Publications by authors named "Akira Ishiko"

72 Publications

Stratum corneum levels of calprotectin proteins S100A8/A9 correlate with disease activity in psoriasis patients.

J Dermatol 2021 Jun 24. Epub 2021 Jun 24.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

Psoriasis is an intractable inflammatory skin disorder characterized by scaly erythema and plaques. The Psoriasis Area and Severity Index (PASI) is widely used to score disease severity, but evaluation is subjective, and an objective biomarker would be useful. The stratum corneum (SC), which can be non-invasively harvested, may reflect psoriasis-associated changes in epidermal keratinocytes, such as the upregulation of the calprotectin proteins S100A8 and S100A9. The aim of this study was to examine the availability of S100A8/A9 protein levels in SC as a biomarker of psoriasis disease activity. Fifty-three patients with psoriasis, 30 with psoriasis vulgaris (PsV), and 23 with psoriatic arthritis (PsA) participated. SC cells from lesional and non-lesional skin were collected by tape-stripping. S100A8/A9 levels in serum and in SC were quantified by enzyme-linked immunosorbent assay and compared with PASI score before and after treatment initiation or switching. Atopic dermatitis (AD) patients and disease-free individuals were used as controls. Expression of S100A8/A9 in SC of lesional skin of psoriasis patients was significantly higher than in non-lesional skin or AD skin. There was no significant difference of SC S100A8/A9 levels between PsV and PsA patients. The S100A8/A9 levels in SC of psoriasis patients were significantly positively correlated with the PASI score. When patients' skin lesions cleared (PASI clear) in response to treatment, expression of S100A8/A9 in SC was no longer detectable. S100A8/A9 protein levels in SC may be available as an objective, non-invasive biomarker of psoriasis activity to complement PASI scoring.
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http://dx.doi.org/10.1111/1346-8138.16032DOI Listing
June 2021

Case of intermediate recessive dystrophic epidermolysis bullosa with negative LH7.2 staining.

J Dermatol 2020 Oct 12;47(10):e370-e372. Epub 2020 Jul 12.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15498DOI Listing
October 2020

A rare case of allergic contact dermatitis caused by 3-O-ethyl-L-ascorbic acid in skin-whitening cosmetics identified under immunosuppressive therapy.

Contact Dermatitis 2020 Dec 12;83(6):520-521. Epub 2020 Oct 12.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/cod.13652DOI Listing
December 2020

Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin.

J Invest Dermatol 2020 10 3;140(10):1919-1926.e7. Epub 2020 Mar 3.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

Anti-desmoglein (Dsg) 1 and Dsg3 IgG autoantibodies in pemphigus foliaceus and pemphigus vulgaris cause blisters through loss of desmosomal adhesion. It is controversial whether blister formation is due to direct inhibition of Dsg, intracellular signaling events causing desmosome destabilization, or both. Recent studies show that heterophilic binding between Dsg and desmocollin (Dsc) is the fundamental adhesive unit of desmosomes. To eliminate cellular contributions to potential pathogenicity of pemphigus antibodies, bead assays coated with recombinant Dsg1, Dsc1, Dsg3, or Dsc3 ectodomains were developed. A mixture of Dsg beads and Dsc beads formed large aggregates, confirming that the heterophilic binding is dominant. The pathogenic anti-Dsg1 and anti-Dsg3 mAbs, which bind the transadhesive interface, blocked the aggregation of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively, whereas nonpathogenic mAbs did not. All sera tested from eight patients with pemphigus foliaceus and eight patients with mucosal pemphigus vulgaris with active disease inhibited the adhesion of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively. When paired sera obtained from seven patients with pemphigus foliaceus and six patients with pemphigus vulgaris in active disease and remission were compared, the former inhibited aggregation better than the latter. These findings strongly suggest that steric hindrance of heterophilic transinteraction between Dsg and Dsc is important for disease pathology in both pemphigus foliaceus and pemphigus vulgaris.
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http://dx.doi.org/10.1016/j.jid.2020.02.010DOI Listing
October 2020

Unusual Bone Lesions with Osteonecrosis Mimicking Bone Metastasis of Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa.

