Concentration of filaggrin monomers, its metabolites and corneocyte surface texture in individuals with a history of atopic dermatitis and controls.

BACKGROUND: Atopic dermatitis (AD) is characterized by skin barrier dysfunction. Notably, a high number of nano-scale protrusions on the surface of corneocytes, which can be expressed by the Dermal Texture Index (DTI), were recently associated with paediatric AD, loss-of-function mutations in filaggrin gene (FLG) and reduced levels of natural moisturizing factors (NMF). No study has so far examined the association between these parameters and monomeric filaggrin levels in adults. OBJECTIVE: To determine DTI, monomeric filaggrin and NMF in healthy controls and a group of patients with controlled dermatitis. METHODS: A total of 67 adults (20 healthy controls and 47 dermatitis patients) were included. In the patient population, a personal history of AD was diagnosed by the U.K. Working Party's Diagnostic Criteria. All participants were tested for FLG mutations (R501X, 2282del4, R2447X). Transepidermal water loss, monomeric filaggrin, DTI and NMF were measured. RESULTS: In the patient population, 78.7% (37/47) had a history of AD and 59.5% (28/47) had FLG mutations. Patients had significantly higher levels of DTI and significantly lower levels of monomeric filaggrin and NMF compared to the 20 healthy controls. Among patients, reduced level of monomeric filaggrin and NMF correlated with the presence of FLG mutations and clinical phenotypes such as xerosis, palmar hyperlinearity and AD. Among healthy controls, DTI was significantly higher in the oldest age group compared to the two younger age groups. CONCLUSION: A significant difference in DTI, monomeric filaggrin and NMF levels was found when comparing dermatitis patients with healthy controls. These findings suggest that even mild dermatitis or non-visible inflammation has a significant and negative effect on the skin barrier as inflammation is known to reduce filaggrin levels. DTI was significantly increased in aged individuals in the healthy control group, suggesting a gradual change in corneocyte morphology with age.

The role of the skin microbiome in atopic dermatitis: a systematic review.

Dysbiosis is a hallmark of atopic dermatitis (AD). The composition of skin microbiome communities and the causality of dysbiosis in eczema have not been well established. The objective of this review is to describe the skin microbiome profile in AD and address whether there is a causal relationship between dysbiosis and AD. The protocol is registered in PROSPERO (CRD42016035813). We searched PubMed, Embase, Scopus and ClinicalTrials.gov for primary research studies applying culture-independent analysis on the microbiome on AD skin of humans and animal models. Two authors independently screened the full text of studies for eligibility and assessed risk of bias. Because of heterogeneity no quantitative synthesis was done. Of 5735 texts, 32 met the inclusion criteria (17 published: 11 human and six animal studies). The studies varied in quality and applied different methodology. The skin in AD had low bacterial diversity (lowest at dermatitis-involved sites) and three studies showed depletion of Malassezia spp. and high non-Malassezia fungal diversity. The relative abundance of Staphylococcus aureus and Staphylococcus epidermidis were elevated and other genera were reduced, including Propionibacterium. A mouse study indicated that dysbiosis is a driving factor in eczema pathogenesis. The data are not sufficiently robust for good characterization; however, dysbiosis in AD not only implicates Staphylococcus spp., but also microbes such as Propionibacterium and Malassezia. A causal role of dysbiosis in eczema in mice should encourage future studies to investigate if this also applies to humans. Other important aspects are temporal dynamics and the influence of methodology on microbiome data.

Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.

