Satomi Igawa

Order and disorder in corneocyte adhesion

Epidermal cornified cells are attached to each other with modified desmosomes, namely corneodesmosomes. Changes in the corneodesmosome degradation process influence the total thickness of the stratum corneum and surface appearance of the skin. The major extracellular constituents of corneodesmosomes are desmoglein 1, desmocollin 1 and corneodesmosin. The intracellular part of corneodesmosomes is cross‐linked into cornified cell envelopes. Corneodesmosomes are degraded from the central surface area of each cell. Peripheral corneodesmosomes retain structural integrity up to the skin surface. A hypothesis where tight junctions in the stratum corneum play a role in this spatial difference in corneodesmosome degradation has recently been proposed. Genetic defects in corneodesmosin and inhibitors for proteases involved in corneodesmosome degradation result in accelerated desquamation and severe barrier impairment, presenting as the inflammatory type of peeling skin syndrome and Netherton syndrome, respectively. Abnormal corneodesmosome degradation is also found in more common skin diseases including ichthyosis vulgaris, atopic dermatitis, psoriasis vulgaris, lichen planus and soap‐induced xerosis.

A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa

BACKGROUND Chronic wounds are a major source of morbidity and mortality in generalized severe recessive dystrophic epidermolysis bullosa (RDEB-GS). OBJECTIVE This was a phase II double-blinded randomized controlled trial of intralesional allogeneic cultured fibroblasts in suspension solution versus suspension solution alone for wound healing in RDEB-GS. METHODS Adult patients with RDEB-GS were screened for chronic ulcers and reduced collagen VII expression. Up to 6 pairs of symmetric wounds were measured and biopsied at baseline, then randomized to cultured allogeneic fibroblasts in a crystalloid suspension solution with 2% albumin or suspension solution alone. Ulcer size, collagen VII protein and messenger RNA expression, anchoring fibril numbers, morphology, and inflammatory markers were measured at 2 weeks and at 3, 6, and 12 months. RESULTS All wounds healed significantly more rapidly with fibroblasts and vehicle injections, with an area decrease of 50% by 12 weeks, compared with noninjected wounds. Collagen VII expression increased to a similar degree in both study arms in wounds from 3 of 5 patients. LIMITATIONS The number of patients with RDEB-GS who met inclusion criteria was a limitation, as was 1 trial center rather than multicenter. CONCLUSIONS The injection of both allogeneic fibroblasts and suspension solution alone improved wound healing in chronic nonhealing RDEB-GS wounds independently of collagen VII regeneration. This may provide feasible therapy for wound healing in patients with RDEB-GS.

Tight junctions in the stratum corneum explain spatial differences in corneodesmosome degradation.

Abstract:  To maintain stratum corneum integrity while simultaneously desquamating at a steady rate, degradation of corneodesmosomes must proceed in a controlled manner. It is unknown why corneodesmosomes are present only at the cell periphery in the upper stratum corneum. To explore this, we studied distributions of three major corneodesmosomal components, corneodesmosin, desmoglein 1 and desmocollin 1 in normal adult human epidermis. Immunofluorescent microscopy studies of skin surface corneocytes detected all three components only at the cell edges. Immunoelectron microscopy revealed selective loss of these components at the central areas starting from the deep cornified layers. We hypothesized that tight junctions (TJs) formed in the superficial granular layer may prevent protease access by functioning as a barrier between the peripheral and the central intercellular spaces in the stratum corneum. Ultrastructural examination demonstrated TJs up to the junctions between the seventh and the eighth deepest cornified layers. Immunoelectron microscopy also detected clusters of occludin and claudin‐1 immunolabels at the cell periphery, and kallikrein 7 immunolabels outside of TJs in the lower cornified layers. With colloidal lanthanum nitrate perfusion assay of stripped stratum corneum, the tracer was excluded from TJ domains. Taken together, we propose that TJs inhibit access of proteases to the peripheral corneodesmosomes forming the structural basis for the basket‐weave‐like appearance of the stratum corneum.

Prognostic Indicators in 35 Patients with Extramammary Paget's Disease

BACKGROUND Extramammary Pagets disease (EMPD) is an uncommon skin tumor that usually occurs in the genital area. Few studies on EMPD have been conducted. OBJECTIVE To evaluate the clinical and pathologic features, treatments, recurrence, survival rates, and prognostic factors of EMPD. METHODS A total of 35 (27 men and 8 women) patients with EMPD was analyzed. The average age of the patients was 73.4 years. RESULT Twenty nine Of the 35 patients had lesions in the genital area, one in the genital and perianal area, three in the axillary area and two in the perianal area. Eighteen patients had in situ lesions, five had inguinal lymph node metastases and two had distant metastases at the time of diagnosis. Surgical resection was performed in 30 cases and radiation therapy, was administered in three cases. Six patients died of EMPD, and the overall 5 year survival rate was 75%. CONCLUSION The presence of a nodule on the primary lesion, clinically palpable lymph nodes, the level of tumor invasion, and lymph node metastases were found to be significant prognostic factors in the 35 EMPD cases at our institution.