Acta Derm Venereol 2019 Nov;99(12):1166-1169

Department of Dermatology, Faculty of Medicine, University of Tsukuba, 305-8575 Tsukuba, Japan.

Some bone lesions are reported to mimic bone metastasis on imaging tests. Herein, we report a case of a 55-year-old Japanese man who presented with a skin tumor on the left lower extremity. He also had a history of recurrent generalized cutaneous blister and erosion formation since childhood. His skin lesions were diagnosed as cutaneous squamous cell carcinoma complicated by recessive dystrophic epidermolysis bullosa. Magnetic resonance imaging of the left lower extremity detected multiple focal bone lesions mimicking bone metastases in the left femur and tibia. However, bone biopsy revealed that the bone lesions were osteonecrosis without tumor cells. We suggest that cancer-induced osteonecrosis should be included in the differential diagnosis of bone lesions suspected of being metastases on magnetic resonance imaging.
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http://dx.doi.org/10.2340/00015555-3303DOI Listing
November 2019

Junctional epidermolysis bullosa without pyloric atresia due to a homozygous missense mutation in ITGB4.

J Dermatol 2019 Feb 6;46(2):e61-e63. Epub 2018 Aug 6.

Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.14591DOI Listing
February 2019

Histopathological and electron microscopic study in dogs with patellar luxation and skin hyperextensibility.

J Vet Med Sci 2018 Aug 6;80(8):1309-1316. Epub 2018 Jul 6.

Synergy Animal General Hospital, 815 Ishigami Kawaguchi, Saitama 333-0823, Japan.

Patellar luxation is abnormal displacement of the patella from the femoral trochlear groove. It is seen primarily in small breed dogs and causes pain and limited mobility of the stifle joint. This study aimed to investigate the relationship among patellar luxation, skin extension, and skin collagen fibril diameter. Nine dogs with patellar luxation and five clinically normal dogs were enrolled in the study. We measured the skin extension and investigated the ultrastructure of the skin and patellofemoral ligament by histopathology and transmission electron microscopy. The mean skin extension in dogs with patellar luxation was 18.5 ± 5.5% which is greater than the reference value (14.5%). Mean skin extension in controls was 8.8 ± 1.7% and was within the normal range. In dogs with patellar luxation, histopathology of the skin and patellofemoral ligament showed sparse and unevenly distributed collagen fibers. Transmission electron microscopy identified poorly organized, irregularly shaped, thin collagen fibrils. Collagen fibril thickness in dogs with patellar luxation was significantly less than fibril thickness in controls (P<0.001). There was a significant negative correlation (ρ= -0.863; P<0.001) between skin collagen fibril diameter and skin extension. Skin extension was correlated with patellar luxation and disease severity. Dogs with patellar luxation, joint dysplasia, and hyperextensible skin appear to be pathologically related. This might represent a phenotype of the Ehlers-Danlos syndrome, a hereditary connective tissue disorder in humans.
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http://dx.doi.org/10.1292/jvms.18-0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115261PMC
August 2018

Splice site mutation in COL7A1 resulting in aberrant in-frame transcripts identified in a case of recessive dystrophic epidermolysis bullosa, pretibial.

