LAUSR

In this issue of the BJD, McAleer et al. provides data from a large and very comprehensive cross-sectional, observational study examining the skin barrier during infancy and early childhood. A total of 188 children, aged 0 to almost 6 years old, were examined for their skin content of natural moisturizing factors (NMFs) on different anatomical sites. About 50% of NMF normally derives from the degradation of filaggrin proteins into hygroscopic amino acids, including the photoreceptor urocanic acid, and with other constituents being lactate, sugars, urea and chloride. The NMF guarantees normal intracellular hydration and osmotic pressure, hence assisting cells to resist premature collapse because of pressure from surrounding extracellular lipids. Although NMF was low in all anatomical sites immediately after birth, there was a rapid increase (weeks) in NMF levels on the nasal tip and elbow flexure followed by a plateau. In contrast, NMF levels in cheek skin remained low for a much longer time, and the slow increase continued into the second year of life. The study is important as it reinforces the importance of cheek skin as one of the crucial starting points of atopic dermatitis (AD) in infancy. The appearance of baby skin is deceptive as it looks nice and moist, but in reality the skin barrier is inadequately matured. The authors nicely raise the hypothesis that not only may AD develop first on the cheeks because of low NMF content, but also that primary sensitization to food allergens may develop following inevitable exposure and epidermal allergen penetration. Interestingly, a Danish birth cohort study showed that a group of children with AD, in particular those with filaggrin gene (FLG) mutations, experienced eczema on the cheeks (and dorsal hands) highlighting the risk of AD in filaggrin-deficient exposed skin. In a recent observational study, NMF levels on the cheeks were lower in the winter compared with the summer in adults highlighting the negative effect of the northern European winter. Along the same lines, historically Inuits attempted to reduce bathing to a bare minimum to prevent frostbite and eczema. Currently, large trials are being conducted to confirm that incident AD can be reduced in highrisk children if they undergo daily treatment with emollients immediately after birth. It is an intriguing thought that such pre-emptive skin barrier restoration could be targeted to the cheeks (and other parts of the face and dorsal hands with low NMF levels) that are exposed to environmental factors associated with AD and which at the same time further reduce NMFs and cause inflammation, for example low temperature, dry air and air pollution. Peter Elias and I have previously hypothesized that the striking latitude-dependent gradient of common FLG mutations in Asian and European populations, with much higher prevalence rates in the north, could be explained by increased survival because of enhanced cutaneous vitamin D synthesis in northerners. Hence, adult heterozygous FLG mutation carriers have, on average, 10% higher serum vitamin D levels, whereas homozygous mutation carriers have about 30% higher concentrations. Moreover, a linear relationship exists between prevalence of FLG mutations and mean vitamin D concentrations in populations residing at various latitudes. However, it is possible that this adaption might have been insufficient in those who resided in the far north, as ultraviolet (UV) B irradiation was dramatically reduced during wintertime and dietary vitamin D intake often inadequate. Therefore, increased capacity to produce cholecalciferol in light-exposed skin areas such as the cheek and dorsal hands might have been required to increase chances of survival. Indeed, an experimental study showed that single suberythemal UVB irradiation resulted in an almost eightfold increased synthesis of cutaneous vitamin D (cholecalciferol) per percentage of UV irradiated skin surface when undertaken on the face and hands compared with other body regions. This raises the hypothesis that the increased capacity to produce cholecalciferol in light-exposed skin areas could be explained by evolutionary benefits of reduced NMF levels. Possibly, the two evolutionary adaptions worked in concert to maintain sufficient levels of vitamin D and survival in equatordistant geographical areas. However, with industrialization, the AD epidemic exploded because of these evolutionary benefits, and skin sites such as the face and hands, where the skin barrier had adapted to allow UVB photons to penetrate for vitamin D production, became particular susceptible predilection sites for skin-barrier impairment and AD.