Tamotsu Ebihara

Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population.

Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (Pcombined = 8.36 × 10−18), the major histocompatibility complex (MHC) region (P = 8.38 × 10−20), OR10A3-NLRP10 (P = 1.54 × 10−22), GLB1 (P = 2.77 × 10−16), CCDC80 (P = 1.56 × 10−19), CARD11 (P = 7.83 × 10−9), ZNF365 (P = 5.85 × 10−20) and CYP24A1-PFDN4 (P = 1.65 × 10−8). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.

Clinical Practice Guidelines for the Management of Atopic Dermatitis 2016.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. Most patients have an atopic predisposition. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution of the eczema; and (iii) chronic and chronically relapsing course. The current strategies to treat AD in Japan from the perspective of evidence‐based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity‐related patient outcomes with respect to several important points requiring decision‐making in clinical practice.

SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing

The stratum corneum (SC), the outermost layer of the epidermis, acts as a barrier against the external environment. It is hydrated by endogenous humectants to avoid desiccation. However, the molecular mechanisms of SC hydration remain unclear. We report that skin‐specific retroviral‐like aspartic protease (SASPase) deficiency in hairless mice resulted in dry skin and a thicker and less hydrated SC with an accumulation of aberrantly processed profilaggrin, a marked decrease of filaggrin, but no alteration in free amino acid composition, compared with control hairless mice. We demonstrated that recombinant SASPase directly cleaved a linker peptide of recombinant profilaggrin. Furthermore, missense mutations were detected in 5 of 196 atopic dermatitis (AD) patients and 2 of 28 normal individuals. Among these, the V243A mutation induced complete absence of protease activity in vitro, while the V187I mutation induced a marked decrease in its activity. These findings indicate that SASPase activity is indispensable for processing profilaggrin and maintaining the texture and hydration of the SC. This provides a novel approach for elucidating the complex pathophysiology of atopic dry skin.

Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes

Thin-film electronic devices can be integrated with skin for health monitoring and/or for interfacing with machines. Minimal invasiveness is highly desirable when applying wearable electronics directly onto human skin. However, manufacturing such on-skin electronics on planar substrates results in limited gas permeability. Therefore, it is necessary to systematically investigate their long-term physiological and psychological effects. As a demonstration of substrate-free electronics, here we show the successful fabrication of inflammation-free, highly gas-permeable, ultrathin, lightweight and stretchable sensors that can be directly laminated onto human skin for long periods of time, realized with a conductive nanomesh structure. A one-week skin patch test revealed that the risk of inflammation caused by on-skin sensors can be significantly suppressed by using the nanomesh sensors. Furthermore, a wireless system that can detect touch, temperature and pressure is successfully demonstrated using a nanomesh with excellent mechanical durability. In addition, electromyogram recordings were successfully taken with minimal discomfort to the user.

Studies of autoantigens recognized by IgA anti-keratinocyte cell surface antibodies

We have examined autoantigens for IgA anti-keratinocyte cell surface antibodies in 17 intercellular IgA vesiculopustular dermatosis (IAVPD) cases showing only IgA antibodies and 5 cases showing both IgG and IgA antibodies (G A cases). IAVPD cases were divided into two subtypes: (1) intraepidermal neutrophilic IgA dermatosis type showing pustule formation throughout the epidermis and IgA antibodies reactive with the entire epidermis and (2) subcorneal pustular dermatosis type containing IgA antibodies reactive with the uppermost portion of the epidermis. Most G A cases showed atypical clinical features. With immunoblot analysis of normal human epidermal extracts, IgA antibodies in these cases showed no specific reactivity with either pemphigus foliaceus antigen (desmoglein 1) or pemphigus vulgaris antigen (desmoglein 3), except that IgC antibodies in one G/A case each recognized one of the two antigens. With immunoblotting of desmosome enriched fraction obtained from bovine snout epidermis, IgA antibodies in 10 IAVPD and 3 G/A cases and IgG antibodies in 4 G/A cases showed reactivity with either desmoglein 1 or desmocollin another desmosomal cadherin. These results indicate that IAVPD and G/A cases are heterogeneous in terms of both clinical features and antigens and that the IgA autoantibodies in these cases may react with different antigens from those for IgG autoantibodies.

Unusual acantholytic bullous dermatosis associated with neoplasia and IgG and IgA antibodies against bovine desmocollins I and II

There are unusual cases of pemphigus that have antibodies nonreactive with either pemphigus vulgaris or pemphigus foliaceus antigens. We describe a patient with an acantholytic bullous dermatosis and lung cancer with intercellular IgG and IgA antibodies that differed in specificity from those of pemphigus vulgaris and pemphigus foliaceus and reacted with bovine desmocollins I and II and recombinant desmocollin protein.

