Natsuga Ken
| Faculty of Medicine Specialized Medicine Sensory Organ Medicine | Associate Professor |
| Research Institute for Electronic Science Research Center of Mathematics for Social Creativity | Associate Professor |
| Hokkaido University Hospital | Associate Professor |
Last Updated :2025/06/08
■Researcher basic information
Mail Address
- natsuga
med.hokudai.ac.jp
Researchmap personal page
Home Page URL
Researcher number
- 70645457
J-Global ID
Educational Organization
- Bachelor's degree program, Departments of Medicine, School of Medicine
- Master's degree program, Graduate School of Medicine
- Doctoral (PhD) degree program, Graduate School of Medicine
■Career
Career
- Apr. 2021 - Present
Hokkaido University, 電子科学研究所附属社会創造数学研究センター, 准教授（兼任） - Feb. 2021 - Present
北海道大学大学院医学研究院皮膚科学分野, 准教授 - Aug. 2016 - Feb. 2021
Hokkaido University, Hokkaido University Hospital, 講師 - Sep. 2012 - Jul. 2016
Hokkaido University, Hokkaido University Hospital, 助教 - Apr. 2011 - Aug. 2012
日本学術振興会, 海外特別研究員 - Sep. 2010 - Aug. 2012
Cancer Research UK Cambridge Research Institute, 客員研究員 - Apr. 2010 - Aug. 2010
Hokkaido University, Hokkaido University Hospital, 客員臨床医師 - Apr. 2006 - Mar. 2007
Hokkaido University, Hokkaido University Hospital, 医員 - Apr. 2005 - Mar. 2006
北海道がんセンター, レジデント - May 2003 - Mar. 2005
Hokkaido University, School of Medicine, 研修医
Educational Background
Committee Memberships
■Research activity information
Awards
- Aug. 2024, 日本研究皮膚科学会, 第25回日本研究皮膚科学会賞
夏賀 健 - Aug. 2024, 2023年度エクセレント・ティーチャー（優秀賞） 北海道大学医学部医学科
夏賀 健 - Aug. 2023, 北海道大学医学部医学科, 2022年度エクセレント・ティーチャー（優秀賞）
夏賀 健 - Aug. 2022, Sun Pharma RISING SUN AWARD 2022 日本研究皮膚科学会
夏賀 健 - Aug. 2022, 2021年度エクセレント・ティーチャー（優秀賞） 北海道大学医学部医学科
夏賀 健 - Aug. 2021, 北海道大学医学部医学科, 2020年度エクセレント・ティーチャー（優秀賞）
夏賀 健 - Aug. 2019, 北海道大学医学部医学科, 2018年度 エクセレント・ティーチャー（最優秀賞）
夏賀 健 - Mar. 2018, マルホ・高木皮膚科学振興財団, 第2回高木賞
夏賀 健 - Feb. 2014, 第6回ロート皮膚医学研究賞
夏賀 健 - Feb. 2013, 第4回日本研究皮膚科学会きさらぎ賞
夏賀 健 - Feb. 2013, 第32回高桑榮松奨学基金奨励賞
夏賀 健 - Jan. 2013, 平成24年度フラテ研究奨励賞
夏賀 健 - Dec. 2009, 日本皮膚科学会第380回北海道地方会ベストスライド賞
夏賀 健 - Jun. 2009, ESDR-JSID Young Fellow Collegiality Award
夏賀 健 - 2007, 第106回日本皮膚科学会総会ポスター賞
夏賀 健 - Jun. 2006, 平成17年度日本皮膚科学会北海道地方会賞
夏賀 健 - Oct. 2005, 日本皮膚科学会第362回北海道地方会ベストスライド賞
夏賀 健 - Dec. 2004, 日本皮膚科学会第359回北海道地方会ベストスライド賞
夏賀 健 - Feb. 2004, 日本皮膚科学会第356回北海道地方会ベストスライド賞
夏賀 健 - Dec. 1998, 北海道大学レーン記念賞
夏賀 健
Papers
- A case of multiple warty dyskeratomas overexpressing SERCA2 in acantholytic cells
Maho Matsuo, Xiaoyu Zang, Dongjun Im, Kayoko Tanaka, Ken Natsuga, Hiroaki Iwata
The Journal of Dermatology, 25 Feb. 2025
Scientific journal - Advanced phasing techniques in congenital skin diseases
Ken Natsuga
The Journal of Dermatology, 26 Dec. 2024
Scientific journal - Intracellular glycogen accumulation in pyodermatitis‐pyostomatitis vegetans
Satsuki Naruse, Ken Natsuga, Sota Itamoto, Mika Watanabe, Teruki Yanagi, Yuji Nakamaru, Hideyuki Ujiie
The Journal of Dermatology, 12 Dec. 2024
Scientific journal - Multiple Acantholytic Acanthomas in Junctional Epidermolysis Bullosa.
Sota Itamoto, Ken Natsuga, Takashi Seo, Shota Takashima, Hideyuki Ujiie
Acta dermato-venereologica, 104, adv42258, 19 Nov. 2024, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal - Spatial confinement induces reciprocating migration of epidermal keratinocytes and forms triphasic epithelia
Takuma Nohara, Junichi Kumamoto, Yosuke Mai, Mayuna Shimano, Sora Kato, Hiroyuki Kitahata, Hideki Nakamura, Shota Takashima, Mika Watanabe, Masaharu Nagayama, Tsukasa Oikawa, Hideyuki Ujiie, Ken Natsuga
Cold Spring Harbor Laboratory, 13 Nov. 2024
Epithelial cells undergo epithelial–mesenchymal transition (EMT) during migration and regain their epithelial phenotype in the post-migration phase (mesenchymal–epithelial transition; MET). We established an experimental system that reproduced three-dimensional triphasic epithelia, i.e., the original epithelium, its EMT, and MET. Keratinocytes (KCs), skin epithelial cells, placed on a microporous membrane migrated through 3.0-um or larger micropores. The 3.0-um-pored membrane induced an epithelial structure with three states: stratified KCs above the membrane, KCs showing EMT within the micropores, and a new stratified epithelium under the membrane. The membrane with larger micropores failed to maintain the triphasic epithelia. Live imaging revealed that KCs moved in a reciprocating manner, with actin-rich filopodia-like KC structures extending into and out of the 3.0-um micropores, while the cells migrated unidirectionally into larger micropores. Piezo1 and keratin 6 were identified as negative modulators of KC entry to and exit from the 3.0-um micropores. These results demonstrate that non-cancerous epithelial cells migrate through confined spaces in a reciprocating manner, which might help form triphasic epithelia, recapitulating wound healing processes. - A case of xanthogranuloma that developed in scar tissue following treatment for diffuse large B‐cell lymphoma
Emi Inamura, Yasuyuki Fujita, Yoko Hirano, Mayuna Shimano, Ken Natsuga, Satoshi Yamamoto, Takahiro Tsuji, Satoko Shimizu
The Journal of Dermatology, 11 Nov. 2024, [Peer-reviewed]
Scientific journal - IL-7-dependent and -independent lineages of IL-7R-dependent human T cells.
Carlos A Arango-Franco, Masato Ogishi, Susanne Unger, Ottavia M Delmonte, Julio César Orrego, Ahmad Yatim, Margarita M Velasquez-Lopera, Andrés F Zea-Vera, Jonathan Bohlen, Marwa Chbihi, Antoine Fayand, Juan Pablo Sánchez, Julian Rojas, Yoann Seeleuthner, Tom Le Voyer, Quentin Philippot, Kathryn J Payne, Adrian Gervais, Lucia V Erazo-Borrás, Luis A Correa-Londoño, Axel Cederholm, Alejandro Gallón-Duque, Pedro Goncalves, Jean-Marc Doisne, Liran Horev, Bénédicte Charmeteau-de Muylder, Jesús Á Álvarez, Diana M Arboleda, Lizet Pérez-Zapata, Estefanía Vásquez-Echeverri, Marcela Moncada-Vélez, Juan A López, Yolanda Caicedo, Boaz Palterer, Pablo J Patiño, Carlos J Montoya, Matthieu Chaldebas, Peng Zhang, Tina Nguyen, Cindy S Ma, Mohamed Jeljeli, Juan F Alzate, Felipe Cabarcas, Taushif Khan, Darawan Rinchai, Jean-Luc Prétet, Bertrand Boisson, Nico Marr, Ruba Ibrahim, Vered Molho-Pessach, Stéphanie Boisson-Dupuis, Dimitra Kiritsi, João T Barata, Nils Landegren, Bénédicte Neven, Laurent Abel, Andrea Lisco, Vivien Béziat, Emmanuelle Jouanguy, Jacinta Bustamante, James P Di Santo, Stuart G Tangye, Luigi D Notarangelo, Rémi Cheynier, Ken Natsuga, Andrés A Arias, José Luis Franco, Klaus Warnatz, Jean-Laurent Casanova, Anne Puel
The Journal of clinical investigation, 134, 19, 01 Oct. 2024, [Peer-reviewed], [International Magazine]
English, Scientific journal, Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development. - Association between nail psoriasis and obesity: A cross-sectional study at a single institution.
Sota Itamoto, Hajime Miyazawa, Ken Natsuga, Misako Yamaga, Hiroaki Iwata, Mika Watanabe, Hideyuki Ujiie
The Journal of dermatology, 30 Sep. 2024, [Peer-reviewed], [Corresponding author], [International Magazine]
English - Type XVII collagen-specific CD4+ T cells induce bullous pemphigoid by producing IL-5.
Norihiro Yoshimoto, Ken Muramastsu, Takamasa Ito, Miao Zheng, Kentaro Izumi, Ken Natsuga, Hiroaki Iwata, Yoshinori Hasegawa, Hideyuki Ujiie
The Journal of investigative dermatology, 19 Sep. 2024, [Peer-reviewed], [International Magazine]
English, Scientific journal, Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease caused by anti-type XVII collagen (COL17) antibodies. BP has some immunological features such as eosinophilic infiltration and the deposition of IgE autoantibodies in the skin; however, the mechanism behind such features remains largely unclear. We focused on the autoantigen-specific CD4+ T cells, which are considered to regulate immune response. We established COL17-specific CD4+ T cell lines in vitro. Wild-type mice were immunized with synthesized peptides that include a pathogenic epitope of COL17, and lymphocytes were subjected to a limiting dilution assay. We established 5 T cell lines and examined the pathogenicity by transferring them with COL17-primed B cells into Rag-2-/-/COL17-humanized mice that express human COL17 but not mouse COL17 in the skin. Notably, 3 lines induced BP-like skin changes associated with subepidermal separation and eosinophilic infiltration histologically, and the production of anti-COL17 antibodies. The other 2 lines did not induce such phenotypes. RNA-sequencing analysis revealed that Th2 cytokines, particularly IL-5, were highly expressed in the pathogenic T cell lines. Anti-IL-5 antibody administration significantly reduced the skin changes and attenuated the production of autoantibodies. Thus, the production of IL-5 is critical for COL17-specific CD4+ T cells to induce BP phenotypes in vivo. - Patterning in stratified epithelia depends on cell-cell adhesion.
Yosuke Mai, Yasuaki Kobayashi, Hiroyuki Kitahata, Takashi Seo, Takuma Nohara, Sota Itamoto, Shoko Mai, Junichi Kumamoto, Masaharu Nagayama, Wataru Nishie, Hideyuki Ujiie, Ken Natsuga
Life science alliance, 7, 9, Sep. 2024, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, Epithelia consist of proliferating and differentiating cells that often display patterned arrangements. However, the mechanism regulating these spatial arrangements remains unclear. Here, we show that cell-cell adhesion dictates multicellular patterning in stratified epithelia. When cultured keratinocytes, a type of epithelial cell in the skin, are subjected to starvation, they spontaneously develop a pattern characterized by areas of high and low cell density. Pharmacological and knockout experiments show that adherens junctions are essential for patterning, whereas the mathematical model that only considers local cell-cell adhesion as a source of attractive interactions can form regions with high/low cell density. This phenomenon, called cell-cell adhesion-induced patterning (CAIP), influences cell differentiation and proliferation through Yes-associated protein modulation. Starvation, which induces CAIP, enhances the stratification of the epithelia. These findings highlight the intrinsic self-organizing property of epithelial cells. - Blaschkoid granulomatous pigmented purpuric dermatosis in childhood.
George Miura, Mika Watanabe, Hideyuki Kosumi, Takuma Nohara, Ken Natsuga, Hideyuki Ujiie
The Journal of dermatology, 17 Jul. 2024, [Peer-reviewed], [International Magazine]
English - Atypical manifestations of hemangiomas in epidermolysis bullosa.
S Itamoto, K Natsuga, S Takashima, H Ujiie
The Journal of dermatology, 14 Jun. 2024, [Peer-reviewed], [Corresponding author], [International Magazine]
English - Collagen 17A1 in the Urothelium Regulates Epithelial Cell Integrity and Local Immunologic Responses in Obstructive Uropathy.
Takashi Namba, Osamu Ichii, Ken Natsuga, Teppei Nakamura, Yuki Otani, Yasuhiro Kon
The American journal of pathology, 194, 8, 1550, 1570, 18 May 2024, [Peer-reviewed], [International Magazine]
English, Scientific journal, Collagen 17A1 (COL17A1), an epidermal hemidesmosome component, is ectopically induced in the urothelium of mouse and human renal pelvis (RP) in parallel with urinary tract-associated lymphoid structure development. Here, we found that COL17A1 was induced in obstructive uropathy-prone ureter of humans and cats. To ascertain its function, murine urinary organs with unilateral ureteral obstruction (UUO) were analyzed during 1 week after surgery. One day after UUO, COL17A1 expression increased in urothelial cells of RP and ureter, and was positively correlated with renal tubulointerstitial lesions. A portion of RP where the smooth muscle layer from the ureter was interrupted was sensitive to urothelium deciduation and COL17A1 induction, showing urine leaked from the RP lumen into the parenchyma. After urine stimulation, cultured immune cells expressed Cxcl2, also up-regulated in CD11b+ cells following COL17A1 stimulation. One day after UUO, CXCL2+ CD11b+ cells infiltrated the urothelium-disrupted area; however, these numbers were significantly lower in Col17a1-deficient mice. COL17A1+ urothelial cells partially co-expressed cytokeratin-14, a progenitor cell marker for urothelium, whereas Col17a1-deficient mice had lower numbers of cytokeratin-14+ cells. Gene Ontology analysis revealed that expression of epithelial- and immune-associated genes was up-regulated and down-regulated, respectively, in the ureter of Col17a1-deficient mice 4 days after UUO. Thus, COL17A1 maintains urothelium integrity by regulating urothelial cell adhesion, proliferation, and differentiation, and activates local immune responses during obstructive uropathy in mammals. - Nail growth arrest under low body temperature during hibernation.
Taiga Ishimoto, Hideyuki Kosumi, Ken Natsuga, Yoshifumi Yamaguchi
The journal of physiological sciences : JPS, 74, 1, 27, 27, 27 Apr. 2024, [Peer-reviewed], [Corresponding author], [Domestic magazines]
English, Scientific journal, Growth and differentiation are reduced or stopped during hibernation, an energy conserving strategy in harsh seasons by lowered metabolism and body temperature. However, few studies evaluated this in a same individual using a non-invasive method. In this study, we applied a non-invasive tracking method of the nail growth throughout the hibernation period in the same hibernating animals, the Syrian hamster (Mesocricetus auratus). We found that nail growth was markedly suppressed during the hibernation period but rapidly recovered by the exit from the hibernation period. Our data suggest that nail growth was arrested during deep torpor, a hypometabolic and hypothermic state, but recovered during periodic arousal, a euthermic phase. Consistent with this, nail stem cells located in the nail matrix did not exit the cell cycle in the deep torpor. Thus, hibernation stops nail growth in a body temperature-dependent manner. - Successful treatment of multicentric Castleman's disease associated with dystrophic epidermolysis bullosa using anti-interleukin-6 receptor antibody.
Satsuki Naruse, Shota Takashima, Yasuyuki Fujita, Hiroshi Kataoka, Nobuaki Kawamura, Ken Natsuga, Hideyuki Ujiie
The Journal of dermatology, 51, 8, e268-e269, 14 Mar. 2024, [Peer-reviewed], [International Magazine]
English - Variable clinical consequences of mosaicism for c.1167dupC in IKBKG in male and female patients with incontinentia pigmenti and related phenotypes.
Roy Luister C Acos, Yi-Han Chang, Yu-Chen Lin, Dianne Katherine R Salazar-Paras, Yu Fujimura, Hajime Nakano, Eijiro Akasaka, Ken Natsuga, Bryan Edgar K Guevara, John A McGrath, Chao-Kai Hsu
Clinical and experimental dermatology, 49, 3, 298, 301, 14 Feb. 2024, [Peer-reviewed], [International Magazine]
English, Scientific journal - Transcriptomic response of peripheral blood mononuclear cells to dupilumab in a 65-year-old patient with bullous pemphigoid.
Meng-Ling Li, Yi-Kai Hong, Yu-Chen Lin, Ken Natsuga, Hideyuki Ujiie, Kentaro Izumi, Hiroaki Iwata, Chao-Kai Hsu
Clinical and experimental dermatology, 49, 1, 73, 74, 19 Dec. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal - Dermal discoloration due to osmium tetroxide.
Satsuki Naruse, Shota Takashima, Ken Natsuga, Hideyuki Ujiie
Clinical toxicology (Philadelphia, Pa.), 61, 11, 1004, 1005, Nov. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, INTRODUCTION: Osmium tetroxide is a strong oxidizing agent. After dermal exposure to osmium tetroxide, skin discoloration and red papules can occur. We describe a patient with skin discoloration due to osmium tetroxide. CASE SUMMARY: A 25-year-old postgraduate student unintentionally exposed his hand to osmium tetroxide while working in a laboratory setting. After immediate washing, he sought medical care due to left middle finger discoloration. He reported no discomfort in the affected area. Thorough water rinsing was continued, and corticosteroid ointment was applied. IMAGES: Our patient developed dark brown pigmentation on the ventral side of the left middle finger. The pigmentation disappeared one week later. CONCLUSION: Osmium tetroxide may induce dark brown skin discoloration. - Full-thickness Skin Grafts for Hand Contractures in an Adult Patient with Junctional Epidermolysis Bullosa: A Case Report
Nakamura Sayaka, Saito Susumu, Ishida Yoshihiro, Kaku Yo, Natsuga Ken, Morimoto Naoki
Journal of Plastic and Reconstructive Surgery, 2, 4, 156, 162, Japan Society of Plastic and Reconstructive Surgery, 27 Oct. 2023, [Peer-reviewed]
English, Epidermolysis bullosa is a group of inherited skin fragility disorders with blister formation in the basement membrane zone. Chronic scarring after repeated blistering of the hands causes narrowing of the first web, flexion contractures of the digits, and pseudosyndactyly. Junctional epidermolysis bullosa is a type of epidermolysis bullosa that is characterized by blister formation in the lamina lucida. This condition is associated with survival into adulthood. In adult survivors, hand function might be required in order to participate in normal social activities. However, there is a lack of literature on the management of hand surgery for adult patients with junctional epidermolysis bullosa. We herein describe an adult patient with junctional epidermolysis bullosa who had pseudosyndactyly and flexion contractures in both hands. Five surgeries were performed. Contractures were released and reconstructed using split- or full-thickness skin grafts. Delayed wound healing was always observed due to epidermal necrosis in the graft. After epithelialization, a satisfactory functional outcome was obtained. - Development of a nutritionally balanced, melt‐in‐the‐mouth chocolate for patients with epidermolysis bullosa
Kosei Nakamura, Shota Takashima, Takuma Nohara, Mika Watanabe, Ken Natsuga, Hideyuki Ujiie
The Journal of Dermatology, 50, 12, 1640, 1643, Wiley, 07 Sep. 2023, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, Abstract
Epidermolysis bullosa (EB) is a group of inherited blistering disorders that primarily affect the skin and mucous membranes of the digestive tract, which can lead to poor nutritional status. Dietary supplements and nutritional support methods, such as nasogastric tubes and gastrostomy, have been employed to improve the nutritional status of patients with EB; however, few foods are suitable for enjoyable eating with family and friends. Here, we introduce a nutritionally balanced, melt‐in‐the‐mouth chocolate called andew, which was specifically designed for patients with EB. The andew chocolate is nutritionally superior and melts more easily than traditional chocolates, thus it is suitable for patients with EB, who are prone to oral erosions. Patients responded more favorably to the taste and texture of andew than to those of other dietary supplements. Not only does andew provide nutritional benefits, but it also promotes enjoyable eating with family members and friends, which could positively impact patients' mental health. - Native Autoantigen Complex Detects Pemphigoid Autoantibodies.
Shoko Mai, Kentaro Izumi, Yosuke Mai, Ken Natsuga, Norito Ishii, Daisuke Sawamura, Franziska Schauer, Dimitra Kiritsi, Wataru Nishie, Hideyuki Ujiie
JID innovations : skin science from molecules to population health, 3, 3, 100193, 100193, May 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering in the skin and mucosa. Among them, mucous membrane pemphigoid (MMP) autoantibodies are characterized by targeting multiple molecules in the hemidesmosomes, including collagen XVII, laminin-332, and integrin a6/β4. Traditionally, recombinant proteins of the autoantigens have been employed to identify circulating autoantibodies by immune assays. However, developing an efficient detection system for MMP autoantibodies has been challenging because the autoantibodies have heterogeneous profiles and the antibody titers are typically low. In this study, we introduce an ELISA that takes advantage of a native autoantigen complex rather than simple recombinant proteins. We generated HaCaT keratinocytes with a DDDDK-tag knocked in at the COL17A1 locus by CRISPR/Cas9-mediated gene editing. Immunoprecipitation using the DDDDK-tag isolated a native complex that contained full-length and processed collagen XVII and integrin α6/β4. Then, we used the complex proteins to prepare an ELISA system and enrolled 55 MMP cases to validate its diagnostic performance. The sensitivity and specificity of the ELISA for detecting MMP autoantibodies were 70.9% and 86.7%, respectively, far superior to those of conventional assays. In autoimmune diseases such as MMP, in which autoantibodies target various molecules, isolating the antigen-protein complexes can help establish a diagnostic system. - Tissue memory relies on stem cell priming in distal undamaged areas.
Chiara Levra Levron, Mika Watanabe, Valentina Proserpio, Gabriele Piacenti, Andrea Lauria, Stefan Kaltenbach, Annalaura Tamburrini, Takuma Nohara, Francesca Anselmi, Carlotta Duval, Luca Elettrico, Daniela Donna, Laura Conti, Denis Baev, Ken Natsuga, Tzachi Hagai, Salvatore Oliviero, Giacomo Donati
Nature cell biology, 25, 5, 740, 753, May 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, Epithelial cells that participated in wound repair elicit a more efficient response to future injuries, which is believed to be locally restricted. Here we show that cell adaptation resulting from a localized tissue damage has a wide spatial impact at a scale not previously appreciated. We demonstrate that a specific stem cell population, distant from the original injury, originates long-lasting wound memory progenitors residing in their own niche. Notably, these distal memory cells have not taken part in the first healing but become intrinsically pre-activated through priming. This cell state, maintained at the chromatin and transcriptional level, leads to an enhanced wound repair that is partially recapitulated through epigenetic perturbation. Importantly wound memory has long-term harmful consequences, exacerbating tumourigenesis. Overall, we show that sub-organ-scale adaptation to injury relies on spatially organized memory-dedicated progenitors, characterized by an actionable cell state that establishes an epigenetic field cancerization and predisposes to tumour onset. - Zonula occludens‐1 distribution and barrier functions are affected by epithelial proliferation and turnover rates
Keisuke Imafuku, Hiroaki Iwata, Ken Natsuga, Makoto Okumura, Yasuaki Kobayashi, Hiroyuki Kitahata, Akiharu Kubo, Masaharu Nagayama, Hideyuki Ujiie
Cell Proliferation, 56, 9, e13441, Wiley, 14 Mar. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, Zonula occludens-1 (ZO-1) is a scaffolding protein of tight junctions, which seal adjacent epithelial cells, that is also expressed in adherens junctions. The distribution pattern of ZO-1 differs among stratified squamous epithelia, including that between skin and oral buccal mucosa. However, the causes for this difference, and the mechanisms underlying ZO-1 spatial regulation, have yet to be elucidated. In this study, we showed that epithelial turnover and proliferation are associated with ZO-1 distribution in squamous epithelia. We tried to verify the regulation of ZO-1 by comparing normal skin and psoriasis, known as inflammatory skin disease with rapid turnover. We as well compared buccal mucosa and oral lichen planus, known as an inflammatory oral disease with a longer turnover interval. The imiquimod (IMQ) mouse model, often used as a psoriasis model, can promote cell proliferation. On the contrary, we peritoneally injected mice mitomycin C, which reduces cell proliferation. We examined whether IMQ and mitomycin C cause changes in the distribution and appearance of ZO-1. Human samples and mouse pharmacological models revealed that slower epithelial turnover/proliferation led to the confinement of ZO-1 to the uppermost part of squamous epithelia. In contrast, ZO-1 was widely distributed under conditions of faster cell turnover/proliferation. Cell culture experiments and mathematical modelling corroborated these ZO-1 distribution patterns. These findings demonstrate that ZO-1 distribution is affected by epithelial cell dynamics. - Interleukin-18 as a severity marker and novel potential therapeutic target for epidermolytic ichthyosis.
