Masataka Saito

Desmosome Disassembly in Response to Pemphigus Vulgaris IgG Occurs in Distinct Phases and Can Be Reversed by Expression of Exogenous Dsg3

Pemphigus vulgaris (PV) is an epidermal blistering disorder caused by antibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). The mechanism by which PV IgG disrupts adhesion is not fully understood. To address this issue, primary human keratinocytes (KCs) and patient IgG were used to define the morphological, biochemical, and functional changes triggered by PV IgG. Three phases of desmosome disassembly were distinguished. Analysis of fixed and living KCs demonstrated that PV IgG cause rapid Dsg3 internalization, which likely originates from a non-junctional pool of Dsg3. Subsequently, Dsg3 and other desmosomal components rearrange into linear arrays that run perpendicular to cell contacts. Dsg3 complexes localized at the cell surface are transported in a retrograde manner along with these arrays before being released into cytoplasmic vesicular compartments. These changes in Dsg3 distribution are followed by depletion of detergent-insoluble Dsg3 pools and by the loss of cell adhesion strength. Importantly, this process of disassembly can be prevented by expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome assembly. These data support a model in which PV IgG cause the loss of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell surface pools of Dsg3 through endocytic pathways.

Classical and desmosomal cadherins at a glance

Cell–cell contact is central to cell polarity, tissue organization and compartmentalization of organ systems. Cadherins are a large superfamily of cell–cell adhesion molecules that are fundamental determinants of how and when cells interact, migrate and undergo morphogenetic conversions ([

Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation

Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. However, conflicting models for pemphigus pathogenicity have arisen from studies using either polyclonal PV patient IgG or monoclonal Dsg3 antibodies. In the present study, the pathogenic mechanisms of polyclonal PV IgG and monoclonal Dsg3 antibodies were directly compared. Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. Furthermore, tyrosine kinase or p38 MAPK inhibition prevents loss of keratinocyte adhesion in response to polyclonal PV IgG. In contrast, disruption of adhesion by pathogenic monoclonal antibodies is not prevented by these inhibitors either in vitro or in human skin explants. Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. These findings have important implications for understanding pemphigus pathophysiology, and for the design of pemphigus model systems and therapeutic interventions.

Desmosome Assembly and Disassembly Are Membrane Raft-Dependent

Strong intercellular adhesion is critical for tissues that experience mechanical stress, such as the skin and heart. Desmosomes provide adhesive strength to tissues by anchoring desmosomal cadherins of neighboring cells to the intermediate filament cytoskeleton. Alterations in assembly and disassembly compromise desmosome function and may contribute to human diseases, such as the autoimmune skin blistering disease pemphigus vulgaris (PV). We previously demonstrated that PV auto-antibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3) cause loss of adhesion by triggering membrane raft-mediated Dsg3 endocytosis. We hypothesized that raft membrane microdomains play a broader role in desmosome homeostasis by regulating the dynamics of desmosome assembly and disassembly. In human keratinocytes, Dsg3 is raft associated as determined by biochemical and super resolution immunofluorescence microscopy methods. Cholesterol depletion, which disrupts rafts, prevented desmosome assembly and adhesion, thus functionally linking rafts to desmosome formation. Interestingly, Dsg3 did not associate with rafts in cells lacking desmosomal proteins. Additionally, PV IgG-induced desmosome disassembly occurred by redistribution of Dsg3 into raft-containing endocytic membrane domains, resulting in cholesterol-dependent loss of adhesion. These findings demonstrate that membrane rafts are required for desmosome assembly and disassembly dynamics, suggesting therapeutic potential for raft targeting agents in desmosomal diseases such as PV.

Additive contribution of multiple factors in the development of pneumatosis intestinalis: a case report and review of the literature

We describe a 53-year-old patient with dermatomyositis, who developed pneumatosis intestinalis (PI) accompanied by pneumoperitoneum, pneumoretroperitoneum, pneumomediastinum, and subcutaneous emphysema of the neck. The development of PI in our patient was possibly attributed to the effect of factors such as dermatomyositis, corticosteroids, methotrexate, and alpha-glucosidase inhibitor (AGI). The coexistence of multiple factors associated with PI might enhance the risk of developing PI, even though each of them alone is not sufficient to induce it. In particular, the use of AGIs for patients treated with immunosuppressive agents such as corticosteroids requires evaluation.

A novel de novo splice-site mutation in the COL7A1 gene in dominant dystrophic epidermolysis bullosa (DDEB): specific exon skipping could be a prognostic factor for DDEB pruriginosa

We report a Japanese infant who had a novel de novo splice‐site mutation in the COL7A1 gene, which resulted in in‐frame exon 87 skipping. Very interestingly, most of the previously reported cases with the same exon skipping presented as dystrophic epidermolysis bullosa (DEB) pruriginosa. The proband in this study showed an extremely mild clinical phenotype, with no nail dystrophy, pruritus or prurigo‐like lesions. However, dominant (DDEB) pruriginosa often shows a typical mild DEB phenotype until the onset of pruritus, making it likely that as she gets older the proband will present with features consistent with DDEB pruriginosa. By knowing in advance the anticipated clinical course, it might be possible to reduce or even prevent development of nodular prurigo‐like lesions by sufficient control of pruritus. Our study should contribute to further refinement of the genotype–phenotype correlations in DEB, emphasizing the significance of mutation analysis for correct diagnosis and possibly for prediction of prognosis.

Genotype–phenotype correlations in six Japanese patients with recessive dystrophic epidermolysis bullosa with the recurrent p.Glu2857X mutation

BACKGROUND General genotype-phenotype correlations have been delineated in recessive dystrophic epidermolysis bullosa (RDEB), but these remain complicated and it is still difficult to assess the clinical consequences of individual COL7A1 mutations. OBJECTIVE To characterize recurrent p.Glu2857X mutations and show how other COL7A1 mutations influence the phenotype in RDEB patients harboring p.Glu2857X. METHODS Genotype-phenotype correlations were studied in six Japanese RDEB patients with the p.Glu2857X mutation. RESULTS Besides the common p.Glu2857X mutation, premature termination codon (PTC) mutations were found in three patients, glycine substitution missense mutations in two patients, and a non-glycine substitution missense mutation in one patient. PTC mutations in both alleles generally cause the most severe, mutilating Hallopeau-Siemens (HS) variant of RDEB, whereas none of the PTC mutations resulted in severe phenotypes consistent with the HS subtype when coupled with p.Glu2857X. Missense glycine and non-glycine mutations caused phenotypes of differing severity, suggesting that the extent of destabilization of anchoring fibrils depends on the type of mutation. CONCLUSION A p.Glu2857X mutation exhibits mild pathogenic effects compared to other PTC mutations in COL7A1, and its uniqueness enables detailed analysis and comparison of the destabilizing effects of missense mutations in RDEB patients.

Atypical dermatitis herpetiformis: a Japanese case that presented with initial lesions mimicking prurigo pigmentosa

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Exploring the biology of the nail: An intriguing but less-investigated skin appendage

The nail is a highly keratinized structure covering the tip of the digit, and considered to have several important functions in our daily life. In recent years, as biological aspects of the nail organ have been characterized, we realize that the nail unit and the hair follicle share various biological and immunological features. In particular, development and homeostasis of the nail unit also requires intimate epithelial-mesenchymal interactions that involve signaling pathways such as Wnt. There is also a striking immunological resemblance between both appendages, since the nail matrix, like the anagen hair bulb and the bulge, was shown to present unique characteristics of an immune privileged site. On the other hand, considerable progress in identifying nail stem cells has succeeded in locating putative stem cell niches in the nail unit. In this context, it is intriguing that nail stem cells residing in the nail matrix were recently shown to possess the ability to organize the process leading to digit regeneration. Further elucidation of signaling pathways governing epithelial-mesenchymal interactions in the nail unit seems to be a key to develop a novel therapeutic tool to treat amputees using nail epithelium. However, it is at least certain that the nail unit has a promising potential for the future of regenerative medicine. This review explores the biology of the nail organ by focusing on intriguing knowledge gained from recent studies.

Rapid growth of malignant melanoma in pregnancy.

Malignant melanoma during pregnancy is a difficult problem as a variety of risks to both the mother and fetus must be weighed. We describe a rapidly progressive malignant melanoma diagnosed during pregnancy. There are no standarized guidelines for treatment; each case requires an individualized approach. We review the literature and present an algorithm to aid in approaching such patients.