J Dermatol 2018 Jun 3;45(6):742-745. Epub 2018 Mar 3.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Dystrophic epidermolysis bullosa (DEB), pretibial, a rare subtype of epidermolysis bullosa (EB), is characterized by recurrent blisters and erosions predominantly on the pretibial region. We report the case of a 60-year-old Japanese woman with persistent blistering eruptions and scar formation on the pretibial region and elbows. Mutational analysis revealed a previously reported c.5797C>T mutation in exon 70 (p.R1933X) and a novel c.6348+1G>A mutation in intron 76 of COL7A1. Reverse transcription polymerase chain reaction revealed that the c.6348+1G>A mutation resulted in the skipping of exon 76 (69 bp) and the retention of intron 76 (75 bp), and both transcripts were in-frame. From these results, we diagnosed the patient as having recessive DEB, pretibial. A review of previously reported mutations in DEB, pretibial, revealed that one-third of DEB, pretibial, cases showed a recessive inheritance pattern, and no case had a combination of premature termination codon (PTC)/PTC mutations. The DEB, pretibial, case described herein is the first reported case of a compound heterozygote with PTC/in-frame mutations. Although no special characteristic features of the mutations were identified, a high diversity of COL7A1 mutations was shown even in DEB, pretibial.
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http://dx.doi.org/10.1111/1346-8138.14271DOI Listing
June 2018

Skin lesions of Birt-Hogg-Dubé syndrome: Clinical and histopathological findings in 31 Japanese patients who presented with pneumothorax and/or multiple lung cysts.

J Dermatol Sci 2018 Jan 2;89(1):77-84. Epub 2017 Nov 2.

Division of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan; The Study Group for Pneumothorax and Cystic Lung Diseases, Tokyo, Japan.

Background: Birt-Hogg-Dubé syndrome (BHDS) (OMIM #135150) is an autosomal dominant disease, characterized by fibrofolliculomas (FFs) of the skin, pulmonary cysts with/without pneumothorax, and renal tumors. The prevalence of skin manifestations reported for Japanese BHDS patients is lower (<30%) compared with that of Western countries (75∼90%), which appear to be underestimated.

Objective: To precisely examine the prevalence of skin lesions with dermoscopy and histopathology with reference to genetic analyses.

Methods: We studied 31 patients (47.0±13.2years old, range 15-71) consisting of 26 unrelated families consecutively from May 2013 to June 2015 specifically for skin-colored papules on their faces and cervicothoracic regions. Patients initially suspected of BHDS from multiple pulmonary cysts that resulted in pneumothorax (30/31; 96.8%) received dermoscopic examinations and skin biopsies if applicable. The diagnosis of BHDS was established by folliculin (FLCN) genetic testing, and the results were compared to the histopathological findings of FFs or trichodiscomas (TDs).

Results: FLCN germline mutation was demonstrated in 25/26 (96.2%) unrelated families tested and 28/29 patients (96.6%) tested. Skin lesions were recognized in 26/31 patients (83.9%); skin biopsies were performed in 23 patients of whom FFs and/or TDs were histologically demonstrated in 17 (73.9%). Although our study population included patients whose skin manifestations were evaluated prior to or after FLCN genetic testing, skin lesions were clearly prevalent and recognizable irrespective of whether genetic testing was or wasn't done. When examined with dermoscopy, distinct FFs appeared as well-demarcated areas of pallor with central follicular openings in 13 of 15 FF-bearing patients (86.7%); however, those manifestations were not recognized for TD.

Conclusions: Skin lesions appear to be more prevalent than previously reported (<30% vs.73.9%) in Japanese BHDS patients. Dermoscopy is a useful diagnostic aid for finding FFs.
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http://dx.doi.org/10.1016/j.jdermsci.2017.10.014DOI Listing
January 2018

Alopecia developed in a transitional case from pemphigus foliaceus to pemphigus vulgaris.

J Dermatol 2017 Nov 5;44(11):e306-e307. Epub 2017 Jul 5.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.13957DOI Listing
November 2017

Experimental Laminin 332 Mucous Membrane Pemphigoid Critically Involves C5aR1 and Reflects Clinical and Immunopathological Characteristics of the Human Disease.

J Invest Dermatol 2017 08 26;137(8):1709-1718. Epub 2017 Apr 26.