Osamu Ansai, Toshinari Miyauchi, Ryota Hayashi, Tatsuya Katsumi, Tomoki Nishiguchi, Akito Hasegawa, Satoru Shinkuma, Ken Natsuga, Toshifumi Nomura, Yutaka Shimomura, Riichiro Abe
Clinical and experimental dermatology, 48, 3, 199, 210, 01 Mar. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, BACKGROUND: Epidermolytic ichthyosis (EI) is a major form of nonsyndromic inherited ichthyosis, characterized by erythroderma, marked hyperkeratosis and scale, bulla and erosion at birth, associated with KRT1/KRT10 mutations. The cytokine and chemokine profiles in EI are poorly understood, and specific treatment options have not been established. AIM: To explore novel biomarkers and therapeutic targets in patients with EI. METHODS: We analysed cytokine levels in serum and skin samples from 10 patients with inherited ichthyosis, including seven patients with EI. Wild-type and mutant KRT1 constructs were established and transfected into HaCaT cells, an immortalized keratinocyte cell line, for in vitro immunoblotting and immunocytochemistry analyses. RESULTS: Multiplex cytokine/chemokine analysis revealed that 10 cytokines/chemokines [interleukin (IL)-1β, IL-4, IL-17A, IL-16, IL-18, IL-1 receptor-α, macrophage colony-stimulating factor, interferon-α2, basic fibroblast growth factor and monocyte chemotactic protein-3] were significantly increased in patients with EI. Furthermore, IL-18 levels were significantly higher in patients with EI [n = 7; 2714.1 (1438.0) pg mL-1] than in healthy controls [n = 11; 218.4 (28.4) pg mL-1, P < 0.01]. Immunohistochemical analyses showed that IL-18 expression was elevated in skin samples from patients with EI. Serum IL-18 levels correlated with the severity of ichthyosis, as measured by the Ichthyosis Scoring System. Immunoblotting analysis revealed that mature IL-18 levels were increased in the supernatant of mutant KRT1 expressing HaCaT cells. Additionally, these cells showed NLRP3 aggregation in the cytoplasm and ASC clustered around mutant keratin aggregations. These findings suggest that mutant keratin might promote the activation of the NLRP3 inflammasome and its downstream caspase-1-mediated IL-18 release in keratinocytes from patients with EI. CONCLUSIONS: Our results suggest that serum IL-18 is a severity marker released from the skin of patients with EI. Blockade of IL-18 may be a useful novel therapeutic option for patients with EI. - A case of epidermolysis bullosa simplex-Ogna with nail involvement.
Shingo Takei, Ryota Hayashi, Tatsuya Katsumi, Osamu Ansai, Akari Sakai, Ken Natsuga, Riichiro Abe
The Journal of dermatology, 50, 6, e177-e178, 30 Dec. 2022, [Peer-reviewed], [International Magazine]
English - Mutational analysis of epidermolysis bullosa in Taiwan by whole-exome sequencing complemented by RNA sequencing: a series of 77 patients.
Wei-Ting Tu, Ping-Chen Hou, Peng-Chieh Chen, Wan-Rung Chen, Hsin-Yu Huang, Jing-Yu Wang, Yi-Ting Huang, Yi-Huei Wu, Chun-Lin Su, Yen-An Tang, Hiroaki Iwata, Ken Natsuga, Sheau-Chiou Chao, H Sunny Sun, Ming-Jer Tang, Julia Yu-Yun Lee, John A McGrath, Chao-Kai Hsu
Orphanet journal of rare diseases, 17, 1, 451, 451, 28 Dec. 2022, [Peer-reviewed], [International Magazine]
English, Scientific journal, BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of hereditary skin diseases characterized by skin fragility. Primary data on Taiwanese population remain scarce. METHODS: We gathered clinical information from EB patients at National Cheng Kung University Hospital from January, 2012, to June, 2021. Diagnostic tests including transmission electron microscopy, immunofluorescence studies, and whole-exome sequencing (WES) were performed. The pathogenicity of novel splice-site mutations was determined through reverse transcriptase-PCR of skin mRNA followed by Sanger and/or RNA sequencing. RESULTS: Seventy-seven EB patients from 45 families were included: 19 EB simplex, six junctional EB, and 52 dystrophic EB. Pathogenic variants were identified in 37 of 38 families (97.4%), in which WES was used as a first-line tool for mutational analysis; RNA sequencing determined pathogenic variants in the remaining one family. A total of 60 mutations in EB-related genes were identified, including 22 novel mutations. The mutations involved KRT5, KRT14, PLEC, COL17A1, LAMB3, LAMA3, ITGB4, and COL7A1. Over one-quarter of DEB patients had EB pruriginosa. CONCLUSIONS: The distinct clinical presentation and molecular pathology of EB in Taiwan expand our understanding of this disorder. WES was an effective first-line diagnostic tool for identifying EB-associated variants. RNA sequencing complemented WES when multiple potentially pathogenic splice-site mutations were found. - Acquired perforating dermatosis induced by necitumumab.
A Kimura, H Kosumi, K Natsuga, T Goda, H Ujiie
Journal of the European Academy of Dermatology and Venereology : JEADV, 36, 10, e822-e823, Oct. 2022, [Peer-reviewed], [International Magazine]
English - Apremilast for lithium-associated psoriasis
Joohyung Youh, Hajime Miyazawa, Hiroaki Iwata, Ken Natsuga, Hideyuki Ujiie
Dermatologica Sinica, Jul. 2022, [Peer-reviewed]
English, Scientific journal - Collagen XVII deficiency alters epidermal patterning.
Yunan Wang, Hiroyuki Kitahata, Hideyuki Kosumi, Mika Watanabe, Yu Fujimura, Shota Takashima, Shin-Ichi Osada, Tomonori Hirose, Wataru Nishie, Masaharu Nagayama, Hiroshi Shimizu, Ken Natsuga
Laboratory investigation; a journal of technical methods and pathology, 102, 6, 581, 588, Jun. 2022, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the role of spatiotemporal regulation of stem cells (SCs) has been implicated in this process, the mechanism underlying the development of such epidermal patterns is poorly understood. Here, we show that collagen XVII (COL17), a niche for epidermal SCs, helps stabilize epidermal patterns. Gene knockout and rescue experiments revealed that COL17 maintains the width of the murine tail scale epidermis independently of epidermal cell polarity. Skin regeneration after wounding was associated with slender scale epidermis, which was alleviated by overexpression of human COL17. COL17-negative skin in human junctional epidermolysis bullosa showed a distinct epidermal pattern from COL17-positive skin that resulted from revertant mosaicism. These results demonstrate that COL17 contributes to defining mouse tail scale shapes and human skin microtopography. Our study sheds light on the role of the SC niche in tissue pattern formation. - Wnt/β-Catenin Signaling Stabilizes Hemidesmosomes in Keratinocytes.
Hideyuki Kosumi, Mika Watanabe, Satoru Shinkuma, Takuma Nohara, Yu Fujimura, Tadasuke Tsukiyama, Giacomo Donati, Hiroaki Iwata, Hideki Nakamura, Hideyuki Ujiie, Ken Natsuga
The Journal of investigative dermatology, 142, 6, 1576, 1586, Jun. 2022, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, Hemidesmosomes (HDs) are adhesion complexes that promote epithelial-stromal attachment in stratified and complex epithelia, including the epidermis. In various biological processes, such as differentiation and migration of epidermal keratinocytes during wound healing or carcinoma invasion, quick assembly and disassembly of HDs are prerequisites. In this study, we show that inhibition of Wnt/β-catenin signaling disturbs HD organization in keratinocytes. Screening with inhibitors identified the depletion of HD components and HD-like structures through Wnt inhibition, but keratinocyte differentiation was not affected. Wnt inhibition significantly diminished plectin and type XVII collagen expression in the basal side of Wnt-inhibited cells and the dermo-epidermal junction of the Wnt-inactive murine basal epidermis. Similar to Wnt inhibition, PLEC-knockout cells or cells with plectin-type XVII collagen binding defects showed type XVII collagen reduction in the basal side of the cells, implying the possible involvement of Wnt/β-catenin signaling in HD assembly. Atypical protein kinase C inhibition ameliorated the phenotypes of Wnt-inhibited cells. These findings show that Wnt/β-catenin signaling regulates the localization of HD components in keratinocytes and that the atypical protein kinase C pathway is involved in Wnt inhibition‒induced HD disarrangement. Our study suggests that the Wnt signaling pathway could be a potential therapeutic target for treating HD-defective diseases, such as epidermolysis bullosa. - Cas9-guided haplotyping of three truncation variants in autosomal recessive disease.
Ken Natsuga, Yoshikazu Furuta, Shota Takashima, Takuma Nohara, Hsin-Yu Huang, Satoru Shinkuma, Hideki Nakamura, Yousuke Katsuda, Hideaki Higashi, Chao-Kai Hsu, Satoshi Fukushima, Hideyuki Ujiie
Human mutation, 43, 7, 877, 881, 21 Apr. 2022, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal, An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient's gene, it is challenging to determine which two of the variants are responsible for the disease phenotype. Here, to decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5' and 3' variants was approximately 19 kb at the level of genomic DNA. nCATS successfully demonstrated that the most 5' and 3' variants were located in one allele while the variant in between was located in the other allele. Interestingly, the proband's mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study highlights the usefulness of nCATS as a tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can determine which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied. - Detection of revertant mosaicism in epidermolysis bullosa through Cas9-targeted long-read sequencing.
Ken Natsuga, Yoshikazu Furuta, Shota Takashima, Takuma Nohara, Hideyuki Kosumi, Yosuke Mai, Hideaki Higashi, Hideyuki Ujiie
Human mutation, 43, 4, 529, 536, Apr. 2022, [Peer-reviewed], [Lead author, Last author], [International Magazine]
English, Scientific journal, Revertant mosaicism (RM) is a phenomenon in which inherited mutations are spontaneously corrected in somatic cells. RM occurs in some congenital skin diseases, but genetic validation of RM in clinically revertant skin has been challenging, especially when homologous recombination (HR) is responsible for RM. Here, we introduce nanopore Cas9-targeted sequencing (nCATS) for identifying HR in clinically revertant skin. We took advantage of compound heterozygous COL7A1 mutations in a patient with recessive dystrophic epidermolysis bullosa who showed revertant skin spots. Cas9-mediated enrichment of genomic DNA (gDNA) covering the two mutation sites (>8 kb) in COL7A1 and subsequent MinION sequencing successfully detected intragenic crossover in the epidermis of the clinically revertant skin. This method enables the discernment of haplotypes of up to a few tens of kilobases of gDNA. Moreover, it is devoid of polymerase chain reaction amplification, which can technically induce recombination. We, therefore, propose that nCATS is a powerful tool for understanding complicated gene modifications, including RM. - New insight of itch mediators and proinflammatory cytokines in epidermolysis bullosa
Hong Ha Nguyen, Satoru Shinkuma, Ryota Hayashi, Tatsuya Katsumi, Tomoki Nishiguchi, Ken Natsuga, Yasuyuki Fujita, Riichiro Abe
Journal of Cutaneous Immunology and Allergy, 5, 3, 78, 87, Frontiers Media SA, 07 Feb. 2022, [Peer-reviewed] - Prevention of chemotherapy-induced hair loss by peroxisome proliferator-activated receptor-γ modulation.
K Natsuga
The British journal of dermatology, 186, 1, 14, 15, Jan. 2022, [Peer-reviewed], [Invited], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal - IgA nephropathy preceded by erythroderma with eosinophilia.
Mina Takatsu, Ken Natsuga, Fumihiko Hattanda, Hideyuki Ujiie
European journal of dermatology : EJD, 32, 1, 127, 129, 01 Jan. 2022, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal - Case of inherited epidermolysis bullosa simplex with KLHL24 gene mutation in Japan.
Tomoko Miyake, Ken Natsuga, Takatsune Umayahara, Seiko Naito, Junko Yoshimoto, Akemi Senoo, Han-Tang Wang, Chao-Kai Hsu, Osamu Yamasaki, Shin Morizane
The Journal of dermatology, 49, 1, e24-e25, Jan. 2022, [Peer-reviewed], [International Magazine]
English - Current topics in Epidermolysis bullosa: Pathophysiology and therapeutic challenges.
Ken Natsuga, Satoru Shinkuma, Chao-Kai Hsu, Yasuyuki Fujita, Akira Ishiko, Katsuto Tamai, John A McGrath
Journal of dermatological science, 104, 3, 164, 176, Dec. 2021, [Peer-reviewed], [Invited], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal, Epidermolysis bullosa (EB) is a group of inherited skin and mucosal fragility disorders resulting from mutations in genes encoding basement membrane zone (BMZ) components or proteins that maintain the integrity of BMZ and adjacent keratinocytes. More than 30 years have passed since the first causative gene for EB was identified, and over 40 genes are now known to be responsible for the protean collection of mechanobullous diseases included under the umbrella term of EB. Through the elucidation of disease mechanisms using human skin samples, animal models, and cultured cells, we have now reached the stage of developing more effective therapeutics for EB. This review will initially focus on what is known about blister wound healing in EB, since recent and emerging basic science data are very relevant to clinical translation and therapeutic strategies for patients. We then place these studies in the context of the latest information on gene therapy, read-through therapy, and cell therapy that provide optimism for improved clinical management of people living with EB. - Unilateral Naevoid Telangiectasia Associated with Oral Contraceptive.