Familial linear and whorled nevoid hypermelanosis

Two patients with familial linear and whorled nevoid hypermelanosis, a 33-year-old woman and her 3-month-old daughter, are described. These are the first cases of linear and whorled nevoid hypermelanosis of familial occurrence reported in the literature. Asymptomatic hyperpigmented macules in streaky configurations had appeared on the trunk and extremities of both patients several weeks after birth and then gradually spread. No previous inflammation or eruption was observed. Histologic examination revealed a slight increase in the number of melanocytes in the epidermis and an irregular basal melanosis. No pigmentary incontinence or melanophages were observed in the dermis. Ultrastructurally the only finding was an increase in the number of normal-appearing mature melanosomes in keratinocytes in the lesion. Chromosomal analysis of cultured peripheral blood lymphocytes and dermal fibroblasts from normal and pigmented skin revealed no evidence of mixoploidy or chimerism. An undescribed genetic abnormality is suggested as the cause.

Pemphigus: from immunofluorescence to molecular biology.

Since the discovery of autoantibodies in patients with pemphigus, pemphigus has been intensively studied by dermatologists and cutaneous or cellular biologists by means of various techniques including immunofluorescence, immunoelectron microscopy, immunoprecipitation, immunoblotting, and molecular biology. In this article, up-dated topics on pemphigus obtained by each individual technique are reviewed. In the course of immunofluorescence studies on unusual cases of blistering diseases, a new entity characterized by immunoglobulin A (IgA)-type autoantibodies directed against keratinocyte cell surfaces has been discovered. Immunoelectron microscopy using low temperature post-embedding gold labeling enabled us to quantitate binding sites of pemphigus autoantibodies within desmosomes at different levels of epidermis. Immunoprecipitation and immunoblot analyses allowed us to characterize antigen complexes in paraneoplastic pemphigus. Finally, approaches using molecular biology not only have given us a fundamental insight that pemphigus autoantigen is a cadherin-type cell adhesion molecule both in pemphigus vulgaris and pemphigus foliaceus, but also provided tools to develop novel diagnostic and therapeutic strategies.

Cutaneous plasmacytosis: Report of 6 cases with or without systemic involvement

BACKGROUND Cutaneous plasmacytosis and systemic plasmacytosis are rare entities arising primarily in patients of Japanese descent. The origin and exact pathogenesis are poorly understood. OBJECTIVE We sought to determine clinicopathologic features of cutaneous and systemic plasmacytosis. METHODS We describe the clinicopathologic features of 6 patients with cutaneous plasmacytosis with or without systemic involvement (male:female = 3:1; mean age: 49.7 years; median age: 50.5 years; age range: 29-64 years). RESULTS Patients presented clinically with multiple, red-brown infiltrated plaques and flat tumors, mainly located on the trunk. Histology revealed in all cases the presence of clusters of mature plasma cells within the dermis. Lymphoid follicles with reactive germinal centers were seen in 3 cases. Five cases showed the expected polyclonal expression of immunoglobulin light chain by the plasma cells, but monoclonality was observed in 1 case, thus showing overlapping features with cutaneous marginal zone lymphoma. One patient revealed overlapping features with multicentric Castleman disease. LIMITATIONS This was a retrospective study on a relatively small number of patients. CONCLUSIONS Despite typical clinical presentation, some of our patients presented with histopathologic and immunohistochemical features that deviated from the conventional appearance. Our observation confirms and expands previous observations of this elusive entity, suggesting that the spectrum of clinicopathologic presentations may be wider than previously recognized.

Filaggrin loss-of-function mutations are not a predisposing factor for atopic dermatitis in an Ishigaki Island under subtropical climate

BACKGROUND Filaggrin (FLG) is a major protein component of the stratum corneum (SC) layer, and FLG loss-of-function mutations are a predisposing factor for atopic dermatitis (AD). Previous cohort studies of children from northern and western Europe have reported FLG loss-of-function mutation frequencies of 15.1-20.9% and 5.8-13.0% in AD and non-AD groups, respectively. OBJECTIVE To elucidate the association between AD prevalence of FLG loss-of-function mutation carriers and climate conditions, we determined the AD prevalence and FLG loss-of-function mutation frequencies in a cohort of children from Ishigaki Island. Ishigaki Island has a subtropical climate with high humidity (monthly average, 60.8-78.7%) and high temperature (monthly average, 18.5-29.4°C) throughout the year. METHODS We diagnosed AD prevalence and analyzed eight FLG loss-of-function mutations in the Japanese population against a cohort of 721 children from the Kyushu University Ishigaki Atopic Dermatitis Study (KIDS) cohort. Parents gave consent for the mutation analysis during their medical examinations from 2001 to 2006. RESULTS Average AD prevalence was 7.3% per year, and a total of 127 children (17.6%) were diagnosed with AD at least once between 2001 and 2006. The average total serum IgE level differed significantly between the AD and non-AD groups (199.0 and 69.0IU/ml, respectively). Although five kinds of FLG loss-of-function mutations isolated in previous Japanese FLG mutation studies were identified, the FLG loss-of-function mutation frequency in children of the KIDS cohort was not significantly different between the AD and non-AD groups (7.9% and 6.1%, respectively; P=0.174). CONCLUSION The FLG loss-of-function mutation frequency was not significantly different between the AD and non-AD groups in a cohort of children from Ishigaki Island, which has a subtropical climate, suggesting that FLG loss-of-function mutations are not always a predisposing factor for AD prevalence.