Summary
This themed edition of BJD is dedicated to the work of Professor Ronald Marks for his untiring work on the understanding of stratum corneum (SC) structure and function. He and his coworkers, ...in my opinion, had the right focus for cosmetic dermatology issues. Namely, consumers experience the wonderful properties of the SC through sight, touch and the somatosensory system. They do not experience, for example, transepidermal water loss and skin conductance or capacitance! Marks understood this and set about developing the methodologies to examine the changes in SC architecture and function when desquamation goes haywire. More importantly, he understood that moisturizers do far more than simply hydrate the SC, as exemplified in the paper by Tree and Marks, ‘An explanation for the placebo effect of bland ointment bases.’ Moisturizing ingredients influence the properties of the SC in many ways with the sole purpose of overcoming the signs and symptoms of dry skin. Marks demonstrated the decrease in SC cohesion following use of hydrating agents, which led to the mechanistic work on the effects of a simple molecule like glycerol on the desquamatory process. In further exploiting forced desquamation and use of abrasion, he showed that improvements in exfoliation contribute to the mitigation of the signs of photodamaged skin, which can explain part of the antiageing effect of simple moisturizers. It is here that I should point out that at least this particular author in 1988 was ‘standing on the shoulders of’ a great corneologist whose work influenced his research directions. So this paper will provide an update on the latest developments for the molecular basis of SC maturation and moisturization, while highlighting the contributions of Professor Marks in the different areas.
What's already known about this topic?
Several reviews have been written on the topic of stratum corneum moisturisation at the molecular level up to 2013.
What does this study add?
This review discusses new, and old, data in the context of Professor Ronald Marks' work. A leading corneologist of our time.
People of skin of colour comprise the majority of the world's population and Asian subjects comprise more than half of the total population of the earth. Even so, the literature on the ...characteristics of the subjects with skin of colour is limited. Several groups over the past decades have attempted to decipher the underlying differences in skin structure and function in different ethnic skin types. However, most of these studies have been of small scale and in some studies interindividual differences in skin quality overwhelm any racial differences. There has been a recent call for more studies to address genetic together with phenotypic differences among different racial groups and in this respect several large-scale studies have been conducted recently. The most obvious ethnic skin difference relates to skin colour which is dominated by the presence of melanin. The photoprotection derived from this polymer influences the rate of the skin aging changes between the different racial groups. However, all racial groups are eventually subjected to the photoaging process. Generally Caucasians have an earlier onset and greater skin wrinkling and sagging signs than other skin types and in general increased pigmentary problems are seen in skin of colour although one large study reported that East Asians living in the U.S.A. had the least pigment spots. Induction of a hyperpigmentary response is thought to be through signaling by the protease-activated receptor-2 which together with its activating protease is increased in the epidermis of subjects with skin of colour. Changes in skin biophysical properties with age demonstrate that the more darkly pigmented subjects retaining younger skin properties compared with the more lightly pigmented groups. However, despite having a more compact stratum corneum (SC) there are conflicting reports on barrier function in these subjects. Nevertheless, upon a chemical or mechanical challenge the SC barrier function is reported to be stronger in subjects with darker skin despite having the reported lowest ceramide levels. One has to remember that barrier function relates to the total architecture of the SC and not just its lipid levels. Asian skin is reported to possess a similar basal transepidermal water loss (TEWL) to Caucasian skin and similar ceramide levels but upon mechanical challenge it has the weakest barrier function. Differences in intercellular cohesion are obviously apparent. In contrast reduced SC natural moisturizing factor levels have been reported compared with Caucasian and African American skin. These differences will contribute to differences in desquamation but few data are available. One recent study has shown reduced epidermal Cathepsin L2 levels in darker skin types which if also occurs in the SC could contribute to the known skin ashing problems these subjects experience. In very general terms as the desquamatory enzymes are extruded with the lamellar granules subjects with lowered SC lipid levels are expected to have lowered desquamatory enzyme levels. Increased pores size, sebum secretion and skin surface microflora occur in Negroid subjects. Equally increased mast cell granule size occurs in these subjects. The frequency of skin sensitivity is quite similar across different racial groups but the stimuli for its induction shows subtle differences. Nevertheless, several studies indicate that Asian skin maybe more sensitive to exogenous chemicals probably due to a thinner SC and higher eccrine gland density. In conclusion, we know more of the biophysical and somatosensory characteristics of ethnic skin types but clearly, there is still more to learn and especially about the inherent underlying biological differences in ethnic skin types.