Takuma Nohara, Ken Natsuga, Atsushi Yasuoka, Hideyuki Ujiie
Acta dermato-venereologica, 101, 11, adv00595, 17 Nov. 2021, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal - Complexity of Transcriptional and Translational Interference of Laminin-332 Subunits in Junctional Epidermolysis Bullosa with LAMB3 Mutations.
Ping-Chen Hou, Ken Natsuga, Wei-Ting Tu, Hsin-Yu Huang, Brandon Chen, Liang-Yu Chen, Wan-Rung Chen, Yi-Kai Hong, Yen-An Tang, Julia Yu-Yun Lee, Peng-Chieh Chen, H Sunny Sun, John A McGrath, Chao-Kai Hsu
Acta dermato-venereologica, 101, 8, adv00522, 24 Aug. 2021, [Peer-reviewed], [Lead author], [International Magazine]
English, Scientific journal - Successful kidney transplantation in a patient with neonatal-onset ILNEB.
Takayuki Okamoto, Akie Nakamura, Asako Hayashi, Takeshi Yamaguchi, Yayoi Ogawa, Ken Natsuga, Kumiko Yanagi, Kiyohiko Hotta
Pediatric transplantation, 25, 5, e13971, Aug. 2021, [Peer-reviewed], [International Magazine]
English, BACKGROUND: ILNEB constitute an autosomal recessive disorder caused by homozygous or compound heterozygous mutation of the gene for the ITGA3. To date, 8 ILNEB patients have been reported, but all 6 neonatal-onset ILNEB patients suffered early death within 2 years. The most common cause of death among previously reported ILNEB patients was exacerbation of the respiratory condition. METHODS: In this study, we describe a case of ILNEB with neonatal onset in a female patient and the genetic and histopathological testing performed. RESULTS: Our patient had a compound heterozygous mutation in ITGA3. Compared to previously reported patients, this patient exhibited milder clinical and histopathological characteristics. After experiencing a life-threatening respiratory infection at 8 months old, the patient started periodic subcutaneous immunoglobulin treatment once every 1-2 weeks for nephrotic-range proteinuria-induced secondary hypogammaglobulinemia. At the age of 3 years, proteinuria gradually increased with severe edema despite strict internal management. Therefore, our patient underwent unilateral nephrectomy and insertion of a peritoneal dialysis catheter followed by another unilateral nephrectomy. One month later, she underwent an ABO-compatible living-donor kidney transplantation at the age of 4 years. CONCLUSIONS: Our patient is a neonatal-onset ILNEB patient who survived for more than 2 years and underwent successful kidney transplantation. - The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia.
Kei Kozawa, Miho Sekai, Kenji Ohba, Shoko Ito, Hiroaki Sako, Takeshi Maruyama, Mai Kakeno, Takanobu Shirai, Keisuke Kuromiya, Tomoko Kamasaki, Koki Kohashi, Shinya Tanaka, Susumu Ishikawa, Nanami Sato, Shota Asano, Hironori Suzuki, Nobuyuki Tanimura, Yohei Mukai, Noriko Gotoh, Mishie Tanino, Shinya Tanaka, Ken Natsuga, Tomoyoshi Soga, Tomonori Nakamura, Yukihiro Yabuta, Mitinori Saitou, Takahiro Ito, Kenkyo Matsuura, Makoto Tsunoda, Toyone Kikumori, Tadashi Iida, Yasuyuki Mizutani, Yuki Miyai, Kozo Kaibuchi, Atsushi Enomoto, Yasuyuki Fujita
Current biology : CB, 31, 14, 3086, 3097, 26 Jul. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions. - Hair follicle stem cell progeny heal blisters while pausing skin development.
Yu Fujimura, Mika Watanabe, Kota Ohno, Yasuaki Kobayashi, Shota Takashima, Hideki Nakamura, Hideyuki Kosumi, Yunan Wang, Yosuke Mai, Andrea Lauria, Valentina Proserpio, Hideyuki Ujiie, Hiroaki Iwata, Wataru Nishie, Masaharu Nagayama, Salvatore Oliviero, Giacomo Donati, Hiroshi Shimizu, Ken Natsuga
EMBO reports, 22, 7, e50882, 05 Jul. 2021, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases. - A computational model of the epidermis with the deformable dermis and its application to skin diseases.
Kota Ohno, Yasuaki Kobayashi, Masaaki Uesaka, Takeshi Gotoda, Mitsuhiro Denda, Hideyuki Kosumi, Mika Watanabe, Ken Natsuga, Masaharu Nagayama
Scientific reports, 11, 1, 13234, 13234, 24 Jun. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, The skin barrier is provided by the organized multi-layer structure of epidermal cells, which is dynamically maintained by a continuous supply of cells from the basal layer. The epidermal homeostasis can be disrupted by various skin diseases, which often cause morphological changes not only in the epidermis but in the dermis. We present a three-dimensional agent-based computational model of the epidermis that takes into account the deformability of the dermis. Our model can produce a stable epidermal structure with well-organized layers. We show that its stability depends on the cell supply rate from the basal layer. Modeling the morphological change of the dermis also enables us to investigate how the stiffness of the dermis affects the structure and barrier functions of the epidermis. Besides, we show that our model can simulate the formation of a corn (clavus) by assuming hyperproliferation and rapid differentiation. We also provide experimental data for human corn, which supports the model assumptions and the simulation result. - Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism.
Toshinari Miyauchi, Shotaro Suzuki, Masae Takeda, Jin Teng Peh, Masayuki Aiba, Ken Natsuga, Yasuyuki Fujita, Takuya Takeichi, Taiko Sakamoto, Masashi Akiyama, Hiroshi Shimizu, Toshifumi Nomura
American journal of human genetics, 108, 6, 1026, 1039, 03 Jun. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, Revertant mosaicism, or "natural gene therapy," refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases. - Zonula occludens-1 demonstrates a unique appearance in buccal mucosa over several layers.
Keisuke Imafuku, Mayumi Kamaguchi, Ken Natsuga, Hideki Nakamura, Hiroshi Shimizu, Hiroaki Iwata
Cell and tissue research, 384, 3, 691, 702, Jun. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, Tight junctions (TJs) firmly seal epithelial cells and are key players in the epithelial barrier. TJs consist of several proteins, including those of the transmembrane claudin family and the scaffold zonula occludens (ZO) family. Epithelial tissues are exposed to different conditions: to air in the stratified epithelium of the skin and to liquids in the monolayer of the intestine. The TJs in stratified oral mucosal epithelium have remained insufficiently elucidated in terms of distributions, appearances and barrier functions of TJ proteins in normal buccal mucosa. We investigated these and ZO-1 and claudin-1 were found to be expressed in the top third and in the bottom three quarters of the mucosal epithelium. ZO-1 in the buccal mucosa was found to have an irregular linear appearance. ZO-1 in the buccal mucosa continuously existed in several layers. Electron microscopy revealed the buccal mucosa to have kissing points. In a biotin permeation assay that sought to investigate inside-outside barrier function, the biotin tracer penetrated several ZO-1 layers but did not pass through all the ZO-1 layers. We found that the oral mucosal cell knockdown of TJP1 or CLDN1 resulted in decreases of TER but no significant change in FITC-dextran leakage. Our results suggest that the distribution and appearance of ZO-1 in the buccal mucosa differ from those in the skin. We were unable to prove barrier function in this study but we did show barrier function against small molecules in vivo and against ions in vitro. - A case of non-bullous pemphigoid induced by IgG4 autoantibodies targeting BP230.
N Yoshimoto, S Takashima, T Kawamura, E Inamura, T Sugai, I Ujiie, K Izumi, K Natsuga, W Nishie, H Shimizu, H Ujiie
Journal of the European Academy of Dermatology and Venereology : JEADV, 35, 4, e282-e285, Apr. 2021, [Peer-reviewed], [International Magazine]
English - Intravenous allogeneic multilineage-differentiating stress-enduring cells in adults with dystrophic epidermolysis bullosa: a phase 1/2 open-label study.
Y Fujita, T Nohara, S Takashima, K Natsuga, M Adachi, K Yoshida, S Shinkuma, T Takeichi, H Nakamura, O Wada, M Akiyama, A Ishiko, H Shimizu
Journal of the European Academy of Dermatology and Venereology : JEADV, 03 Mar. 2021, [Peer-reviewed], [International Magazine]
English - A case of mucous membrane pemphigoid with anti-BP230 autoantibodies alone.
Norihiro Yoshimoto, Inkin Ujiie, Emi Inamura, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu, Hideyuki Ujiie
International journal of dermatology, 60, 3, e92-e94, Mar. 2021, [Peer-reviewed], [International Magazine]
English - Five novel mutations in SASH1 contribute to lentiginous phenotypes in Japanese families.
Yuta Araki, Ken Okamura, Toru Saito, Kazuhiko Matsumoto, Ken Natsuga, Junko Nishimoto, Yoko Funasaka, Yaei Togawa, Tamio Suzuki
Pigment cell & melanoma research, 34, 2, 174, 178, Mar. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun-exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun-exposed areas, using next-generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression. - Dominance of Methicillin-Resistant Staphylococcus aureus in a Japanese Infant with Recessive Dystrophic Epidermolysis Bullosa.
Makoto Kondo, Shota Takashima, Hiroyuki Goto, Koji Habe, Ken Natsuga, Keiichi Yamanaka
Case reports in dermatology, 13, 2, 278, 281, 2021, [Peer-reviewed], [International Magazine]
English, A male infant had the very fragile skin and easily formed bullas by rubbing and scratching from his birth. He was diagnosed with severe recessive dystrophic epidermolysis bullosa (RDEB) due to the lack of type VII collagen by performing an immunofluorescence mapping method from a skin biopsy specimen of the patient's bulla. We analyzed the skin microbiome using next-generation sequencer. The species from the patient's skin revealed the dominance of Staphylococcus aureus (S. aureus) similar to the reports from Austria and Chile severe RDEB patients, and these results are same as the pattern isolated from the skin of atopic dermatitis (AD) patients with flares. The interaction of microbiome and skin microenvironment may be similar between RDEB and AD worldwide. - Type XVII collagen interacts with the aPKC-PAR complex and maintains epidermal cell polarity.
Mika Watanabe, Hideyuki Kosumi, Shin-Ichi Osada, Shota Takashima, Yunan Wang, Wataru Nishie, Tsukasa Oikawa, Tomonori Hirose, Hiroshi Shimizu, Ken Natsuga
Experimental dermatology, 30, 1, 62, 67, Jan. 2021, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English, Scientific journal, Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes. - Calcinosis cutis in self-healing dominant dystrophic epidermolysis bullosa.
Shota Takashima, Yasuyuki Fujita, Satoru Shinkuma, Satoko Shimizu, Tomoka Hasegawa, Norio Amizuka, Hiroshi Shimizu, Ken Natsuga
The Journal of dermatology, 47, 12, e457-e458, Dec. 2020, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
English - Contribution of GATA6 to homeostasis of the human upper pilosebaceous unit and acne pathogenesis.
Bénédicte Oulès, Christina Philippeos, Joe Segal, Matthieu Tihy, Matteo Vietri Rudan, Ana-Maria Cujba, Philippe A Grange, Sven Quist, Ken Natsuga, Lydia Deschamps, Nicolas Dupin, Giacomo Donati, Fiona M Watt
Nature communications, 11, 1, 5067, 5067, 20 Oct. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal, Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne. - Multidisciplinary care of epidermolysis bullosa during the COVID-19 pandemic-Consensus: Recommendations by an international panel of experts.
Dedee F Murrell, Anne W Lucky, Julio C Salas-Alanis, David T Woodley, Francis Palisson, Ken Natsuga, Milos Nikolic, Mae Ramirez-Quizon, Amy S Paller, Irene Lara-Corrales, Mohammadreza Amir Barzegar, Eli Sprecher, Cristina Has, Martin Laimer, Anna L Bruckner, Asli Bilgic, Arti Nanda, Diana Purvis, Alain Hovnanian, Slobodna Murat-Sušić, Johannes Bauer, Johannes S Kern, Christine Bodemer, Linda K Martin, Jemima Mellerio, Cezary Kowaleski, Susan J Robertson, Leena Bruckner-Tuderman, Elena Pope, M Peter Marinkovich, Jean Y Tang, John Su, Jouni Uitto, Lawrence F Eichenfield, Joyce Teng, Mark Jean Aan Koh, Sang Eun Lee, Phuong Khuu, Heather I Rishel, Mette Sommerlund, Karen Wiss, Chao-Kai Hsu, Tor Wo Chiu, Anna E Martinez
Journal of the American Academy of Dermatology, 83, 4, 1222, 1224, Oct. 2020, [Peer-reviewed], [International Magazine]
English - Plectin Missense Mutation p.Leu319Pro in the Pathogenesis of Autosomal Recessive Epidermolysis Bullosa Simplex.
