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

The tight junction (TJ) and its adhesion molecules, claudins, are responsible for the barrier function of simple epithelia, but TJs have not been thought to play an important role in the barrier function of mammalian stratified epithelia, including the epidermis. Here we generated claudin-1–deficient mice and found that the animals died within 1 d of birth with wrinkled skin. Dehydration assay and transepidermal water loss measurements revealed that in these mice the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared to be normal. These unexpected findings prompted us to reexamine TJs in the epidermis of wild-type mice. Close inspection by immunofluorescence microscopy with an antioccludin monoclonal antibody, a TJ-specific marker, identified continuous TJs in the stratum granulosum, where claudin-1 and -4 were concentrated. The occurrence of TJs was also confirmed by ultrathin section EM. In claudin-1–deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4–positive) TJs. Interestingly, in the wild-type epidermis these occludin-positive TJs efficiently prevented the diffusion of subcutaneously injected tracer (∼600 D) toward the skin surface, whereas in the claudin-1–deficient epidermis the tracer appeared to pass through these TJs. These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin.

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Claudin-based tight junctions are crucial for the mammalian epidermal barrier a lesson from claudin-1–deficient mice

Over recent years cadherins have emerged as a growing superfamily of molecules, and a complex picture of their structure and their biological functions is becoming apparent. Variation in their extracellular region leads to the large potential for recognition properties of this superfamily. This is demonstrated strikingly by the recently discovered FYN-binding CNR-protocadherins; these exhibit alternative expression of the extracellular portion, which could lead to distinct cell recognition in different neuronal populations, whereas their cytoplasmic part, and therefore intracellular interactions, is constant. Diversity in the cytoplasmic moiety of the cadherins imparts specificity to their interactions with cytoplasmic components; for example, classical cadherins interact with catenins and the actin filament network, desmosomal cadherins interact with catenins and the intermediate filament system and CNR-cadherins interact with the SRC-family kinase FYN. Recent evidence suggests that CNR-cadherins, 7TM-cadherins and T-cadherin, which is tethered to the membrane by a GPI anchor, all localise to lipid rafts, specialised cell membrane domains rich in signalling molecules. Originally thought of as cell adhesion molecules, cadherin superfamily molecules are now known to be involved in many biological processes, such as cell recognition, cell signalling, cell communication, morphogenesis, angiogenesis and possibly even neurotransmission.

The cadherin superfamily: diversity in form and function.

Desmosome structure, composition and function

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.

https://www.jacionline.org/article/S0091-6749(06)00935-3/pdf

New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene–environment interactions

Patients with pemphigus foliaceus (PF) have blisters on skin, but not mucous membranes, whereas patients with pemphigus vulgaris (PV) develop blisters on mucous membranes and/or skin. PF and PV blisters are due to loss of keratinocyte cell–cell adhesion in the superficial and deep epidermis, respectively. PF autoantibodies are directed against desmoglein (Dsg) 1; PV autoantibodies bind Dsg3 or both Dsg3 and Dsg1. In this study, we test the hypothesis that coexpression of Dsg1 and Dsg3 in keratinocytes protects against pathology due to antibody-induced dysfunction of either one alone. Using passive transfer of pemphigus IgG to normal and DSG3null neonatal mice, we show that in the areas of epidermis and mucous membrane that coexpress Dsg1 and Dsg3, antibodies against either desmoglein alone do not cause spontaneous blisters, but antibodies against both do. In areas (such as superficial epidermis of normal mice) where Dsg1 without Dsg3 is expressed, anti-Dsg1 antibodies alone can cause blisters. Thus, the anti-desmoglein antibody profiles in pemphigus sera and the normal tissue distributions of Dsg1 and Dsg3 determine the sites of blister formation. These studies suggest that pemphigus autoantibodies inhibit the adhesive function of desmoglein proteins, and demonstrate that either Dsg1 or Dsg3 alone is sufficient to maintain keratinocyte adhesion.

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Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris

Exfoliative toxin A, produced by Staphylococcus aureus, causes blisters in bullous impetigo and its more generalized form, staphylococcal scalded-skin syndrome. The toxin shows exquisite specificity in causing loss of cell adhesion only in the superficial epidermis. Although exfoliative toxin A has the structure of a serine protease, a target protein has not been identified. Desmoglein (Dsg) 1, a desmosomal cadherin that mediates cell-cell adhesion, may be the target of exfoliative toxin A, because it is the target of autoantibodies in pemphigus foliaceus, in which blisters form with identical tissue specificity and histology. We show here that exfoliative toxin A cleaved mouse and human Dsg1, but not closely related cadherins such as Dsg3. We demonstrate this specific cleavage in cell culture, in neonatal mouse skin and with recombinant Dsg1, and conclude that Dsg1 is the specific receptor for exfoliative toxin A cleavage. This unique proteolytic attack on the desmosome causes a blister just below the stratum corneum, which forms the epidermal barrier, presumably allowing the bacteria in bullous impetigo to proliferate and spread beneath this barrier.

/pdf/toxin-in-bullous-impetigo-and-staphylococcal-scalded-skin-2n4mklx83c.pdf

Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1

Desmogleins are desmosomal cadherins that mediate cell–cell adhesion. In stratified squamous epithelia there are two major isoforms of desmoglein, 1 and 3, with different distributions in epidermis and mucous membrane. Since either desmoglein isoform alone can mediate adhesion, the reason for their differential distribution is not known. To address this issue, we engineered transgenic mice with desmoglein 3 under the control of the involucrin promoter. These mice expressed desmoglein 3 with the same distribution in epidermis as found in normal oral mucous membranes, while expression of other major differentiation molecules was unchanged. Although the nucleated epidermis appeared normal, the epidermal stratum corneum was abnormal with gross scaling, and a lamellar histology resembling that of normal mucous membrane. The mice died shortly after birth with severe dehydration, suggesting excessive transepidermal water loss, which was confirmed by in vitro and in vivo measurement. Ultrastructure of the stratum corneum showed premature loss of cohesion of corneocytes. This dysadhesion of corneocytes and its contribution to increased transepidermal water loss was confirmed by tape stripping. These data demonstrate that differential expression of desmoglein isoforms affects the major function of epidermis, the permeability barrier, by altering the structure of the stratum corneum.

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Desmoglein Isoform Distribution Affects Stratum Corneum Structure and Function

Pemphigus foliaceus is an autoantibody-mediated blistering disease in which antibodies against desmoglein 1 cause loss of adhesion among keratinocytes in the superficial epidermis.1 Desmogleins are transmembrane glycoproteins found in desmosomes, which provide physical connections between cells. The main desmogleins expressed in the epidermis are desmoglein 1 and desmoglein 3. In adults, desmoglein 1 is present throughout the epidermis, but desmoglein 3 is present only in the basal and immediate suprabasal layers.2,3 It has been proposed that in patients with pemphigus foliaceus the antibodies interfere with the adhesive function of desmoglein 1 and that blisters occur only in the superficial . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM200007063430105

Zhi Hong Wang

Papers

Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris

Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1

Desmoglein Isoform Distribution Affects Stratum Corneum Structure and Function

Protection against pemphigus foliaceus by desmoglein 3 in neonates.

Pemphigus Vulgaris and Pemphigus Foliaceus Antibodies are Pathogenic in Plasminogen Activator Knockout Mice