Research on understanding of the chemistry, function and (patho)physiology of stratum corneum (SC) lipids and especially ceramides has evolved over the last two decades. This has been made successful ...through the application of separation techniques that have become increasingly more sophisticated, and it has become increasingly evident that our understanding of these molecules remains in its infancy. Thirteen classes of ceramides with over 300 and possibly up to 1000 distinct ceramide species have been identified suggesting an exquisitely subtle relationship between the types of ceramides and physical and chemical behaviour. Nevertheless, research has demonstrated the importance of the correct SC lipid lamellar architecture with conformationally‐ordered lipid bilayers, the presence of long‐chain ceramides, as either free or covalently bound lipids, greater quantities of phytosphingosine‐containing ceramides and a high SC lipid/protein ratio is essential for optimal barrier function. These features are known to change in a variety of physiological and pathophysiological conditions. Clearly, there is more to be learned but as we further decipher the complexity of SC lipids and understand their individual roles in the SC, we will learn how to better treat the disorders of cornification.
Résumé
Des recherches sur la compréhension de la chimie, de la fonction et de la (patho)physiologie des lipides du stratum corneum (SC) et en particulier des céramides ont évolué au cours des deux dernières décennies. Cela a été couronné de succès grâce à l'application de techniques de séparation qui sont devenues de plus en plus sophistiquées et il est devenu de plus en plus évident que notre compréhension de ces molécules reste à ses débuts. Treize classes de céramides avec plus de 300 et éventuellement jusqu’à 1000 espèces distinctes de céramide ont été identifiées, ce qui suggère une relation très subtile entre les types de céramides et le comportement physicochimique. Néanmoins, la recherche a démontré l'importance de l'exactitude de l'architecture lamellaire lipidique du SC avec la conformation en bicouches lipidiques, de la présence de céramides à longue chaîne, qu'ils soient libres ou liés de façon covalante, de la plus grandes quantités de céramides contenant de la phytosphingosine et un taux élevé de lipides / protéines du SC, est essentiel pour une fonction de barrière optimale. Ces caractéristiques sont connues pour varier suivant les conditions physiologiques et pathophysiologiques. De toute évidence, il y a plus à apprendre, mais à mesure que nous déchiffrions davantage la complexité des lipides du SC et que nous comprenons leurs rôles individuels dans le SC, nous apprendrons à mieux traiter les troubles de la kératinisation.
Summary
Background Atopic dermatitis (AD) is a chronic inflammatory disease associated with changes in stratum corneum (SC) structure and function. The breakdown of epidermal barrier function in AD ...is associated with changes in corneocyte size and maturation, desquamation, lipid profiles, and some protease activities.
Objectives The purpose of this study was: (i) to examine physiological changes in lesional (L) skin of acute eczematous AD, compared with nonlesional (NL) AD skin and healthy (H) skin, using sequential tewametry and SC protein analysis to estimate SC thickness; and (ii) to assess which serine proteases might be involved in pathogenesis.
Methods Six subjects with H skin, six AD patients with NL skin and six AD patients with mild to moderate eczema (L skin) were enrolled. Skin was assessed using several noninvasive techniques but SC thickness was estimated using tewametry and SC protein content of D‐Squame strippings. SC integrity was determined by sequential tape stripping (D‐Squame) and infrared densitometry. Kallikreins, plasmin, urokinase and leucocyte elastase protease activities together with a novel SC tryptase‐like enzyme activity were quantified.
Results Transepidermal water loss (TEWL) levels after D‐Squame stripping were elevated in L compared with NL and H skin at all sampling points (P < 0·05). Conversely, the amount of SC removed by sequential tape stripping was decreased in L skin, indicating increased intracorneocyte cohesion (P < 0·05). By correlating 1/TEWL values and SC removed as an estimate of SC thickness, a significantly thinner SC was observed in L compared with NL and H skin (P < 0·05). Elevated extractable serine protease activity was measured in AD skin in the order: SC tryptase‐like enzyme (45×), plasmin (30×), urokinase (7·1×), trypsin‐like kallikreins (5·8×) and chymotrypsin‐like kallikreins (3·9×). Leucocyte elastase activity was not detected in H and NL skin but was observed in AD SC samples (L skin). All enzymes were elevated in the deeper layers of L SC compared with NL and H SC samples. All consistently elevated SC protease activities were significantly correlated with the bioinstrumental data.
Conclusions We report increased serine protease activities in acute eczematous AD, especially in deeper layers of the SC, including SC tryptase‐like enzyme, plasmin, urokinase and leucocyte elastase activities. These elevations in protease activities were associated with impaired barrier function, irritation, and reduced skin capacitance. Increased SC cohesion was apparent despite elevated TEWL during tape stripping, which would indicate reduced SC thickness in acute eczematous lesions of AD. Indeed, this was observed using an estimate of SC thickness.
Summary
Background Moisturizers are the most commonly used topically applied product for the treatment of dry skin conditions. They affect many properties and functions of the stratum corneum but ...some moisturizers have been reported to be detrimental to barrier function. Stratum corneum barrier function is a composite of its total structure and thickness but few studies have taken this into account. As a biosensor, the stratum corneum (SC) will change its structure in response to treatment and a swelling effect has been clearly demonstrated by skin hydration. Recently several moisturizing agents have been shown to have an effect on SC swelling behaviour with conflicting results. However, there is a paucity of data reported for measuring the effects of long‐term usage of moisturizers on SC thickness in vivo as, until recently, traditional techniques did not have the resolution to measure the effects of moisturizers on nonpalmoplantar body sites. The development of confocal Raman spectroscopy for use in human subjects provides noninvasive, real‐time, in vivo measurement of SC water concentration profiles and we have also used this state of the art equipment to measure the effect of the long‐term use of moisturizers on SC thickness for the first time.
Objectives To validate the use of confocal Raman spectroscopy (CRS) to measure SC thickness and then use it to investigate the short‐ and long‐term effects of moisturizers (one of which is known to improve SC barrier function) on SC thickness, water gradients and hydration.
Methods Two studies were conducted: (i) to validate the use of CRS for measuring SC thickness through comparison with optical coherence tomography (OCT); and (ii) once validated to use CRS to measure the long‐term effects of three commercially available moisturizers (A, B, C) on SC thickness and water gradients, together with total hydration, over a 3‐week period (2 weeks of treatment and 1 week regression) and compare the spectroscopy‐derived hydration value with instrumentally derived capacitance hydration values.
Results (i) A strong, positive correlation in SC thickness was obtained between CRS and OCT (OCT‐derived thickness = 0·96 × CRS‐derived thickness, r2 = 0·93; P <0·0001). OCT was shown, however, to have a lower resolution than CRS in distinguishing SC thickness on thinner nonpalmoplantar body sites. Using the CRS method, differences in SC thickness were readily apparent on different body sites (cheek 12·8 ± 0·9 μm, volar forearm 18·0 ± 3·9 μm, leg 22·0 ± 6·9 μm). (ii) Examining the effects of moisturizers in a blinded, randomized 3‐week study in human volunteers (n = 14) demonstrated that only one commercially available formulation (A) changed SC water gradients, thickness and hydration as measured by CRS. These hydration data did not directly correlate with capacitance hydration values.