Wei-Ting Tu, Peng-Chieh Chen, Ping-Chen Hou, Hsin-Yu Huang, Jing-Yu Wang, Sheau-Chiou Chao, Julia Yu-Yun Lee, John A McGrath, Ken Natsuga, Chao-Kai Hsu
Acta dermato-venereologica, 100, 15, adv00242, 18 Aug. 2020, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, is missing (Short communication). - Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.
E Inamura, W Nishie, Y Yamaguchi, Y Fujimura, H Ujiie, K Natsuga, H Shimizu
The British journal of dermatology, 182, 4, 1061, 1062, Apr. 2020, [Peer-reviewed], [International Magazine]
English - Speckled lentiginous nevus in a patient with Hermansky-Pudlak syndrome type 1.
Shoko Mai, Wataru Nishie, Yosuke Mai, Ken Natsuga, Toshifumi Nomura, Shotaro Suzuki, Yuta Araki, Tamio Suzuki, Hiroshi Shimizu
The Journal of dermatology, 47, 1, e20-e21, Jan. 2020, [Peer-reviewed], [International Magazine]
English - Life before and beyond blistering: The role of collagen XVII in epidermal physiology.
Ken Natsuga, Mika Watanabe, Wataru Nishie, Hiroshi Shimizu
Experimental dermatology, 28, 10, 1135, 1141, Wiley, Oct. 2019, [Peer-reviewed], [Invited], [Lead author, Last author], [International Magazine]
English, Type XVII collagen (COL17) is a transmembranous protein that is mainly expressed in the epidermal basal keratinocytes. Epidermal-dermal attachment requires COL17 expression at the hemidesmosomes of the epidermal basement membrane zone because congenital COL17 deficiency leads to junctional epidermolysis bullosa and acquired autoimmunity to COL17 induces bullous pemphigoid. Recently, in addition to facilitating epidermal-dermal attachment, COL17 has been reported to serve as a niche for hair follicle stem cells, to regulate proliferation in the interfollicular epidermis and to be present along the non-hemidesmosomal plasma membrane of epidermal basal keratinocytes. This review focuses on the physiological properties of COL17 in the epidermis, its role in maintaining stem cells and its association with signalling pathways. We propose possible solutions to unanswered questions in this field. - Efficient Gene Reframing Therapy for Recessive Dystrophic Epidermolysis Bullosa with CRISPR/Cas9.
Shota Takashima, Satoru Shinkuma, Yasuyuki Fujita, Toshifumi Nomura, Hideyuki Ujiie, Ken Natsuga, Hiroaki Iwata, Hideki Nakamura, Artem Vorobyev, Riichiro Abe, Hiroshi Shimizu
The Journal of investigative dermatology, 139, 8, 1711, 1721, Aug. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system induces site-specific double-strand breaks, which stimulate cellular DNA repair through either the homologous recombination or non-homologous end-joining pathways. The non-homologous end-joining pathway, which is activated more frequently than homologous recombination, is prone to introducing small insertions and/or deletions at the double-strand break site, leading to changes in the reading frame. We hypothesized that the non-homologous end-joining pathway is applicable to genetic diseases caused by a frameshift mutation through restoration of the reading frame. Recessive dystrophic epidermolysis bullosa is a hereditary skin disorder caused by mutations in COL7A1. In this study, we applied gene reframing therapy to a recurrent frameshift mutation, c.5819delC, in COL7A1, which results in a premature termination codon. CRISPR/Cas9 targeting this specific mutation site was delivered to recessive dystrophic epidermolysis bullosa patient fibroblasts. After genotyping a large collection of gene-edited fibroblast clones, we identified a significant number (17/50) of clones in which the frameshift in COL7A1 was restored. The reframed COL7 was functional, as shown by triple-helix formation assay in vitro, and was correctly distributed in the basement membrane zone in mice. Our data suggest that mutation site-specific non-homologous end-joining might be a highly efficient gene therapy for inherited disorders caused by frameshift mutations. - Mutant Lef1 controls Gata6 in sebaceous gland development and cancer.
Bénédicte Oulès, Emanuel Rognoni, Esther Hoste, Georgina Goss, Ryan Fiehler, Ken Natsuga, Sven Quist, Remco Mentink, Giacomo Donati, Fiona M Watt
The EMBO journal, 38, 9, 02 May 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer. - Multiple cutaneous reticulohistiocytomas after haematopoietic cell transplantation: contribution of donor- and host-derived cells.
H Kosumi, K Natsuga, M Watanabe, K Okada, H Shimizu
The British journal of dermatology, 180, 3, 680, 681, Mar. 2019, [Peer-reviewed], [Corresponding author], [International Magazine]
English - Image Gallery: Multiple localized lipoatrophy in recessive dystrophic epidermolysis bullosa.
T Nohara, Y Fujita, S Takashima, K Natsuga, H Shimizu
The British journal of dermatology, 180, 3, e64, Mar. 2019, [Peer-reviewed], [International Magazine]
English - Fc-binding proteins enhance autoantibody-induced BP180 depletion in pemphigoid.
Hiroaki Iwata, Mayumi Kamaguchi, Hideyuki Ujiie, Inkin Ujiie, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu
The Journal of pathology, 247, 3, 371, 380, Mar. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Immunoglobulins (Igs) consist of two antigen-binding regions (Fab) and one constant region (Fc). Protein A and protein G are bacterial proteins used for the purification of IgG by virtue of their high affinities for the Fc fragment. Rheumatoid factors are autoantibodies against IgG Fc fragments, which are present in the body under physiological conditions. Little is known about the influence of Fc-binding proteins on the pathogenicity of antibody-induced autoimmune diseases. Pemphigoid diseases are a group of autoimmune subepidermal blistering disorders that includes bullous pemphigoid and mucous membrane pemphigoid. IgGs targeting the non-collagenous NC16A domain of the 180-kDa bullous pemphigoid antigen (BP180) are known to induce skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, mAb against NC16A in combination with Fc-binding proteins was found to enhance BP180 depletion. Although mAb against the C-terminus of BP180 does not show pathogenicity in vivo or in vitro, mAb treatment with Fc-binding proteins clearly induced skin fragility in mice and BP180 depletion in keratinocytes. Anti-BP180 mAbs and Fc-binding proteins were colocalized in the cytoplasm and at the basement membrane zone. Cell adhesion strengths were decreased in parallel with BP180 amounts. Clinically, bullous pemphigoid patients had higher rheumatoid factor titers than controls. Anti-BP180 mAb in combination with high-titer rheumatoid factor serum was found to enhance BP180 depletion. Furthermore, saliva from mucous membrane pemphigoid patients contained larger quantities of bacteria and Fc-binding proteins than controls. Our results suggest that Fc-binding proteins (rheumatoid factor or protein G) may enhance the pathogenicity of autoantibodies in pemphigoid diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. - A Nodular Lesion of the Foot Detected by 18F-FDG PET/CT in Mycosis Fungoides: A Plantar Wart.
Yasuyuki Fujita, Ken Natsuga, Osamu Manabe, Kenji Hirata, Hiroshi Shimizu
Clinical nuclear medicine, 44, 3, 244, 245, Mar. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, A 34-year-old Japanese woman presented with widespread scaly erythema that had enlarged over 2 years. A skin biopsy revealed the diagnosis of mycosis fungoides (patch stage, T1b N0 M0 B0), a most frequent cutaneous T-cell lymphoma. F-FDG PET/CT scan unexpectedly showed intense uptake on the left sole, which suggested a tumorous mycosis fungoides lesion (SUVmax = 6.2). Careful examination revealed the mass to be a typical plantar wart of 2 cm in diameter that the patient had not recognized. With repeated cryotherapy, the wart disappeared in 6 months, and follow-up F-FDG PET/CT showed no abnormal uptake on the left sole. - Congenital nevi with hypomelanosis and fine scales.
Ken Natsuga, Naoki Oiso, Ichiro Kurokawa, Airo Tsubura, Hideki Nakamura, Yuka Maya, Wataru Nishie, Akira Kawada, Hiroshi Shimizu
European journal of dermatology : EJD, 29, 1, 45, 48, 01 Feb. 2019, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
English, Scientific journal, BACKGROUND: Nevus is a hamartoma or malformation of one or more skin components, resulting in aberrant differentiation of the cell lineage(s) mostly during developmental stages. Although multiple lineages may be involved in a nevus, the combination of melanocyte and keratinocyte abnormalities has been rarely discussed. OBJECTIVES: To present two cases of congenital nevi with hypomelanosis and superficial fine scales. MATERIALS & METHODS: Skin specimens of the patients were analysed by immunohistochemistry and electron microscopy. RESULTS: Morphological and immunohistochemical studies indicated aberrant epidermal differentiation in the lesional skin specimens. Electron microscopy showed defective melanosome maturation in the melanocytes of the nevi samples. CONCLUSION: These results demonstrate that both epidermal and melanocytic lineages can concomitantly contribute to the formation of a nevus lesion. - Immune Reaction to Type XVII Collagen Induces Intramolecular and Intermolecular Epitope Spreading in Experimental Bullous Pemphigoid Models.
Hideyuki Ujiie, Norihiro Yoshimoto, Ken Natsuga, Ken Muramatsu, Hiroaki Iwata, Wataru Nishie, Hiroshi Shimizu
Frontiers in immunology, 10, 1410, 1410, 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Bullous pemphigoid (BP), the most common autoimmune blistering disease, is induced by autoantibodies to type XVII collagen (COL17). Previous studies demonstrated that COL17 harbors several epitopes targeted by autoreactive T and B cells and that the target epitopes change sequentially during the disease course. To elucidate the details of the humoral immune response to COL17, we used an active BP mouse model in which BP is induced by the adoptive transfer of spleen cells from wild-type mice immunized with human COL17-expressing skin grafting to immunodeficient COL17-humanized (Rag-2-/-, mouse Col17-/-, human COL17+) mice. By immunoblot analysis, antibodies to the NC16A domain and other extracellular domains (ECDs) of COL17 were detected earlier than antibodies to intracellular domains (ICDs) in the active BP model. Time course analysis by enzyme-linked immunosorbent assay demonstrated a delayed peak of antibodies to ICD epitopes in active BP model. The blockade of CD40-CD40 ligand interaction soon after the adoptive transfer suppressed the production of antibodies to the non-collagenous 16A (NC16A) domain but not to an ICD epitope, suggesting the sequential activation from T and B cells against the ECD epitopes including the NC16A domain to those against ICD epitopes in vivo. Both wild-type mice immunized with a fragment of the NC16A domain and the recipients of those spleen cells produced IgG antibodies to ICD and ECD epitopes, showing intramolecular epitope spreading from the NC16A domain to other epitopes of COL17. Furthermore, we found that a portion of the active BP model mice show intermolecular epitope spreading from human COL17 to murine BP230. The appearance of antibodies to ICD epitopes of COL17 or of antibodies to murine BP230 did not correlate with the skin changes in the mice, suggesting that those antibodies have low pathogenicity. These results suggest that the immune response to the ECD epitopes of COL17, especially to the NC16A domain, triggers intramolecular, and intermolecular epitope spreading to ICD epitopes of COL17 and to murine BP230. These novel findings provide insight into the mechanism of epitope spreading in organ-specific, antibody-mediated autoimmune disorders. - The direct binding of collagen XVII and collagen IV is disrupted by pemphigoid autoantibodies.
Mayumi Kamaguchi, Hiroaki Iwata, Wataru Nishie, Ellen Toyonaga, Hideyuki Ujiie, Ken Natsuga, Yoshimasa Kitagawa, Hiroshi Shimizu
Laboratory investigation; a journal of technical methods and pathology, 99, 1, 48, 57, Springer Nature America, Inc, Jan. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, The basement membrane zone (BMZ) is framed by hemidesmosomes and extracellular matrix (ECM) including collagen IV (COL4). Hemidesmosomes are multiprotein complexes that include collagen XVII (COL17). BMZ proteins can be targeted in autoimmune subepidermal blistering diseases, e.g., pemphigoid targeting COL17. The blistering mechanisms in pemphigoid have not been fully elucidated, especially in mucous membrane pemphigoid (MMP), which mainly affects the mucosa. In this study, we showed that oral lesions in pemphigoid may be attributed to the inhibition of protein-protein interactions by autoantibodies. Using immunoprecipitation, we revealed that COL17 directly binds to COL4 in normal human keratinocytes and normal human oral keratinocytes. In particular, the C-terminus of COL17 is binding site to COL4 in oral keratinocytes. The precise COL4-binding region on COL17 was determined by protein-protein binding assay to be from amino acid Gly1175 to Asp1340 on the C-terminus. MMP-IgG or mAb recognizing the C-terminus hindered the interaction of COL17 with COL4 in oral keratinocytes. Furthermore, keratinocyte adhesion strength to COL4-coated plates was significantly reduced by the treatment of mAb against the C-terminus. In addition, the inflammatory infiltrates around perilesions were significantly less in MMP compared to BP. These results indicate that pemphigoid IgG targeting the C-terminus plays a pathogenic role in blister formation in the oral mucosa to inhibit protein interactions with less inflammation. - Bullous Pemphigoid IgG Induces Cell Dysfunction and Enhances the Motility of Epidermal Keratinocytes via Rac1/Proteasome Activation.
