytes with age as well as of the difference in AGIF bands between normal and the galactosemic were discussed with regard to the pathology of classical galactosemia.