Lübeck Institute for Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address:

Mucous membrane pemphigoid is an autoantibody-mediated disease predominantly affecting the oral cavity, pharynx, and conjunctiva. Conjunctival lesions may lead to impaired vision and, finally, blindness. About 25% of mucous membrane pemphigoid patients generate autoantibodies against the α3 chain of laminin 332 (LAMα3), a structural protein of epidermal/epithelial basement membranes. Here, we established a mouse model by the passive transfer of rabbit IgG against the murine homologs of two immunodominant fragments in adult C57BL/6 mice (mLAMα3). After repeated subcutaneous injections of anti-mLAMα3 IgG erosions and crusts occurred predominantly around the snout, eyes, and on ears. Conjunctival and oral/pharyngeal lesions with subepithelial splitting were found in 80% and 100% of mice, respectively. In contrast, disease development was abrogated in FcRγ chain-deficient mice and markedly reduced in C5aR1-deficient mice. Furthermore, wild-type mice injected with anti-mLAMα3 F(ab') were completely protected. Our findings suggest a crucial codominant role of FcRγ and complement activation of the anti-mLAMα3 IgG-induced mouse model of mucous membrane pemphigoid. This model will help further discover the pathomechanisms of this devastating disease. Furthermore, it may be of use to explore the effect of urgently needed more specific anti-inflammatory mediators on mucosal and skin lesions in autoantibody-mediated diseases.
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http://dx.doi.org/10.1016/j.jid.2017.03.037DOI Listing
August 2017

Dermoscopic features of nail psoriasis treated with biologics.

J Dermatol 2017 May 2;44(5):538-541. Epub 2017 Feb 2.

Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan.

Although psoriatic nail lesions are small, they cause considerable discomfort for patients and adversely affect quality of life. Few studies have evaluated the dermoscopic features of psoriatic nails. The aim of this study was to clarify the dermoscopic features of nail psoriasis and identify those that reflect psoriatic activity. During biologic treatment of psoriasis, six patients with psoriatic nails twice underwent dermoscopic examination, with an interval of 17-42 weeks. We used the modified Nail Psoriasis Severity Index score and Psoriasis Area and Severity Index score to identify and assess dermoscopic features. We identified 10 dermoscopic findings, of which disappearance of diffuse scaling of the nail plate, transverse step-like notches and splinter hemorrhages of the nail bed, and appearance of erythematous borders of the onycholytic area were associated with improvement in Psoriasis Area and Severity Index score. Dermoscopy can detect nail changes during psoriasis treatment and should be used to evaluate treatment success.
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http://dx.doi.org/10.1111/1346-8138.13752DOI Listing
May 2017

A scabies outbreak in a diabetic and collagen disease ward: Management and prevention.

Exp Ther Med 2016 Dec 27;12(6):3711-3715. Epub 2016 Oct 27.

Department of General Medicine and Emergency Care, Toho University School of Medicine, Omori Hospital, Ota-ku, Tokyo 143-8541, Japan.

Scabies is an infection caused by . In developed countries, scabies remains an important public health problem in hospitals and care facilities among elderly or immunocompromised patients. There are a number of medical providers who have not experienced scabies and there has been confusion surrounding its management and prevention. Therefore, the aim of the present study was to identify the optimal approach for the management and prevention of scabies. A scabies outbreak occurred between June 2014 and October 2014 in the Toho University School of Medicine, Omori Hospital (Tokyo, Japan), and the current study investigates factors concerning the outbreak, such as disease recognition, diagnostic strategy, medical staff experience and correspondence after the outbreak occurred. Six patients were newly diagnosed with scabies including patients, medical staff and family of the medical staff. An infection control committee was implemented and required a follow-up survey of 181 people (144 patients and 37 medical staff). It took ~4 months to resolve the outbreak. Scabies is highly infectious, and sufficient knowledge is required to care for the patients and prevent the infection of healthy people. In this example, the spread of infection was controlled by prompt action.
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http://dx.doi.org/10.3892/etm.2016.3845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228462PMC
December 2016

Non-pathogenic pemphigus foliaceus (PF) IgG acts synergistically with a directly pathogenic PF IgG to increase blistering by p38MAPK-dependent desmoglein 1 clustering.

J Dermatol Sci 2017 Mar 12;85(3):197-207. Epub 2016 Dec 12.

Dermatology, Toho University School of Medicine, Tokyo, Japan.

Background: Pemphigus foliaceus (PF) is an autoimmune blistering disease caused by autoantibodies (Abs) against desmoglein 1 (Dsg1). PF sera contain polyclonal Abs which are heterogeneous mixture of both pathogenic and non-pathogenic Abs, as shown by isolation of monoclonal Abs (mAbs).

Objective: To investigate how pathogenic and non-pathogenic anti-Dsg1 Abs contribute to blister formation in PF.

Methods: Using organ-cultured human skin, we compared the effect of a single pathogenic anti-Dsg1 IgG mAb, a single non-pathogenic anti-Dsg1 IgG mAb, and their mixture on blister formation as analyzed by histology, subcellular localization of IgG deposits and desmosomal proteins by confocal microscopy, and desmosomal structure by electron microscopy. In addition, we measured keratinocyte adhesion by an in vitro dissociation assay.

Results: 24h after injection, a single pathogenic anti-Dsg1 IgG caused a subcorneal blister with IgG and Dsg1 localized linearly on the cell surface of keratinocytes. A single non-pathogenic anti-Dsg1 IgG bound linearly on the keratinocytes but did not induce blisters. A pathogenic and a non-pathogenic IgG mAb injected together caused an aberrant granular pattern of IgG and Dsg1 in the lower epidermis with blister formation in the superficial epidermis. Electron microscopy demonstrated that the mixture of mAbs shortened desmosomal lengths more than a single mAb in the basal and spinous layers. Furthermore, although Dsg1 clustering required both cross-linking of Dsg1 molecules by the non-pathogenic IgG plus a pathogenic antibody, the latter could be in the form of a monovalent single chain variable fragment, suggesting that loss of trans-interaction of Dsg1 is required for clustering. Finally, a p38MAPK inhibitor blocked Dsg1 clustering. When pathogenic strength was measured by the dissociation assay, a mixture of pathogenic and non-pathogenic IgG mAbs disrupted keratinocyte adhesion more than a single pathogenic mAb. This pathogenic effect was only partially suppressed by the p38MAPK inhibitor.

Conclusion: These findings indicate that a polyclonal mixture of anti-Dsg1 IgG antibodies enhances pathogenic activity for blister formation associated with p38MAPK-dependent Dsg1 clustering and that not only pathogenic antibodies but also non-pathogenic antibodies coordinately contribute to blister formation in PF.
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http://dx.doi.org/10.1016/j.jdermsci.2016.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510496PMC
March 2017

Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia.

J Dermatol 2017 Feb 8;44(2):160-166. Epub 2016 Sep 8.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a rare congenital bullous disease with gastrointestinal disturbance that has been associated with mutations in ITGA6 or ITGB4 encoding the α6 or β4 subunit of integrin, respectively. Only six ITGA6 mutations in PA-JEB have been reported while many ITGB4 mutations have been identified, and all the ITGA6 mutations were homozygous. Here, we report a case of lethal type PA-JEB, in which immunofluorescence showed the lack of both α6 and β4 integrins resulting from compound heterozygous splice site mutation in ITGA6, c.387G>T and c.2506-1G>C. Maternal c.387G>T induced the skipping of the entire exon 3 and both exons 3 and 4, resulting in premature termination codon and in-frame deletion, respectively. Paternal c.2506-1G>C caused the skipping of the exon 20 and resulted in in-frame deletion. As a reason why the present case showed lethal phenotype despite the in-frame deletion mutation, rapid degradation of neo-synthesized α6 protein and/or impaired transport of integrin were suggested from previous reports, and the lack of localization of integrin α6β4 to the epidermal basement membrane resulted in skin fragility. Our case expands the variety of integrin α6 mutations in PA-JEB.
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http://dx.doi.org/10.1111/1346-8138.13575DOI Listing
February 2017

Case of isolated epidermolytic acanthoma: Genetic and immunohistochemical analysis.