Duerna Tie, Xia Da, Ken Natsuga, Nanako Yamada, Osamu Yamamoto, Eishin Morita
Frontiers in immunology, 10, 200, 200, 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Bullous pemphigoid (BP) is an autoimmune disease characterized by the formation of blisters, in which autoantibodies mainly target type XVII collagen (ColXVII) expressed in basal keratinocytes. BP IgG is known to induce the internalization of ColXVII from the plasma membrane of keratinocytes through macropinocytosis. However, the cellular dynamics following ColXVII internalization have not been completely elucidated. BP IgG exerts a precise effect on cultured keratinocytes, and the morphological/functional changes in BP IgG-stimulated cells lead to the subepidermal blistering associated with BP pathogenesis. Based on the electron microscopy examination, BP IgG-stimulated cells exhibit alterations in the cell membrane structure and the accumulation of intracellular vesicles. These morphological changes in the BP IgG-stimulated cells are accompanied by dysfunctional mitochondria, increased production of reactive oxygen species, increased motility, and detachment. BP IgG triggers the cascade leading to metabolic impairments and stimulates cell migration in the treated keratinocytes. These cellular alterations are reversed by pharmacological inhibitors of Rac1 or the proteasome pathway, suggesting that Rac1 and proteasome activation are involved in the effects of BP IgG on cultured keratinocytes. Our study highlights the role of keratinocyte kinetics in the direct functions of IgG in patients with BP. - Interplay between epidermal stem cell dynamics and dermal deformation
Yasuaki Kobayashi, Yusuke Yasugahira, Hiroyuki Kitahata, Mika Watanabe, Ken Natsuga, Masaharu Nagayama
npj Computational Materials, 4, Dec. 2018, [Peer-reviewed]
English, Scientific journal - Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects.
Ken Muramatsu, Hideyuki Ujiie, Ichiro Kobayashi, Wataru Nishie, Kentaro Izumi, Takamasa Ito, Norihiro Yoshimoto, Ken Natsuga, Hiroaki Iwata, Hiroshi Shimizu
The Journal of allergy and clinical immunology, 142, 6, 1818, 1830, Dec. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, BACKGROUND: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear. OBJECTIVE: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6-/- scurfy mice and scurfy mice. RESULTS: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype. CONCLUSIONS: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo. - Novel COL7A1 mutation in a family with bullous dermolysis of the newborn: Phenotypic variability associated with a COL7A1 mutation within the same family.
Shota Takashima, Satoru Shinkuma, Yasuyuki Fujita, Ken Natsuga, Toshifumi Nomura, Tokimasa Hida, Shuku Ishikawa, Hideki Nakamura, Riichiro Abe, Hiroshi Shimizu
The Journal of dermatology, 45, 9, e260-e261, e261, Sep. 2018, [Peer-reviewed], [International Magazine]
English - Remission of Cutaneous Involvement in Splenic Marginal Zone Lymphoma after Splenectomy.
Shoko Mai, Ken Natsuga, Souichi Shiratori, Yoshimasa Takahashi, Hiroshi Shimizu
Acta dermato-venereologica, 98, 8, 801, 802, 29 Aug. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal - High Expression of Collagen XVII Compensates for its Depletion Induced by Pemphigoid IgG in the Oral Mucosa.
Mayumi Kamaguchi, Hiroaki Iwata, Hideyuki Ujiie, Ken Natsuga, Wataru Nishie, Yoshimasa Kitagawa, Hiroshi Shimizu
The Journal of investigative dermatology, 138, 8, 1707, 1715, Aug. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, The basement membrane zone consists of multiple components, including collagen XVII (COL17), which is the target of bullous pemphigoid. To our knowledge, no research has addressed the differences in basement membrane zone components between the skin and oral mucosa; therefore, we investigated the basement membrane zone proteins, with a focus on COL17. The mRNA and protein expression levels of COL17 were significantly higher in oral keratinocytes than in skin keratinocytes. Hemidesmosomal COL17 expression was markedly higher in oral keratinocytes than in skin keratinocytes, and its level was associated with adhesion strength. Oral keratinocytes adhered to the extracellular matrix more tightly than did skin keratinocytes in vitro. Based on these results, we attempt to explain the clinical diversity of bullous pemphigoid. COL17 depletion was more prominent in skin keratinocytes than in oral keratinocytes after treatment with COL17-NC16A mAbs, which have in vivo pathogenicity. COL17 C-terminus mAbs, which are not pathogenic, facilitated COL17 depletion in combination treatment with COL17-NC16A mAbs in both types of keratinocytes. In summary, the greater amount of COL17 in oral keratinocytes than in skin keratinocytes is associated with the higher strength of oral keratinocyte hemidesmosomal adhesion at the basement membrane zone. Our results may explain why bullous pemphigoid blistering tends to be more prevalent in the skin than in the oral mucosa. - Acute vascular reaction due to lipo-prostaglandin E1.
Y Fujimura, M Watanabe, K Natsuga, H Shimizu
Journal of the European Academy of Dermatology and Venereology : JEADV, 32, 7, e273-e274, Jul. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English - Sweet's Syndrome Mimicking Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis.
Hideyuki Kosumi, Mika Watanabe, Ken Natsuga, Toshinari Miyauchi, Chihiro Shiiya, Hideyuki Ujiie, Hiroshi Shimizu
The American journal of medicine, 131, 6, e241-e242, e242, Jun. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English - Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models.
Tetsumasa Sasaoka, Hideyuki Ujiie, Wataru Nishie, Hiroaki Iwata, Makoto Ishikawa, Hiroshi Higashino, Ken Natsuga, Satoru Shinkuma, Hiroshi Shimizu
The Journal of investigative dermatology, 138, 6, 1260, 1267, Jun. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies to COL17. Currently, systemic corticosteroids are used as first-line treatments for BP; alternatively, intravenous administration of high-dose IgG (IVIG) has been shown to be effective for patients with steroid-resistant BP in clinical practice. However, the effect of IVIG on BP has not fully been investigated. To examine the effects and mechanisms of action of IVIG against BP, we performed IVIG experiments using two experimental BP mouse models. One is a passive-transfer BP model that reproduces subepidermal separation in neonatal mice by the passive transfer of IgGs against COL17, such as polyclonal or monoclonal mouse IgG or IgG from BP patients. The other is an active BP model that continuously develops a disease phenotype in adult mice. IVIG decreased pathogenic IgG and the disease scores in both models. Injected IVIG distributed throughout the dermis and the intercellular space of the lower epidermis. Notably, IVIG inhibited the increase of IL-6 in both models, possibly by suppressing the production of IL-6 by keratinocytes. These results suggest that the inhibitory effects of IVIG on BP are associated with the reduction of pathogenic IgG and the modulation of cytokine production. - Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita.
Mika Watanabe, Ken Natsuga, Satoru Shinkuma, Hiroshi Shimizu
The Journal of dermatology, 45, 5, 515, 521, Wiley, May 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, Type VII collagen (COL7), a major component of anchoring fibrils in the epidermal basement membrane zone, has been characterized as a defective protein in dystrophic epidermolysis bullosa and as an autoantigen in epidermolysis bullosa acquisita. Although COL7 is produced and secreted by both epidermal keratinocytes and dermal fibroblasts, the role of COL7 with regard to the epidermis is rarely discussed. This review focuses on COL7 physiology and pathology as it pertains to epidermal keratinocytes. We summarize the current knowledge of COL7 production and trafficking, its involvement in keratinocyte dynamics, and epidermal carcinogenesis in COL7 deficiency and propose possible solutions to unsolved issues in this field. - Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases.
Yasuyuki Yamaguchi, Teruki Yanagi, Kazumasa Sato, Norihiro Yoshimoto, Yu Hirata, Inkin Ujiie, Machiko Nishimura, Ken Natsuga, Chihiro Shiiya, Ichiro Tsukinaga, Hiroshi Shimizu
The Journal of dermatology, 45, 4, 483, 486, Apr. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Pyoderma gangrenosum is a chronic non-infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative-pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative-pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative-pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative-pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative-pressure wound therapy systems do. - Oral mucosa is a useful substrate for detecting autoantibodies of mucous membrane pemphigoid
M. Kamaguchi, H. Iwata, H. Ujiie, K. Izumi, K. Natsuga, W. Nishie, T. Asaka, Y. Kitagawa, H. Shimizu
British Journal of Dermatology, 178, 2, e119, e121, Blackwell Publishing Ltd, 01 Feb. 2018, [Peer-reviewed]
English - Extensive Eruptive Syringoma After Liver Transplantation.
Takuya Maeda, Ken Natsuga, Wataru Nishie, Kenichiro Yamashita, Hiroshi Shimizu
Acta dermato-venereologica, 98, 1, 119, 120, 12 Jan. 2018, [Peer-reviewed], [Corresponding author], [International Magazine]
English - Appearance of antidesmocollin 1 autoantibodies leading to a vegetative lesion in a patient with pemphigus vulgaris
Y. Yamaguchi, S. Shinkuma, N. Ishii, S. Takashima, K. Natsuga, H. Ujiie, H. Iwata, T. Nomura, Y. Fujita, A. Hamasaka, K. Hamasaka, T. Hashimoto, H. Shimizu
British Journal of Dermatology, 178, 1, 294, 295, Blackwell Publishing Ltd, 01 Jan. 2018, [Peer-reviewed]
English - C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies
Ellen Toyonaga, Wataru Nishie, Kentaro Izumi, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Yoshiaki Hirako, Daisuke Sawamura, Wataru Fujimoto, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 137, 12, 2552, 2559, Dec. 2017, [Peer-reviewed]
English, Scientific journal - Loss of interaction between plectin and type XVII collagen results in epidermolysis bullosa simplex
Ken Natsuga, Wataru Nishie, Machiko Nishimura, Satoru Shinkuma, Mika Watanabe, Kentaro Izumi, Hideki Nakamura, Yoshiaki Hirako, Hiroshi Shimizu
HUMAN MUTATION, 38, 12, 1666, 1670, Dec. 2017, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Autoantibodies of non-inflammatory bullous pemphigoid hardly deplete type XVII collagen of keratinocytes
Keisuke Imafuku, Hiroaki Iwata, Mayumi Kamaguchi, Kentaro Izumi, Ken Natsuga, Hideyuki Ujiie, Wataru Nishie, Hiroshi Shimizu
Experimental Dermatology, 26, 12, 1171, 1174, Blackwell Publishing Ltd, 01 Dec. 2017, [Peer-reviewed]
English - Cutis verticis gyrata fluctuation with atopic dermatitis disease activity
Hideyuki Kosumi, Kentaro Izumi, Ken Natsuga, Yasuyuki Yamaguchi, Akira Itami, Hiroshi Shimizu
Acta Dermato-Venereologica, 97, 10, 1245, 1246, Medical Journals/Acta D-V, 01 Nov. 2017, [Peer-reviewed], [Corresponding author]
English - Detection of mucous membrane pemphigoid autoantibodies by full-length BP180 enzyme-linked immunosorbent assay
Kentaro Izumi, Wataru Nishie, Yosuke Mai, Hideyuki Ujiie, Hiroaki Iwata, Ken Natsuga, Hiroshi Shimizu