BACKGROUND: Cellular T-helper (Th)17 infiltrates dominate skin inflammation in filaggrin-deficient flaky tail (ft/ft) mice, and Th17 cells are found in both the skin and blood of patients with acute atopic dermatitis. However, the potential role of loss-of-function mutations in the filaggrin gene (FLG) for increased peripheral Th17 cells is unclear. OBJECTIVES: To study whether mutations in FLG influence the frequency of peripheral Th17 cells. METHODS: We studied blood samples from six adults with mutations in FLG and five controls without mutations for frequencies of cytokine-producing CD4(+) T cells. We evaluated ft/ft mice and wild-type (WT) control mice for interleukin (IL)-17-producing CD4(+) T cells in naive mice and following 2,4-dinitrofluorobenzene (DNFB) challenge. In addition, the T-cell receptor (TCR) Vß-chain repertoire was analysed by flow cytometry. RESULTS: Human studies showed increased frequency of peripheral Th17 cells in FLG mutation carriers when compared with WT individuals. Mouse studies showed increased frequency of peripheral Th17 cells in adult ft/ft mice but not in 2-week-old ft/ft mice. Moreover, altered TCR Vß-chain repertoire was found in ft/ft mice when compared with WT mice. An increased frequency of CD4(+) Vß10(+) T cells producing IL-17 was found in the spleen of adult ft/ft mice when compared with WT mice. Finally, DNFB challenge induced an increased number of Th17 cells in ft/ft mice compared with WT mice. CONCLUSIONS: Deficiency of filaggrin appeared to be a driver of increased peripheral levels of Th17 cells. This increase must be acquired as peripheral Th17 cells were found in adult ft/ft mice but not in 2-week-old ft/ft mice indicating involvement of exogenous factors.

Skin reaction and regeneration after single sodium lauryl sulfate exposure stratified by filaggrin genotype and atopic dermatitis phenotype.

BACKGROUND: Filaggrin is key for the integrity of the stratum corneum. Mutations in the filaggrin gene (FLGnull) play a prominent role in atopic dermatitis (AD) pathogenesis. People with AD have increased susceptibility to irritants. However, little is known about the effect of filaggrin genotype and AD phenotype on irritant response and skin regeneration. OBJECTIVES: To investigate the role of FLGnull and AD groups for skin reaction and recovery after sodium lauryl sulfate (SLS) irritation. METHODS: This is a case-control study comprising 67 subjects, including healthy controls and patients with and without FLGnull and AD. Reactivity to different doses of SLS at 24, 48, 72 and 145 h after SLS application was measured by transepidermal water loss (TEWL) and laser Doppler flowmetry (LDF). Reactivity was assessed univariately and by pattern analysis. RESULTS: All patient groups showed a higher degree of skin-barrier disruption and inflammation than did controls in response to SLS. Assessing reactivity by the delta value of the area under the curve for both TEWL and LDF showed significant differences between healthy controls and those with the AD phenotype, irrespective of filaggrin mutation. The poorest regeneration was among those with the AD phenotype. The two AD phenotype groups were separated by multivariate technique, due to earlier inflammatory reactivity among subjects with FLGnullplus AD compared with the AD phenotype alone. CONCLUSIONS: Both skin reaction and regeneration were significantly different between the patient population and the healthy controls. Additionally, response severity and regeneration depended more on AD phenotype than on filaggrin genotype, whereas the response was more rapid among the FLGnullplus AD individuals.

Skin prick test reactivity to aeroallergens by filaggrin mutation status.

BACKGROUND: Studies have shown that filaggrin gene (FLG) mutations are positively associated with sensitization to aero allergens. We hypothesized that FLG mutations would also have an effect on the mean size of positive skin prick test (SPT) reactions as well as the number of positive reactions. OBJECTIVE: To investigate the effect of FLG mutations on the mean size and the number of positive SPT reactions, as well as the association with positive specific IgE. METHODS: A random sample of 3335 adults from the general population in Denmark was genotyped for the R501X and 2282del4 mutations in the FLG. SPT and specific IgE measurements to common aeroallergens were also performed. RESULTS: FLG mutations did not influence the mean size and number of positive SPT reactions. Also, no association was found between FLG mutations and specific IgE measurements. CONCLUSION: Our findings suggest that FLG mutations alone are insufficient to cause secondary sensitization to allergens. The positive association seen in patients must be explained by a combination of further barrier abnormality caused by dermatitis as well as increased allergen exposure.