Conclusions (i) In vivo CRS was validated as a technique to measure SC thickness on both palmoplantar and, particularly, on nonpalmoplantar skin sites. (ii) Moisturizers improve skin moisturization but in this study only formulation A improved SC thickness, water gradients and hydration as measured by CRS. We hypothesize that this was due to compositional differences between the products. We believe that niacinamide (nicotinamide, vitamin B3) is probably contributing significantly to this effect, as it has been proven to increase epidermal lipogenesis and SC barrier function in other studies. These results show that by using CRS, we were able for the first time to determine the effect of moisturizer on multiple SC barrier endpoints including SC thickness, and water content as a function of depth and total SC water content.
In this paper, we describe the first data release of the Visible and Infrared Survey Telescope for Astronomy (VISTA) Deep Extragalactic Observations (VIDEO) survey. VIDEO is a ∼12 deg2 survey in the ...near-infrared Z, Y, J, H and K
s bands, specifically designed to enable the evolution of galaxies and large structures to be traced as a function of both epoch and environment from the present day out to z = 4, and active galactic nuclei (AGNs) and the most massive galaxies up to and into the epoch of reionization. With its depth and area, VIDEO will be able to fully explore the period in the Universe where AGN and starburst activity were at their peak and the first galaxy clusters were beginning to virialize. VIDEO therefore offers a unique data set with which to investigate the interplay between AGN, starbursts and environment, and the role of feedback at a time when it was potentially most crucial.
We provide data over the VIDEO-XMM3 tile, which also covers the Canada-France-Hawaii Telescope Legacy Survey Deep-1 field (CFHTLS-D1). The released VIDEO data reach a 5σ AB-magnitude depth of Z = 25.7, Y = 24.5, J = 24.4, H = 24.1 and K
s = 23.8 in 2 arcsec diameter apertures (the full depth of Y = 24.6 will be reached within the full integration time in future releases). The data are compared to previous surveys over this field and we find good astrometric agreement with the Two Micron All Sky Survey, and source counts in agreement with the recently released UltraVISTA survey data. The addition of the VIDEO data to the CFHTLS-D1 optical data increases the accuracy of photometric redshifts and significantly reduces the fraction of catastrophic outliers over the redshift range 0 < z < 1 from 5.8 to 3.1 per cent in the absence of an i-band luminosity prior. However, we expect that the main improvement in photometric redshifts will come in the redshift range 1 < z < 4 due to the sensitivity to the Balmer and 4000 Å breaks provided by the near-infrared VISTA filters. All images and catalogues presented in this paper are publicly available through ESO's phase 3 archive and the VISTA Science Archive.
Objective
Plasmin, a relatively unspecific trypsin‐like serine protease, is involved in many physiological and pathological conditions, particularly in dermatoses with barrier impairment. It is ...secreted as the inactive zymogen plasminogen and is activated to plasmin by plasminogen activators, such as urokinase. There still exists a paucity of data on the precise localization of epidermal plasmin(ogen) within the epidermis and the stratum corneum. The aim of the present study was to get information about its origin and ultrastructural localization within normal human epidermis.
Method
We performed immunoelectron transmission electron microscopy immunogold labelling in normal abdominal human skin.
Result
Plasmin was only observed in the terminally differentiated cell layers of the epidermis and was largely associated with the corneocyte envelopes and to some extent with the intercellular lipid matrix in the stratum corneum.
Conclusion
Our results indicate that in normal human skin, plasmin(ogen) is synthesized by differentiated epidermal keratinocytes of the stratum granulosum and is not serum‐born.
Résumé
Objectif
Plasmine, une relativement peu spécifique ‘ trypsin‐like’ protéase sérine, participe aux plusieurs processus physiologiques et pathologiques et, plus particulièrement, à la physiopathologie des dermatoses caractérisées par l’altération de la barrière de perméabilité. Elle est sécrétée sous forme d’un zymogene inactif, plasminogène, et devient activée par les activateurs du plasminogène, telle urokinase. A l’heure actuelle, on manque de précision quant à la localisation de plasmine (ou son précurseur) dans l’épiderme et le stratum corneum. Le but du présent travail a été de d’apporter l’information sur la provenance et la localisation ultrastructurale de plasmine/plasminogène présents dans l’épiderme humain.