J Dermatol 2016 Aug 6;43(8):974-5. Epub 2016 Mar 6.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.13323DOI Listing
August 2016

Identification and Characterization of a Recessive Missense Mutation p.P277L in SERPINB7 in Nagashima-Type Palmoplantar Keratosis.

J Invest Dermatol 2016 Jan;136(1):325-8

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1038/JID.2015.347DOI Listing
January 2016

Japanese recurrent mutation c.6216+5G>T in COL7A1 leads to a mild phenotype of dystrophic epidermolysis bullosa.

J Dermatol Sci 2015 Dec 9;80(3):220-3. Epub 2015 Oct 9.

Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582 Tokyo, Japan; Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omori-nishi, Ota-ku, 143-8541 Tokyo, Japan.

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http://dx.doi.org/10.1016/j.jdermsci.2015.09.011DOI Listing
December 2015

Radiosensitive Hematopoietic Cells Determine the Extent of Skin Inflammation in Experimental Epidermolysis Bullosa Acquisita.

J Immunol 2015 Sep 22;195(5):1945-54. Epub 2015 Jul 22.

Department of Dermatology, University of Lübeck, D-23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, D-23538 Lübeck, Germany;

Animal models have enhanced our understanding of the pathogenesis of autoimmune diseases. For these models, genetically identical, inbred mice have commonly been used. Different inbred mouse strains, however, show a high variability in disease manifestation. Identifying the factors that influence this disease variability could provide unrecognized insights into pathogenesis. We established a novel Ab transfer-induced model of epidermolysis bullosa acquisita (EBA), an autoimmune disease characterized by (muco)-cutaneous blistering caused by anti-type VII collagen (COL7) autoantibodies. Blistering after anti-COL7 IgG (directed against the von Willebrand factor A-like domain 2) transfer showed clear variability among inbred mouse strains, that is, severe cutaneous blistering and inflammation in C57BL/6J and absence of skin lesions in MRL/MpJ mice. The transfer of anti-COL7 IgG into irradiated, EBA-resistant MRL/MpJ mice, rescued by transplantation with bone marrow from EBA-susceptible B6.AK-H2k mice, induced blistering. To the contrary, irradiated EBA-susceptible B6.AK-H2k mice that were rescued using MRL/MpJ bone marrow were devoid of blistering. In vitro, immune complex activation of neutrophils from C57BL/6J or MRL/MpJ mice showed an impaired reactive oxygen species release from the latter, whereas no differences were observed after PMA activation. This finding was paralleled by divergent expression profiles of immune complex-activated neutrophils from either C57BL/6J or MRL/MpJ mice. Collectively, we demonstrate that radiosensitive cells determine the varying extent of skin inflammation and blistering in the end-stage effector phase of EBA.
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http://dx.doi.org/10.4049/jimmunol.1501003DOI Listing
September 2015

Pathological characterization of pachydermia in pachydermoperiostosis.

J Dermatol 2015 Jul 11;42(7):710-4. Epub 2015 May 11.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

Pachydermoperiostosis is a rare hereditary disease, which presents with the cutaneous manifestations of pachydermia and cutis verticis gyrata. Histological findings in pachydermia frequently include dermal edema, mucin deposition, elastic fiber degeneration, dermal fibrosis and adnexal hyperplasia. However, the severity of these findings varies between clinical reports, and a systematic multiple-case clinicopathological correlative analysis has not been performed to date. In the present study, we reviewed the skin biopsy specimens obtained from the pachydermia of six pachydermoperiostosis patients. The severity of the characteristic histological features was semiquantitatively evaluated and correlated with the grade of pachydermia. Dermal edema, mucin deposition and elastic fiber degeneration were observed in all cases. Patients with severe pachydermia had sebaceous gland hyperplasia and fibrosis. These results suggest that the triad of mucin deposition, dermal edema and elastic fiber degeneration are found from very early stage pachydermia, and could be considered diagnostic findings. To ensure an earlier diagnosis of pachydermoperiostosis, a biopsy should be taken when a patient has grade 1 pachydermia to determine the presence of this histological triad.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029778PMC
http://dx.doi.org/10.1111/1346-8138.12869DOI Listing
July 2015

Application of electron microscopic analysis and fluorescent in situ hybridization technique for the successful diagnosis of extraskeletal Ewing's sarcoma.

J Dermatol 2015 Sep 11;42(9):893-6. Epub 2015 May 11.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

The diagnosis of soft tissue tumors is often challenging. Immunohistochemical investigation, let alone routine histopathological investigation, may not allow definitive diagnosis in some cases. To overcome such difficulties, more advanced techniques need to be adopted. Herein, we report an extremely rare 56-year-old Japanese female case of extraskeletal Ewing's sarcoma (ES), successfully diagnosed by electron microscopy (EM) using formalin-fixed sections and fluorescence in situ hybridization (FISH). The patient had a 2-year history of a tumor growing on the leg. In routine histopathology, invasive proliferation of tumor cells was observed in the dermis. Tumor cells were round and uniform with large hyperchromatic nuclei, which were positively stained for CD56, VS38c, Ki-67, MIC2 and vimentin, but not for pan-keratin AE1 + AE3, cytokeratin 20, chromogranin A, synaptophysin and neuron-specific enolase. As these findings were not conclusive to make the final diagnosis, EM specimens were prepared from formalin-fixed sections and subjected to investigation. Cell surface projections and dense core granules were detected, suggestive of either Merkel cell carcinoma or extraskeletal ES. Subsequent FISH analysis identified reciprocal translocation of the ESWR1 gene, enabling the final diagnosis of extraskeletal ES. This study provides useful information enabling the diagnosis of this uncommon soft tissue tumor.
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http://dx.doi.org/10.1111/1346-8138.12930DOI Listing
September 2015

Splicing abnormality of integrin β4 gene (ITGB4) due to nucleotide substitutions far from splice site underlies pyloric atresia-junctional epidermolysis bullosa syndrome.

J Dermatol Sci 2015 Apr 7;78(1):61-6. Epub 2015 Feb 7.

Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 162-8582, Japan; Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.

Background: Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is a rare subgroup of epidermolysis bullosa, which is inherited disorder characterized by skin fragile. PA-JEB is caused by mutation of ITGB4 or ITGA6, which encodes integrin β4 or α6, respectively.

Objective: To clarify the molecular basis of PA-JEB and to expand the mutational database, we carried out the mutational analysis of a 29-year-old Japanese PA-JEB patient.

Methods: Standard methods were used to prepare, PCR-amplify, and sequence DNA or mRNA in peripheral blood or skin samples, respectively.

Results: Sequence analysis revealed two novel mutations in ITGB4, c.264+2TtoA and c.1762-25TtoA. The paternal c.264+2TtoA resided within a splice site consensus region and generated two splice variants resulting in a premature termination codon (PTC). The maternal c.1762-25TtoA was a unique mutation because of its location, 25 bp away from the splice site, and resided in branch-point consensus sequence. This c.1762-25TtoA substitution resulted in generation of two abnormal transcripts each with a PTC. Genotype-phenotype correlation in this case was also unique because the proband showed a non-lethal phenotype regardless of both mutations resulted in only abnormal transcripts with a PTC.

Conclusion: The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB.
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http://dx.doi.org/10.1016/j.jdermsci.2015.01.016DOI Listing
April 2015

Case of non-Herlitz junctional epidermolysis bullosa with COL17A1 mutation.

J Dermatol 2015 Mar 9;42(3):323-5. Epub 2015 Jan 9.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.12755DOI Listing
March 2015

Fcγ receptors III and IV mediate tissue destruction in a novel adult mouse model of bullous pemphigoid.

