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Background: Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation. Methods: By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnr −/− ) mouse model lacking both genes including the intergenomic sequence. Results: Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnr −/− mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, FlgHrnr −/− mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the stratum corneum. Surprisingly, although the immune system revealed no aberrations under steady-state conditions, FlgHrnr −/− mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions. Conclusions: Together, our FlgHrnr −/− mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions.

Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation.By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnrNeonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnrTogether, our FlgHrnr

Background Prior to the discovery of filaggrin (FLG) mutations, evidence for an impaired skin barrier in atopic dermatitis (AD) has been documented, and changes in ceramide profile, altered skin pH and increased trans-epidermal water loss (TEWL) in patients with AD have been reported. Until now, no studies have analysed stratum corneum (SC) lipids combined with skin barrier parameters in subjects of known FLG genotype. Methods A cohort of 49 German individuals genotyped for the most common FLG mutations (R501X, 2282del4) had SC samples taken for lipid analysis by high-performance thin layer chromatography. In addition, TEWL, erythema, skin hydration and pH were measured. In 27 of the 49 individuals, a 24-h irritation patch test with sodium lauryl sulphate was performed. For the analysis, both the AD group and the control group were stratified by FLG mutation status (FLGmut/FLGwt). Results In the FLGmut AD group, significantly lower levels of ceramide 4 and significantly higher levels of ceramide 7 were observed when compared to both healthy control groups. However, ceramide 7 levels also significantly differed between FLGwt AD and FLGwt controls, as did ceramide 1 levels. No significant differences were observed for ceramide 2, 3, 5 and 6. FLGmut individuals had significantly higher skin pH values than individuals not carrying FLG mutations. Patients with AD with FLG mutations had significantly higher erythema compared to patients with AD without FLG mutations. Conclusion Our results confirm previous observations of altered ceramide levels in AD, which however appear to show no clear relationship with FLG mutations.

To cite this article: Mahachie John JM, Baurecht H, Rodriguez E, Naumann A, Wagenpfeil S, Klopp N, Mempel M, Novak N, Bieber T, Wichmann H-E, Ring J, Illig T, Cattaert T, Van Steen K, Weidinger S. Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants eczema risk. Allergy 2010; 65: 875–882. Abstract Background: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. Methods: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. Results: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. Conclusions: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.

Background: Flow cytometric basophil activation tests have been developed as cellular tests for in vitro diagnosis of IgE-mediated reactions. Different activation markers (CD63 or CD203c) with distinct ways of regulation have been used after stimulation with various allergens. Objective: It was the aim of the present study to compare basophil activation tests by measuring both CD63 and CD203c upregulation in patients with insect venom allergy. Materials and methods: 43 patients with a history of insect venom anaphylaxis were examined. A careful allergy history was taken, and skin tests and determination of specific IgE-antibodies were performed. Basophil activation tests (BAT) using CD63 or CD203c expression were done after stimulation with different concentrations of bee and wasp venom extracts. 25 healthy subjects with negative history of insect venom allergy were studied as controls. Results: The CD203c protocol showed a slightly higher sensitivity than the CD63 protocol (97% vs. 89%) with regard to patients’ history. The magnitude of basophil response was higher with CD203c in comparison to CD63 for both insect venoms. Specificity was 100% for the CD63 protocol and 89% for the CD203c protocol with regard to controls with negative history and negative RAST. Conclusion: These results support the reliability of basophil activation tests using either CD63 or CD203c as cellular tests in the in vitro diagnosis of patients with bee or wasp venom allergy with a slightly higher sensitivity for the CD203c protocol.