Genetic skin diseases related to desmosomes and corneodesmosomes

The integrity of the epidermis depends on the cohesion between keratinocytes, and desmosomes are the main adhesion structures. When cells become cornified, desmosomes are modified and transformed into corneodesmosomes. Mutations in the genes encoding desmosomal components underlie several skin diseases including palmoplantar keratoderma and forms of epidermolysis bullosa, indicating the importance of desmosomes as mechanical stress-bearing structures. Other types of genetic defects in a desmosome component (desmoglein 1), a corneodesmosome component (corneodesmosin), and an inhibitor for proteases involved in corneodesmosome degradation (LEKTI) result in three clinically overlapping conditions: SAM syndrome, an inflammatory type of peeling skin disease, and Netherton syndrome. All three result in allergies to multiple allergens due to severe barrier impairment. Conversely, impaired corneodesmosomal degradation due to matriptase mutations could lead to ichthyosis. By discovering the diverse clinical phenotypes of these diseases, we can enrich our understanding of the multifunctional roles of desmosomes and corneodesmosomes in skin biology.

The biology and regulation of corneodesmosomes.

The stratum corneum of the epidermis is composed of stacked dead corneocytes embedded in lipid layers and is the main protective shield of the skin. The thickness of the stratum corneum is maintained fairly constantly through the balance between new cell creation and old cell removal. Corneodesmosomes are the main intercellular adhesive structures in the stratum corneum. They are transformed from desmosomes at the most superficial layer of the stratum granulosum of the epidermis. The major compositional distinction from desmosomes is the presence of corneodesmosin in the extracellular portion. Furthermore, corneodesmosomes are structurally different from desmosomes in that (1) they do not have a tri-lamellar desmoglea but rather one that is homogeneously electron-dense and (2) attachment plaques are integrated into a part of the cornified cell envelopes. When the extracellular regions of corneodesmosomes are fully degraded, desquamation occurs. The degradation process of corneodesmosomes is carefully controlled by a number of proteases and their inhibitors. The most important proteases involved in this process are the kallikrein-related peptidases. Their main inhibitor is the lympho-epithelial Kazal-type related inhibitor. Other regulators of this process include matriptase, meprin and mesotrypsin.

Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small‐scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49–72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.

Novel postzygotic KRAS mutation in a Japanese case of epidermal nevus syndrome presenting with two distinct clinical features, keratinocytic epidermal nevi and sebaceous nevi.

Dear Editor, Epidermal nevus syndrome (ENS) is a heterogeneous congenital disorder characterized by the presence of epidermal nevi associated with systemic involvement. Keratinocytic epidermal nevus (KEN) syndrome and sebaceous nevus (SN) syndrome are included in ENS which share the same postzygotic HRAS and KRAS gene mutations that are relevant for cell proliferation. A HRAS mutation can induce nevus marginatus, a combined nevus of KEN and SN, and this suggests an identical genetic background of KEN and SN. Here, we report a case of ENS exhibiting both KEN and SN characteristics caused by a novel postzygotic KRAS mutation. A 3-year-old Japanese girl presented with multiple nevoid lesions along Blaschko lines on the left side of her body that she had had since birth. The skin lesions, which were light red at the neonatal stage (Fig. 1a), had transformed into two distinct types: yellowish plaques suggesting SN on the sebaceous gland-rich craniofacial area, and brownish verrucous lesions suggesting KEN on the trunk and extremities (Fig. 1b). Histological evaluation showed papillomatosis and acanthosis with overlying laminated hyperkeratosis (Fig. 1c,d).

Skin microbiome and mast cells

&NA; Microbiotas in the skin have high levels of diversity at the species level, but low phylum‐level diversity. The human skin microbiota is composed predominantly of Gram‐positive bacteria especially Actinobacteria, which are the dominant bacterial phylum on the skin. Lipoteichoic acid (LTA) is a major constituent of the cell wall of Gram‐positive bacteria and is therefore abundant in the skin microbiome. Recent studies have shown that LTA, and other bacterial products, permeates the whole skin and comes into contact with epidermal and dermal cells, including mast cells (MCs), with the potential of stimulating MC toll‐like receptors (TLRs). MCs express a variety of pattern recognition receptors, including TLRs, on their cell surface in order to detect bacteria. Recent publications suggest that the skin microbiome has influence on MC migration, localization and maturation in the skin. Germ free (no microbiome) animals possess an underdeveloped immune system and immature MCs. Despite much research done on skin microbiota and many papers describing skin interaction with “the good microbiota”, there is still controversy regarding how mast cells, communicate with surface bacteria. The present review intends to quell the controversy by illuminating the communication mechanism between bacteria and MCs.

Cutaneous necrotizing vasculitis as a manifestation of familial Mediterranean fever

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, which is characterized by recurrent and paroxysmal fever, peritonitis, arthritis, myalgia, and skin rashes. Although various skin lesions such as “erysipelas‐like erythema”, urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. We report a Japanese case of sporadic FMF accompanied by cutaneous arteritis at the time of febrile attacks of FMF. Gene analysis revealed M694I mutation in a single allele of the MEFV gene, and oral colchicine successfully controlled both periodic fever and subcutaneous nodules of arteritis. Cutaneous necrotizing vasculitis repeatedly emerging with febrile attacks should be included among the skin manifestations of FMF.