Méthode
L’étude ultrastructurale de l’épiderme humain normal (plastie abdominale) a fait appel à l’immunomarquage à l’or colloïdal sur coupes ultrafines des tissus inclus à froid dans des résines acryliques.
Résultat
L’anticorps monoclonal anti –plasmine/plasminogène a détecté l’antigène situé exclusivement dans la partie la plus différenciée de l’épiderme et persistant dans la couche cornée. Il n’y a pas eu de réactivité dans les couches épineuse et basale. Le marquage a été prédominant sur les enveloppes cornifiées des kératinocytes granuleux et cornéocytes. Des foyers du marquage ont été également présents dans le cytoplasme et les espaces intercellulaires de la couche granuleuse, ainsi que dans la matrice lipidique de la couche cornée profonde.
Conclusion
Nos résultats indiquent la production de novo de plasmine/plasminogène dans les kératinocytes le plus différenciés et ne suggèrent pas l’origine sérique de cette enzyme dans l’épiderme.
There exists a paucity of data on the subcellular localization of plasmin(ogen) within normal human epidermis. Immunoelectron transmission electron microscopy labelling revealed that the inflammatory serine protease is located in the terminally differentiated keratinocytes and was largely associated with the corneocyte envelopes and to some extent with the intercellular lipid matrix in the stratum corneum.
Summary
Background
Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin ...degradation products natural moisturizing factors (NMFs), activities of filaggrin‐processing enzymes bleomycin hydrolase (BH) and calpain‐1 (C‐1) and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown.
Objectives
We conducted a cross‐sectional, observational study investigating regional and age‐dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life.
Methods
We measured NMF using a tape‐stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C‐1 and plasmin activities were determined.
Results
NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek corneocytes remain immature. Plasmin, BH and C‐1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin.
Conclusions
Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD.
What's already known about this topic?
Atopic dermatitis (AD) frequently starts in early infancy, and the first eczematous lesions emerge on the cheeks.
Filaggrin is a major structural protein in the stratum corneum (SC).
Filaggrin deficiency is associated with the development of AD and, in the context of AD, food allergies and asthma.
Filaggrin is metabolized into natural moisturizing factors (NMFs), which can be measured in the SC.
What does this study add?
Regional differences in NMF levels, corneocyte envelope immaturity and protease activities may help explain why infantile AD most often initially affects the cheeks.
Filaggrin processing, corneocyte maturity, and protease activities show regional and temporal differences in infant skin.
These findings may explain disease patterns in early‐life AD.
What is the translational message?
Cheek skin may be highly relevant for allergen priming.
Emollient therapy at the vulnerable cheek site might help to prevent AD and/or food sensitization.
Linked Editorial: Thyssen. Br J Dermatol 2018; 179:235–236.