JOURNAL OF DERMATOLOGICAL SCIENCE, 88, 2, 247, 248, Nov. 2017, [Peer-reviewed]
English - A case of recessive dystrophic epidermolysis bullosa with a novel c.6885_6898de114 mutation in the COL7A1 gene
Satoru Shinkuma, Tae Masunaga, Saori Miyawaki, Shota Takashima, Ken Natsuga, Toshifumi Nomura, Yasuyuki Fujita, Hideki Nakamura, Hiroshi Shimizu
JOURNAL OF DERMATOLOGICAL SCIENCE, 88, 1, 139, 141, Oct. 2017, [Peer-reviewed]
English - Generalized Pustular Psoriasis
Hideyuki Kosumi, Takamasa Ito, Yasuyuki Fujita, Kentaro Izumi, Yuka Maya, Teruki Yanagi, Ken Natsuga, Hideyuki Ujiie, Satoru Shinkuma, Toshifumi Nomura, Naoya Sadanobu, Hiroshi Shimizu
JOURNAL OF PEDIATRICS, 188, 305, +, Sep. 2017, [Peer-reviewed]
English - Type XVII collagen coordinates proliferation in the interfollicular epidermis
Mika Watanabe, Ken Natsuga, Wataru Nishie, Yasuaki Kobayashi, Giacomo Donati, Shotaro Suzuki, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Satoru Shinkuma, Hideki Nakamura, Masamoto Murakami, Michitaka Ozaki, Masaharu Nagayama, Fiona M. Watt, Hiroshi Shimizu
ELIFE, 6, Jul. 2017, [Peer-reviewed], [Corresponding author]
English, Scientific journal - Crusted impetigo-like lesion on the face: a case of IgG/IgA pemphigus
R. Moriuchi, T. Ito, K. Kikuchi, N. Nakashita, R. Muramatsu, K. Natsuga, H. Shimizu, S. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 31, 6, E289, E290, Jun. 2017, [Peer-reviewed]
English - Psoriasiform mycosis fungoides mas-querading as tumourous plaques
Yasuyuki Yamaguchi, Yasuyuki Fujita, Yu Hirata, Machiko Nishimura, Satoru Shinkuma, Ken Natsuga, Toshifumi Nomura, Tokimasa Hida, Naoko Kato, Hiroshi Shimizu
EUROPEAN JOURNAL OF DERMATOLOGY, 27, 3, 295, 296, May 2017, [Peer-reviewed]
English - Early severe pachyonychia congenita subtype PC-K6a with a novel mutation in the KRT6A gene
F. Cammarata-Scalisi, K. Natsuga, E. Toyonaga, W. Nishie, H. Shimizu, A. Avendano, D. Araque, G. Da Silva, E. Bellacchio, M. Callea
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 31, 2, E94, E96, Feb. 2017, [Peer-reviewed]
English - Lichenoid drug eruption caused by clonazepam
K. Muramatsu, H. Ujiie, K. Natsuga, W. Nishie, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 31, 2, E117, E118, Feb. 2017, [Peer-reviewed]
English - Macropinocytosis of type XVII collagen induced by bullous pemphigoid IgG is regulated via protein kinase C
Hiroaki Iwata, Mayumi Kamaguchi, Hideyuki Ujiie, Machiko Nishimura, Kentaro Izumi, Ken Natsuga, Satoru Shinkuma, Wataru Nishie, Hiroshi Shimizu
LABORATORY INVESTIGATION, 96, 12, 1301, 1310, Dec. 2016, [Peer-reviewed]
English, Scientific journal - Generalized acute subcutaneous edema as a rare cutaneous manifestation of severe dermatomyositis
M. Watanabe, K. Natsuga, K. Arita, R. Abe, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 30, 11, E151, E152, Nov. 2016, [Peer-reviewed]
English - Two cases of erosive oral lichen planus with autoantibodies to desmoglein 3
Ken Muramatsu, Wataru Nishie, Ken Natsuga, Yasuyuki Fujita, Hiroaki Iwata, Tamaki Yamada, Emi Yamashita, Takuya Asaka, Hiroshi Shimizu
JOURNAL OF DERMATOLOGY, 43, 11, 1350, 1353, Nov. 2016, [Peer-reviewed]
English, Scientific journal - Autoantibody Profile Differentiates between Inflammatory and Noninflammatory Bullous Pemphigoid
Kentaro Izumi, Wataru Nishie, Yosuke Mai, Mayumi Wada, Ken Natsuga, Hideyuki Ujiie, Hiroaki Iwata, Jun Yamagami, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 136, 11, 2201, 2210, Nov. 2016, [Peer-reviewed]
English, Scientific journal - Galectin-6 is a novel skin anti-microbial peptide that is modulated by the skin barrier and microbiome
Ken Natsuga, Fiona M. Watt
JOURNAL OF DERMATOLOGICAL SCIENCE, 84, 1, 97, 99, Oct. 2016, [Peer-reviewed], [Lead author]
English - Stem cell markers of skin appendages in human skin tumours
K. Natsuga
BRITISH JOURNAL OF DERMATOLOGY, 175, 3, 459, 459, Sep. 2016, [Invited], [Lead author, Last author, Corresponding author]
English - Silicone medical adhesive removers for hyperkeratosis in epidermolysis bullosa
Yasuyuki Fujita, Satoru Shinkuma, Wakana Matsumura, Ken Natsuga, Hiroo Hata, Toshifumi Nomura, Hiroshi Shimizu
EUROPEAN JOURNAL OF DERMATOLOGY, 26, 5, 501, 502, Sep. 2016, [Peer-reviewed]
English - mTOR expression correlates with invasiveness and progression of extramammary Paget's disease
H. Hata, S. Kitamura, Y. Inamura, K. Imafuku, E. Homma, K. Muramatsu, K. Natsuga, R. Abe, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 30, 7, 1238, 1239, Jul. 2016, [Peer-reviewed]
English - Verrucous hyperplasia associated with neuropathy from schistorrhachis
K. Imafuku, H. Hata, Y. Inamura, S. Kitamura, K. Natsuga, H. Iwata, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 30, 5, 876, 878, May 2016, [Peer-reviewed]
English - Epitope-Dependent Pathogenicity of Antibodies Targeting a Major Bullous Pemphigoid Autoantigen Collagen XVII/BP180
Mayumi Wada, Wataru Nishie, Hideyuki Ujiie, Kentaro Izumi, Hiroaki Iwata, Ken Natsuga, Hideki Nakamura, Yoshimasa Kitagawa, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 136, 5, 938, 946, May 2016, [Peer-reviewed]
English, Scientific journal - Mucosal hyperpigmentation from prophylactic minocycline for EGFR inhibitor
K. Imafuku, K. Natsuga, S. Aoyagi, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 30, 4, 690, 692, Apr. 2016, [Peer-reviewed], [Corresponding author]
English - Metal implant-induced skin ulcer mimicking scrofuloderma
S. Kitamura, K. Natsuga, K. Imafuku, E. Homma, N. Yamane, S. Aoyagi, T. Matsumura, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 30, 3, 449, 450, Mar. 2016, [Peer-reviewed], [Corresponding author]
English - Concomitant neoplasms in the skin and stomach unveil the role of type IV collagen and E-cadherin in mucin core protein 5AC expression in vivo
H. Hata, K. Natsuga, S. Kitamura, K. Imafuku, Y. Yamaguchi, Y. Ebihara, T. Shichinohe, S. Hirano, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 174, 2, 395, 397, Feb. 2016, [Peer-reviewed]
English, Scientific journal - Pyoderma Gangrenosum Associated with Acute Respiratory Distress Syndrome
M. Watanabe, K. Natsuga, M. Ota, K. Ito
American Journal of Medicine, 129, 2, e17, e18, Elsevier Inc., 01 Feb. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal - Epidermolysis Bullosa Acquisita Develops in Dominant Dystrophic Epidermolysis Bullosa
Ryota Hayashi, Ken Natsuga, Mika Watanabe, Hiroaki Iwata, Satoru Shinkuma, Akiko Ito, Yukiko Masui, Masaaki Ito, Yutaka Shimomura
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 136, 1, 320, 323, Jan. 2016, [Peer-reviewed]
English - Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice with Reduced Cancer Susceptibility
Ken Natsuga, Sara Cipolat, Fiona M. Watt
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 136, 1, 99, 106, Jan. 2016, [Peer-reviewed], [Lead author]
English, Scientific journal - Mucocutaneous pyoderma gangrenosum due to trisomy 8 neutrophilic infiltrates in a patient with myelodysplastic syndrome
N. Haga, H. Iwata, Y. Yamaguchi, T. Shirato, K. Nishimura, N. Yamane, S. Shinkuma, K. Natsuga, T. Kondo, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 174, 1, 239, 241, Jan. 2016, [Peer-reviewed]
English - Anti-BP180-type mucous membrane pemphigoid: report of two cases
Mayumi Wada, Jun Sato, Masanobu Shindoh, Hideyuki Ujiie, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu, Yoshimasa Kitagawa
ODONTOLOGY, 104, 1, 114, 118, Jan. 2016, [Peer-reviewed]
English, Scientific journal - Anti-laminin-gamma 1 Pemphigoid with Generalized Pustular Psoriasis and Psoriasis Vulgaris
Yu Fujimura, Ken Natsuga, Yohei Hamade, Yukiko Nomura, Yo Kaku, Ryuichi Muramatsu, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 96, 1, 120, 121, 2016, [Peer-reviewed], [Corresponding author]
English, Scientific journal - Extracellular cleavage of collagen XVII is essential for correct cutaneous basement membrane formation
Machiko Nishimura, Wataru Nishie, Yoshinori Shirafuji, Satoru Shinkuma, Ken Natsuga, Hideki Nakamura, Daisuke Sawamura, Keiji Iwatsuki, Hiroshi Shimizu
HUMAN MOLECULAR GENETICS, 25, 2, 328, 339, Jan. 2016, [Peer-reviewed]
English, Scientific journal - Nodular morphoea: a first case associated with linear morphoea
Shinichi Nakazato, Toshifumi Nomura, Naoko Yamane, Satoru Shinkuma, Ken Natsuga, Yasuyuki Fujita, Ken Arita, Hiroshi Shimizu
EUROPEAN JOURNAL OF DERMATOLOGY, 26, 1, 95, 96, Jan. 2016, [Peer-reviewed]
English - Extensive Erythema and Hyperkeratosis on the Extremities and Lumbar Area as an Unusual Manifestation of Nagashima-type Palmoplantar Keratosis
Toshinari Miyauchi, Toshifumi Nomura, Shotaro Suzuki, Yuka Ohg-Uchi, Yasuyuki Yamaguchi, Satoru Shinkuma, Ken Natsuga, Yasuyuki Fujita, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 96, 6, 856, 858, 2016, [Peer-reviewed]
English - Plasma cell cheilitis extending beyond vermillion border
Yu Fujimura, Ken Natsuga, Riichiro Abe, Yusuke Morita, Toshifumi Nomura, Hiroshi Shimizu
JOURNAL OF DERMATOLOGY, 42, 9, 935, 936, Sep. 2015, [Peer-reviewed], [Corresponding author]
English - Non-solar-induced elastotic bands on the forearm
Naoya Haga, Riichiro Abe, Yusuke Morita, Yu Fujimura, Ken Natsuga, Toshifumi Nomura, Masanobu Kumakiri, Hiroshi Shimizu
EUROPEAN JOURNAL OF DERMATOLOGY, 25, 5, 508, 509, Sep. 2015, [Peer-reviewed]
English - Context-Dependent Regulation of Collagen XVII Ectodomain Shedding in Skin
Wataru Nishie, Ken Natsuga, Hiroaki Iwata, Kentaro Izumi, Hideyuki Ujiie, Ellen Toyonaga, Hiroo Hata, Hideki Nakamura, Hiroshi Shimizu
AMERICAN JOURNAL OF PATHOLOGY, 185, 5, 1361, 1371, May 2015, [Peer-reviewed]
English, Scientific journal - Skipped exon in COL7A1 determines the clinical phenotypes of dystrophic epidermolysis bullosa
E. Toyonaga, W. Nishie, M. Komine, S. Murata, S. Shinkuma, K. Natsuga, H. Nakamura, M. Ohtsuki, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 172, 4, 1141, 1144, Apr. 2015, [Peer-reviewed]
English - In vivo analysis of IgE autoantibodies in bullous pemphigoid: A study of 100 cases
Reine Moriuchi, Wataru Nishie, Hideyuki Ujiie, Ken Natsuga, Hiroshi Shimizu
JOURNAL OF DERMATOLOGICAL SCIENCE, 78, 1, 21, 25, Apr. 2015, [Peer-reviewed]
English, Scientific journal - Plectin-related skin diseases
Ken Natsuga
JOURNAL OF DERMATOLOGICAL SCIENCE, 77, 3, 139, 145, Mar. 2015, [Peer-reviewed], [Invited], [Lead author, Last author, Corresponding author]
English - Bowen's disease on the palm presents refractory skin erosion without erythematous plaque
Shinya Kitamura, Hiroaki Iwata, Keisuke Imafuku, Hiroo Hata, Ken Natsuga, Satoru Aoyagi, Hiroshi Shimizu
JOURNAL OF DERMATOLOGY, 42, 2, 225, 226, Feb. 2015, [Peer-reviewed]
English - Bullous Pemphigoid Autoantibodies Directly Induce Blister Formation without Complement Activation
Hideyuki Ujiie, Tetsumasa Sasaoka, Kentaro Izumi, Wataru Nishie, Satoru Shinkuma, Ken Natsuga, Hideki Nakamura, Akihiko Shibaki, Hiroshi Shimizu
JOURNAL OF IMMUNOLOGY, 193, 9, 4415, 4428, Nov. 2014, [Peer-reviewed]
English, Scientific journal - BLIMP1 Is Required for Postnatal Epidermal Homeostasis but Does Not Define a Sebaceous Gland Progenitor under Steady-State Conditions
Kai Kretzschmar, Denny L. Cottle, Giacomo Donati, Ming-Feng Chiang, Sven R. Quist, Harald P. Gollnick, Ken Natsuga, Kuo-I Lin, Fiona M. Watt