Am J Pathol 2014 Aug;184(8):2185-96

Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address:

Bullous pemphigoid (BP) and epidermolysis bullosa acquisita are subepidermal autoimmune blistering diseases mediated by autoantibodies against type XVII collagen (Col17) and Col7, respectively. For blister formation, Fc-mediated events, such as infiltration of inflammatory cells in the skin, complement activation, and release of proteases at the dermal-epidermal junction, are essential. Although in the neonatal passive transfer mouse model of BP, tissue destruction is mediated by Fcγ receptors (FcγRs) I and III, the passive transfer model of epidermolysis bullosa acquisita completely depends on FcγRIV. To clarify this discrepancy, we developed a novel experimental model for BP using adult mice. Lesion formation was Fc mediated because γ-chain-deficient mice and mice treated with anti-Col17 IgG, depleted from its sugar moiety at the Fc portion, were resistant to disease induction. By the use of various FcγR-deficient mouse strains, tissue destruction was shown to be mediated by FcγRIV, FcγRIII, and FcγRIIB, whereas FcγRI was not essential. Furthermore, anti-inflammatory mediators in already clinically diseased mice can be explored in the novel BP model, because the pharmacological inhibition of FcγRIV and depletion of granulocytes abolished skin blisters. Herein, we extended our knowledge about the importance of FcγRs in experimental BP and established a novel BP mouse model suitable to study disease development over a longer time period and explore novel treatment strategies in a quasi-therapeutic setting.
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http://dx.doi.org/10.1016/j.ajpath.2014.05.007DOI Listing
August 2014

Japanese case of Herlitz junctional epidermolysis bullosa that initially showed a few blisters on the limited area.

J Dermatol 2014 Apr 12;41(4):351-3. Epub 2014 Mar 12.

Department of Dermatology, Faculty of Medicine, Toho University, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.12441DOI Listing
April 2014

Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.

Am J Hum Genet 2013 Nov 24;93(5):945-56. Epub 2013 Oct 24.

Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Integrated Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address:

"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.
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http://dx.doi.org/10.1016/j.ajhg.2013.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824127PMC
November 2013

B cells, dendritic cells, and macrophages are required to induce an autoreactive CD4 helper T cell response in experimental epidermolysis bullosa acquisita.

J Immunol 2013 Sep 19;191(6):2978-88. Epub 2013 Aug 19.

Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany.

In autoimmune bullous dermatoses (AIBD), autoantibodies induce blisters on skin or mucous membranes, or both. Mechanisms of continued autoantibody production and blistering have been well characterized using AIBD animal models. Mechanisms leading to the initial autoantibody production, however, have not been investigated in detail. Epidermolysis bullosa acquisita (EBA) is an AIBD associated with autoantibodies to type VII collagen (COL7). The majority of EBA patients' sera recognize the noncollagenous domain 1, including the von Willebrand factor A-like domain 2 (vWFA2). In experimental EBA induced by immunization with GST-COL7, disease manifestation depended on the genetic background, a Th1 polarization, and the GST-tag. In this model, nude mice neither produced autoantibodies nor blisters. It has remained uncertain which APC and T cell subsets are required for EBA induction. We established a novel EBA model by immunization with vWFA2 fused to intein (lacking the GST-tag). All tested mouse strains developed autoantibodies, but blisters were exclusively observed in mice carrying H2s. In immunized mice, CD4 T cells specific for vWFA2 were detected, and their induction required presence of B cells, dendritic cells, and macrophages. Anti-vWFA2 autoantibodies located at the lamina densa bound to the dermal side of salt-split skin and induced blisters when transferred into healthy mice. Absence of CD8 T cells at time of immunization had no effect, whereas depletion of CD4 T cells during the same time period delayed autoantibody production and blisters. Collectively, we demonstrate the pathogenic relevance of Abs targeting the vWFA2 domain of COL7 and show the requirement of APC-induced CD4 T cells to induce experimental EBA.
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http://dx.doi.org/10.4049/jimmunol.1300310DOI Listing
September 2013
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