Plain language summary available online
Respond to this article
Dry skin is one of the most important concerns of consumers worldwide. Despite huge efforts over several decades, the personal care industry still does not offer a perfect solution to satisfy the ...unmet needs of consumers for moisturising treatments in different ethnic groups. The paucity of data for the underlying cellular and biochemical problems in, and the effects of moisturisers on photodamaged facial skin may partly explain this. Mainly, single point measurements are used to understand the effects of products on skin physiology even on surrogate skin sites such as the non‐photodamaged volar forearm. Some groups have developed discontinuous facial maps of skin biophysical properties, however, in 2014 a continuous facial analysis of bio‐instrumental evaluations was developed using a heat map approach. These maps enabled a continuous visualization of features that not only revealed an unexpected complexity of facial skin but also indicated that use of surrogate skin sites for facial skin is inappropriate. We have demonstrated that remarkable gradients of skin hydration, TEWL, skin surface pH and sebum exist within short distances across the face and the gradients are distinctive among different ethnic groups. In addition, these studies have demonstrated that darkly‐pigmented individuals do not necessarily have a better skin barrier function than their less‐pigmented counterparts and that Caucasians have a lower facial skin surface pH compared with more pigmented subjects. Overall, there are no correlations between capacitance, TEWL and skin surface pH including individual topology angle values. Novel 3D camera approaches have also been used to facilitate a more precise assignment of measurement sites and visualisation. The 3D facial colour mappings illustrated precisely the local moisturising effects of a moisturising cream. There were subtle ethnic differences in efficacy that may be related to underlying skin biochemistry and/or ethnic differences in product application. A placebo‐controlled study using conductance measurements in Chinese subjects is also reported. Finally, a new whole face statistical approach has been taken to prove differences in skin parameters but also of moisturiser treatment that adds further to our understanding of the ethnic differences in skin physiology and product application. This paper reviews the background of the development and application of this methodology.
Résumé
L'assèchement de la peau est l'un des problèmes les plus importants chez les consommateurs à travers le monde. En dépit des efforts fournis dans les dernières décennies, l’industrie du soin ne propose pas encore une solution parfaite qui répond aux attentes des consommateurs de différentes ethnies pour des traitements hydratants. Le manque de données concernant les problèmes de mécanisme cellulaire et biochimique, ainsi que les effets des soins hydratants sur la peau du visage photo‐endommagée peuvent en partie expliquer cela. En général, une mesure ponctuelle est réalisée pour comprendre les effets des produits sur la physiologie de la peau sur des sites de substitution tels que l’avant‐bras non photo‐endommagé. Certains groupes ont développé des cartographies du visages discontinues des propriétés biophysiques de la peau, mais ce n’est qu’en 2014 qu’une analyse continue du visage de l’évaluation bio‐instrumentale a été proposée en utilisant une approche par cartographie de chaleur. Ces cartographies permettent une visualisation continue des caractéristiques qui ne révèlent pas seulement une complexité inattendue de la peau du visage mais indique également que l’utilisation de sites de substitution est inappropriée. Nous avons démontré que certains gradients liés à l’hydratation de la peau, à la PIE, au pH à la surface de la peau et au sébum sont présents sur de faibles distances à travers le visage et que ces gradients sont différents selon les groupes ethniques. De plus, ces études ont démontré que les individus ayant une pigmentation de peau importante n’ont pas nécessairement une meilleure fonction de barrière cutanée que leurs homologues ayant une peau moins pigmentée et que les Caucasiens ont une plus faible surface de pH sur le bas du visage en comparaison avec des sujets ayant plus de pigmentation. Globalement, en incluant les aspects typologiques individuels, il n’y a pas de corrélation entre la capacitance, la PIE et le pH à la surface de la peau. Une nouvelle approche par caméra 3D à également été utilisée pour faciliter l’attribution et la visualisation plus précise de la mesure par site. Les cartographies du visage 3D en couleur illustrent précisément les effets hydratants localisés d’une crème hydratante. Il y avait des différences ethniques subtiles dans l’efficacité qui peuvent être liées au mécanisme de la biochimie cutanée et/ou dans l’application des produits des différentes ethnies. Une étude contrôlée par placebo utilisant une mesure de conductance chez les sujets d’origine chinoise est également communiquée. Enfin, une nouvelle approche statistique sur le visage complet a été adoptée afin de prouver les différences dans les paramètres de la peau mais aussi dans le traitement hydratant, ce qui nous permet de mieux comprendre les différences ethniques dans la physiologie de la peau et l'application des produits. Cette publication retrace les éléments de développement ainsi que l’application des méthodologies.
The skin mapping technology enables the transformation of bio‐instrumental data to continuous 2D and 3D visualisation of facial skin features. This approach reveals the complexity of facial skin and the differences of differently pigmented skin types.
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