STEM CELL REPORTS, 3, 4, 620, 633, Oct. 2014, [Peer-reviewed]
English, Scientific journal - Solitary fibrous tumour fluctuating in size with menstrual cycle
H. Hata, K. Natsuga, S. Aoyagi, E. Homma, H. Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 39, 6, 753, 755, Aug. 2014, [Peer-reviewed]
English - A recurrent 'hot spot' glycine substitution mutation, G2043R in COL7A1, induces dominant dystrophic epidermolysis bullosa associated with intracytoplasmic accumulation of pro-collagen
Wataru Nishie, Ken Natsuga, Hideki Nakamura, Takamasa Ito, Ellen Toyonaga, Hidetsugu Sato, Hiroshi Shimizu
JOURNAL OF DERMATOLOGICAL SCIENCE, 75, 1, 69, 71, Jul. 2014, [Peer-reviewed]
English - Ultrasound B-mode and elastographic findings of angiomatoid fibrous histiocytoma
H. Hata, K. Natsuga, S. Aoyagi, E. Homma, H. Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 39, 4, 538, 539, Jun. 2014, [Peer-reviewed], [Corresponding author]
English - Paper-Based ELISA for the Detection of Autoimmune Antibodies in Body Fluid-The Case of Bullous Pemphigoid
Chao-Kai Hsu, Hsin-Yu Huang, Wan-Rung Chen, Wataru Nishie, Hideyuki Ujiie, Ken Natsuga, Shu-Ting Fan, Hsi-Kai Wang, Julia Yu-Yun Lee, Wei-Lun Tsai, Hiroshi Shimizu, Chao-Min Cheng
ANALYTICAL CHEMISTRY, 86, 9, 4605, 4610, May 2014, [Peer-reviewed]
English, Scientific journal - Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility
Sara Cipolat, Esther Hoste, Ken Natsuga, Sven R. Quist, Fiona M. Watt
ELIFE, 3, 3, e01888, May 2014, [Peer-reviewed]
English, Scientific journal - Epidermal Barriers
Ken Natsuga
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 4, 4, a018218, Apr. 2014, [Peer-reviewed], [Invited], [Lead author, Last author, Corresponding author]
English, Scientific journal - Epidermal Wnt/beta-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors
Giacomo Donati, Valentina Proserpio, Beate Maria Lichtenberger, Ken Natsuga, Rodney Sinclair, Hironobu Fujiwara, Fiona M. Watt
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111, 15, E1501, E1509, Apr. 2014, [Peer-reviewed]
English, Scientific journal - Dermoscopic Features of Plasma Cell Cheilitis and Actinic Cheilitis
Takamasa Ito, Ken Natsuga, Shintaro Tanimura, Satoru Aoyagi, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 94, 5, 593, 594, 2014, [Peer-reviewed], [Corresponding author]
English - Coexistence case of bullous pemphigoid and pemphigus foliaceus
Masumi Tsujiwaki, Riichiro Abe, Yukiko Nomura, Machiko Nishimura, Daichi Hoshina, Satoru Shinkuma, Ken Natsuga, Hideyuki Ujiie, Ken Arita, Hiroshi Shimizu
EUROPEAN JOURNAL OF DERMATOLOGY, 23, 4, 552, 553, Jul. 2013, [Peer-reviewed]
English - C-MYC-Induced Sebaceous Gland Differentiation Is Controlled by an Androgen Receptor/p53 Axis
Denny L. Cottle, Kai Kretzschmar, Pawel J. Schweiger, Sven R. Quist, Harald P. Gollnick, Ken Natsuga, Satoru Aoyagi, Fiona M. Watt
Cell Reports, 3, 2, 427, 441, 2, 2013, [Peer-reviewed]
English, Scientific journal - A Novel Keratin 5 Mutation in an African Family with Epidermolysis Bullosa Simplex Indicates the Importance of the Amino Acid Located at the Boundary Site Between the H1 and Coil 1A Domains
Satoru Shinkuma, Wataru Nishie, Witold K. Jacyk, Ken Natsuga, Hideyuki Ujiie, Hideki Nakamura, Masashi Akiyama, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 93, 5, 585, 587, 2013, [Peer-reviewed]
English - The beta 9 Loop Domain of PA-PLA(1)alpha Has a Crucial Role in Autosomal Recessive Woolly Hair/Hypotrichosis
Satoru Shinkuma, Asuka Inoue, Junken Aoki, Wataru Nishie, Ken Natsuga, Hideyuki Ujiie, Toshifumi Nomura, Riichiro Abe, Masashi Akiyama, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 132, 8, 2093, 2095, Aug. 2012, [Peer-reviewed]
English - Antibodies to Pathogenic Epitopes or Type XVII Collagen Cause Skin Fragility in a Complement-Dependent and -Independent Manner
Ken Natsuga, Wataru Nishie, Satoru Shinkuma, Hideyuki Ujiie, Machiko Nishimura, Daisuke Sawamura, Hiroshi Shimizu
JOURNAL OF IMMUNOLOGY, 188, 11, 5792, 5799, Jun. 2012, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Mucous membrane pemphigoid with generalized blisters: IgA and IgG autoantibodies target both laminin-332 and type XVII collagen
I. Hayashi, S. Shinkuma, S. Shimizu, K. Natsuga, H. Ujiie, C. Yasui, K. Tsuchiya, W. Nishie, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 166, 5, 1116, 1120, May 2012, [Peer-reviewed]
English, Scientific journal - Possible modifier effects of keratin 17 gene mutation on keratitis-ichthyosis-deafness syndrome
K. Natsuga, S. Shinkuma, M. Kanda, Y. Suzuki, N. Chosa, Y. Narita, M. Setoyama, W. Nishie, M. Akiyama, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 166, 4, 903, 905, Apr. 2012, [Peer-reviewed], [Lead author, Corresponding author]
English - Subepidermal blistering disease with 3 distinct autoantibodies: Anti-BP230, anti-laminin gamma-1, and anti-laminin-332
Kazuhiro Kikuchi, Ken Natsuga, Satoru Shinkuma, Wataru Nishie, Satoshi Kajita, Hidetsugu Sato, Hiroshi Shimizu
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 65, 4, 878, 880, Oct. 2011, [Peer-reviewed], [Corresponding author]
English - Consequences of Two Different Amino-Acid Substitutions at the Same Codon in KRT14 Indicate Definitive Roles of Structural Distortion in Epidermolysis Bullosa Simplex Pathogenesis
Ken Natsuga, Wataru Nishie, Brian J. Smith, Satoru Shinkuma, Thomasin A. Smith, David A. D. Parry, Naoki Oiso, Akira Kawada, Kozo Yoneda, Masashi Akiyama, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 131, 9, 1869, 1876, Sep. 2011, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Malignant skin tumours in patients with inherited ichthyosis
K. Natsuga, M. Akiyama, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 165, 2, 263, 268, Aug. 2011, [Peer-reviewed], [Lead author, Corresponding author]
English - Spontaneous remission of solitary-type infantile myofibromatosis.
Kazuhiro Kikuchi, Riichiro Abe, Satoru Shinkuma, Erika Hamasaka, Ken Natsuga, Hiroo Hata, Yasuki Tateishi, Masahiko Shibata, Yuki Tomita, Yukiko Abe, Satoru Aoyagi, Makio Mukai, Hiroshi Shimizu
Case reports in dermatology, 3, 2, 181, 5, 2, May 2011, [Peer-reviewed], [International Magazine]
English, Infantile myofibromatosis is a rare fibrous tumor of infancy. The cutaneous solitary type has typically an excellent prognosis. However, histologically, it is important to rule out leiomyosarcoma, which has a poor prognosis. The low frequency of mitosis was definitive for a diagnosis of infantile myofibromatosis. We present a cutaneous solitary-type case of infantile myofibromatosis. Following incisional biopsy, the tumor remitted spontaneously. - DNA-based prenatal diagnosis of plectin-deficient epidermolysis bullosa simplex associated with pyloric atresia
Hideki Nakamura, Ken Natsuga, Wataru Nishie, James R. McMillan, Hiroyuki Nakamura, Daisuke Sawamura, Masashi Akiyama, Hiroshi Shimizu
INTERNATIONAL JOURNAL OF DERMATOLOGY, 50, 4, 439, 442, Apr. 2011, [Peer-reviewed]
English, Scientific journal - Childhood subepidermal blistering disease with autoantibodies to type VII collagen and laminin-332
H. -Y. Lin, T. Yanagi, M. Akiyama, M. M. Iitani, R. Moriuchi, K. Natsuga, S. Shinkuma, N. Yamane, D. Inokuma, K. Arita, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 164, 2, 452, 454, Feb. 2011, [Peer-reviewed]
English - Type XVII collagen ELISA indices significantly decreased after bullous pemphigoid remission
Erika Kusajima, Masashi Akiyama, Megumi Sato, Ken Natsuga, Hiroshi Shimizu
INTERNATIONAL JOURNAL OF DERMATOLOGY, 50, 2, 238, 240, Feb. 2011, [Peer-reviewed]
English - A founder effect of c.1938delC in ITGB4 underlies junctional epidermolysis bullosa and its application for prenatal testing
Ken Natsuga, Wataru Nishie, Satoru Shinkuma, Hideki Nakamura, Ken Arita, Kozo Yoneda, Takashi Kusaka, Toshihiro Yanagihara, Rika Kosaki, Haruhiko Sago, Masashi Akiyama, Hiroshi Shimizu
EXPERIMENTAL DERMATOLOGY, 20, 1, 74, 76, Jan. 2011, [Peer-reviewed], [Lead author, Corresponding author]
English - Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome
Ken Natsuga, Wataru Nishie, Satoru Shinkuma, Hideki Nakamura, Yoichiro Matsushima, Aya Tatsuta, Mayumi Kornine, Hiroshi Shimizu
JOURNAL OF DERMATOLOGICAL SCIENCE, 61, 1, 38, 44, Jan. 2011, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Human IgG1 Monoclonal Antibody against Human Collagen 17 Noncollagenous 16A Domain Induces Blisters via Complement Activation in Experimental Bullous Pemphigoid Model
Qiang Li, Hideyuki Ujiie, Akihiko Shibaki, Gang Wang, Reine Moriuchi, Hong-jiang Qiao, Hiroshi Morioka, Satoru Shinkuma, Ken Natsuga, Heather A. Long, Wataru Nishie, Hiroshi Shimizu
JOURNAL OF IMMUNOLOGY, 185, 12, 7746, 7755, Dec. 2010, [Peer-reviewed]
English, Scientific journal - Complete Paternal Isodisomy of Chromosome 17 in Junctional Epidermolysis Bullosa with Pyloric Atresia
Ken Natsuga, Wataru Nishie, Ken Arita, Satoru Shinkuma, Hideki Nakamura, Shogo Kubota, Sumihisa Imakado, Masashi Akiyama, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 130, 11, 2671, 2674, Nov. 2010, [Peer-reviewed], [Lead author, Corresponding author]
English - Plectin Deficiency Leads to Both Muscular Dystrophy and Pyloric Atresia in Epidermolysis Bullosa Simplex
Ken Natsuga, Wataru Nishie, Satoru Shinkuma, Ken Arita, Hideki Nakamura, Makiko Ohyama, Hitoshi Osaka, Takeshi Kambara, Yoshiaki Hirako, Hiroshi Shimizu
HUMAN MUTATION, 31, 10, E1687, E1698, Oct. 2010, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice
Yasuyuki Fujita, Riichiro Abe, Daisuke Inokuma, Mikako Sasaki, Daichi Hoshina, Ken Natsuga, Wataru Nishie, James R. McMillan, Hideki Nakamura, Tadamichi Shimizu, Masashi Akiyama, Daisuke Sawamura, Hiroshi Shimizu
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107, 32, 14345, 14350, Aug. 2010, [Peer-reviewed]
English, Scientific journal - Prevalent LIPH Founder Mutations Lead to Loss of P2Y5 Activation Ability of PA-PLA(1)alpha in Autosomal Recessive Hypotrichosis
Satoru Shinkuma, Masashi Akiyama, Asuka Inoue, Junken Aoki, Ken Natsuga, Toshifumi Nomura, Ken Arita, Riichiro Abe, Kei Ito, Hideki Nakamura, Hideyuki Ujiie, Akihiko Shibaki, Hiraku Suga, Yuichiro Tsunemi, Wataru Nishie, Hiroshi Shimizu
HUMAN MUTATION, 31, 5, 602, 610, May 2010, [Peer-reviewed]
English, Scientific journal - Epidermolysis Bullosa in Japan
Satoru Shinkuma, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu
DERMATOLOGIC CLINICS, 28, 2, 431, +, Apr. 2010, [Peer-reviewed]
English, Scientific journal - Circulating IgA and IgE autoantibodies in antilaminin-332 mucous membrane pemphigoid
K. Natsuga, W. Nishie, S. Shinkuma, R. Moriuchi, M. Shibata, M. Nishimura, T. Hashimoto, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 162, 3, 513, 517, Mar. 2010, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Plectin Expression Patterns Determine Two Distinct Subtypes of Epidermolysis Bullosa Simplex
Ken Natsuga, Wataru Nishie, Masashi Akiyama, Hideki Nakamura, Satoru Shinkuma, James R. McMillan, Akari Nagasaki, Cristina Has, Takeshi Ouchi, Akira Ishiko, Yoshiaki Hirako, Katsushi Owaribe, Daisuke Sawamura, Leena Bruckner-Tuderman, Hiroshi Shimizu
HUMAN MUTATION, 31, 3, 308, 316, Mar. 2010, [Peer-reviewed], [Lead author]
English, Scientific journal - Animal Models of Epidermolysis Bullosa
Ken Natsuga, