BackgroundLoss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status.ObjectiveWe sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD.MethodsWe studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy.ResultsWe found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = −0.80 and −0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients.ConclusionsNMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations.

Filaggrin (FLG) loss-of-function skin barrier gene mutations are associated with atopic dermatitis (AD) and transepidermal water loss (TEWL). We investigated whether FLG mutation inheritance, skin barrier impairment, and AD also predispose to allergic sensitization to foods. Six hundred and nineteen exclusively breastfed infants were recruited at 3 months of age and examined for AD and disease severity (SCORing Atopic Dermatitis (SCORAD)), and screened for the common FLG mutations. TEWL was measured on unaffected forearm skin. In addition, skin prick testing was performed to six study foods (cow's milk, egg, cod, wheat, sesame, and peanut). Children with AD were significantly more likely to be sensitized (adjusted odds ratio (OR)=6.18, 95% confidence interval (CI): 2.94-12.98, P<0.001), but this effect was independent of FLG mutation carriage, TEWL, and AD phenotype (flexural vs. non-flexural). There was also a strong association between food sensitization and AD severity (adjusted ORSCORAD<20=3.91, 95% CI: 1.70-9.00, P=0.001 vs. adjusted ORSCORAD20=25.60, 95% CI: 9.03-72.57, P<0.001). Equally, there was a positive association between AD and sensitization with individual foods (adjusted ORegg=9.48, 95% CI: 3.77-23.83, P<0.001; adjusted ORcow's milk=9.11, 95% CI: 2.27-36.59, P=0.002; adjusted ORpeanut=4.09, 95% CI: 1.00-16.76, P=0.05). AD is the main skin-related risk factor for food sensitization in young infants. In exclusively breastfed children, this suggests that allergic sensitization to foods can be mediated by cutaneous antigen-presenting cells.

Background: Domestic water hardness and chlorine have been suggested as important risk factors for atopic dermatitis (AD). Objective: We sought to examine the link between domestic water calcium carbonate (CaCO 3) and chlorine concentrations, skin barrier dysfunction (increased transepidermal water loss), and AD in infancy. Methods: We recruited 1303 three-month-old infants from the general population and gathered data on domestic water CaCO 3 (in milligrams per liter) and chlorine (Cl 2 ; in milligrams per liter) concentrations from local water suppliers. At enrollment, infants were examined for AD and screened for filaggrin (FLG) skin barrier gene mutation status. Transepidermal water loss was measured on unaffected forearm skin. Results: CaCO 3 and chlorine levels were strongly correlated. A hybrid variable of greater than and less than median levels of CaCO 3 and total chlorine was constructed: a baseline group of low CaCO 3 /low total chlorine (CaL/ClL), high CaCO 3 /low total chlorine (CaH/ClL), low CaCO 3 /high total chlorine (CaL/ClH) and high CaCO 3 /high total chlorine (CaH/ClH). Visible AD was more common in all 3 groups versus the baseline group: adjusted odds ratio (AOR) of 1.87 (95% CI, 1.25-2.80; P 5 .002) for the CaH/ClL group, AOR of 1.46 (95% CI, 0.97-2.21; P 5 .07) for the CaL/ClH, and AOR of 1.61 (95% CI, 1.09-2.38; P 5 .02) for the CaH/ClH group. The effect estimates were greater in children carrying FLG mutations, but formal interaction testing between water quality groups and filaggrin status was not statistically significant. Conclusions: High domestic water CaCO 3 levels are associated with an increased risk of AD in infancy. The influence of increased total chlorine levels remains uncertain. An intervention trial is required to see whether installation of a domestic device to decrease CaCO 3 levels around the time of birth can reduce this risk.

Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.