Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed. Cell Death and Differentiation (2003) 10, 45–65. doi:10.1038/ sj.cdd.4401189

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Tumor necrosis factor signaling.

The skin is the human body's largest organ, colonized by a diverse milieu of microorganisms, most of which are harmless or even beneficial to their host. Colonization is driven by the ecology of the skin surface, which is highly variable depending on topographical location, endogenous host factors and exogenous environmental factors. The cutaneous innate and adaptive immune responses can modulate the skin microbiota, but the microbiota also functions in educating the immune system. The development of molecular methods to identify microorganisms has led to an emerging view of the resident skin bacteria as highly diverse and variable. An enhanced understanding of the skin microbiome is necessary to gain insight into microbial involvement in human skin disorders and to enable novel promicrobial and antimicrobial therapeutic approaches for their treatment.

The skin microbiome

The epidermis functions as a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes - the cornified layer, which forms the endpoint of epidermal differentiation and death. The cornified envelope replaces the plasma membrane of differentiating keratinocytes and consists of keratins that are enclosed within an insoluble amalgam of proteins, which are crosslinked by transglutaminases and surrounded by a lipid envelope. New insights into the molecular mechanisms and the physiological endpoints of cornification are increasing our understanding of the pathological defects of this unique form of programmed cell death, which is associated with barrier malfunctions and ichthyosis.

The cornified envelope: a model of cell death in the skin

The skin forms an effective barrier between the organism and the environment preventing invasion of pathogens and fending off chemical and physical assaults, as well as the unregulated loss of water and solutes In this review we provide an overview of several components of the physical barrier, explaining how barrier function is regulated and altered in dermatoses The physical barrier is mainly localized in the stratum corneum (SC) and consists of protein-enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipid-enriched intercellular domains The nucleated epidermis also contributes to the barrier through tight, gap and adherens junctions, as well as through desmosomes and cytoskeletal elements During epidermal differentiation lipids are synthesized in the keratinocytes and extruded into the extracellular domains, where they form extracellular lipid-enriched layers The cornified cell envelope, a tough protein/lipid polymer structure, resides below the cytoplasmic membrane on the exterior of the corneocytes Ceramides A and B are covalently bound to cornified envelope proteins and form the backbone for the subsequent addition of free ceramides, free fatty acids and cholesterol in the SC Filaggrin is cross-linked to the cornified envelope and aggregates keratin filaments into macrofibrils Formation and maintenance of barrier function is influenced by cytokines, 3',5'-cyclic adenosine monophosphate and calcium Changes in epidermal differentiation and lipid composition lead to a disturbed skin barrier, which allows the entry of environmental allergens, immunological reaction and inflammation in atopic dermatitis A disturbed skin barrier is important for the pathogenesis of contact dermatitis, ichthyosis, psoriasis and atopic dermatitis

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The skin: an indispensable barrier

Skin barrier function, epidermal proliferation and differentiation in eczema

Impaired Sphingomyelinase Activity and Epidermal Differentiation in Atopic Dermatitis

Epidermal TNF expression increases in response to cutaneous permeability barrier disruption and wound healing. TNF signaling is mediated by acid and neutral sphingomyelinases (A- and N-SMase), which generate ceramide, an important regulator of proliferation, differentiation, and apoptosis. In the epidermis, ceramide is known to be an integral part of the extracellular stratum corneum (SC) lipid bilayers that constitute the permeability barrier of the skin. We show here that topical application of TNF after experimental injury to the SC of hairless mice (hr ‐/‐ ) enhances barrier repair. In TNF receptor p55‐deficient (TNF-R55‐deficient) mice (hr+/+), cutaneous barrier repair was delayed compared with wild-type (hr +/+ ) or TNF-R75‐deficient (hr +/+ ) animals. After barrier disruption in hairless (hr ‐/‐ ) and wild-type (hr+/+), but not in TNF-R55‐deficient (hr+/+) mice, the enzymatic activities of both ASMase and N-SMase were significantly enhanced. Stimulation of SMase activities was accompanied by an increase in C24-ceramide levels. Most A-SMase activity in hairless mice (hr‐/‐) was found in the outer epidermal cell layers and colocalized in the lamellar bodies with A-SMase and sphingomyelin. Reduction of epidermal A-SMase activity by the inhibitor imipramine resulted in delayed permeability barrier repair after SC injury. Together, these results suggest that TNF-R55 signaling pathways contribute to cutaneous permeability barrier repair through SMase-mediated generation of ceramide. J. Clin. Invest. 104:1761‐1770 (1999).

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Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier

Background Genetic defects leading to skin barrier dysfunction were recognized as risk factors for atopic dermatitis (AD) It is essential that drugs applied to patients with AD restore the impaired epidermal barrier to prevent sensitization by environmental allergens Objectives We investigated the effect of 2 common treatments, a calcineurin inhibitor and a corticosteroid, on the skin barrier Methods In a randomized study 15 patients with AD were treated on one upper limb with pimecrolimus and on the other with betamethasone twice daily for 3 weeks Results Stratum corneum hydration and transepidermal water loss, a marker of the inside-outside barrier, improved in both groups Dye penetration, a marker of the outside-inside barrier, was also reduced in both drugs Electron microscopic evaluation of barrier structure displayed prevalently ordered stratum corneum lipid layers and regular lamellar body extrusion in pimecrolimus-treated skin but inconsistent extracellular lipid bilayers and only partially filled lamellar bodies after betamethasone treatment Both drugs normalized epidermal differentiation and reduced epidermal hyperproliferation Betamethasone was superior in reducing clinical symptoms and epidermal proliferation; however, it led to epidermal thinning Conclusion The present study demonstrates that both betamethasone and pimecrolimus improve clinical and biophysical parameters and epidermal differentiation Because pimecrolimus improved the epidermal barrier and did not cause atrophy, it might be more suitable for long-term treatment of AD

https://www.jacionline.org/article/S0091-6749(09)01125-7/pdf

Jens-Michael Jensen

Papers

The skin: an indispensable barrier

Skin barrier function, epidermal proliferation and differentiation in eczema

Impaired Sphingomyelinase Activity and Epidermal Differentiation in Atopic Dermatitis

Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier

Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis.