Another representative clinical case associated with disrupt

Another representative clinical case associated with disruption of this remodeling is recessive X-linked ichthyosis (MIM 30810), which is characterized by generalized hyperkeratosis, showing large dark brown scales predominantly on both the extensors. This disease demonstrates characteristic histopathologic features of a much thicker hyperkeratosis than ichthyosis vulgaris, compact stratum corneum, and a complete loss of the basket-weave pattern of stratum corneum, although associated with either a normal or thickened granular cell layer (Figure 4). This disease is caused by mutations of the gene for steroid sulfatase, which depletes sulfate of cholesterol sulfate, and is characterized by the accumulation of cholesterol sulfate in the stratum corneum. It has been shown that excess cholesterol sulfate: (1) produces nonlamellar phase separation in the stratum corneum interstices, explaining the observed barrier abnormality; and (2) inhibits protease activity sufficiently to delay corneodesmosome degradation. The latter is thought to be involved in the generation of the nonperipheral distribution of corneodesmosomes (compare Figure 3 and Figure 4).
Conclusion
Epidermal barrier function in stratum corneum One of the major functions of the epidermis is as a permeability barrier to prevent the inward or outward passage of water and small molecules. The permeability barrier of the skin resides largely in the stratum corneum (SC), and it depends upon a two-compartment system, that is, corneocytes (cellular) and lipid-rich matrix (intercellular). SC lipids are derived from the content of lamellar bodies in granular cells and comprise a mixture of sphingolipids, cholesterol, and fatty acids, arranged as intercellular membrane bilayers that are required for the epidermal permeability barrier. Sphingolipids, particularly ceramides, representing approximately 50% of SC lipid content by weight, play an essential role for the permeability barrier in the intercellular space and for the water retention of SC.De novo synthesis of sphingolipids starts with condensation of serine and palmitoyl-CoA (Coenzyme A), and this reaction is catalyzed by serine palmitoyl transferase (SPT), the rate-limiting enzyme, which is ubiquitously found in various tissues, particularly in epidermal keratinocytes. Previous studies have demonstrated that de novo synthesis of SC lipids was stimulated by barrier perturbations, including extraction of lipids from SC with organic solvents, removal of SC layer by tape stripping, and dietary restriction of an essential fatty acid. Barrier disruption induces biosynthesis of epidermal ceramides, cholesterol, and fatty acids, through an increase in the activities of respective rate limiting enzymes, SPT, 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), acetyl-CoA carboxylase, and fatty topirimate synthase. By contrast, the topical application of inhibitors of either HMG CoA reductase or SPT immediately after barrier disruption resulted in reduction of cholesterol or sphingolipid synthesis, respectively, thereby demonstrating delayed barrier repair. Thus, epidermal lipid synthesis is tightly regulated by the barrier condition to maintain epidermal integrity.
Inflammatory skin diseases and barrier disruption Inflammatory skin diseases are often associated with barrier defects, although the cause and effect relationship is complex. The discovery of loss-of-function mutations in the filaggrin (FLG) gene in patients with atopic dermatitis (AD) revealed that disruption of the skin barrier is the primary cause of the disease. Skin barrier dysfunction in AD contributes to an increase of allergic risk due to increased sensitization to environmental antigens. Psoriasis is also a common inflammatory skin disease that develops through genetic and epigenetic factors. Until 30 years ago, psoriasis was considered to be a keratinocyte disease, but the intervention by use of cyclosporine A with a successful efficacy has disclosed that an immune-mediated mechanism contributes to the development of psoriasis. Genetic studies and further evidence from animal models, in which xenotransplant of skins from psoriasis patients converted to psoriatic lesions by the injection of peripheral blood T cells taken from the patients. also supported the immune-mediated mechanism for psoriasis. However, the pendulum has begun to swing back lately. Previous studies have demonstrated skin barrier abnormality in psoriasis, and recently, some epidermal genes have been documented as susceptibility genes for psoriasis. To date, approximately 40 genes have been considered to be psoriasis susceptibility genes. GWAS (genome-wide association study) of psoriasis were summarized in detail by Zhang. Representative genes and their potential functions are listed in Table 1. Candidate genes specific for epidermal cells, not for immune cells, involve β-defensin cluster genes, late cornified envelope (LCE) 3B and 3C genes, and corneodesmosin genes. The functions of these genes are antimicrobial protection, innate immunity of the epidermis, barrier function, and keratinocyte differentiation, respectively. A very recent study demonstrated that barrier discovery was compromised in uninvolved skin of psoriasis patients, supporting that barrier abnormality is the underlying pathogenesis of psoriasis. Given that AD and psoriasis share many features regarding epidermal gene abnormalities, barrier defect, and involvement of immune cells, there is a difference in the balance of immune cell subsets that could cause the phenotypes that distinguish these diseases. Previous studies revealed that epidermal barrier function directly regulates the cutaneous and/or systemic immune system (Figure 1).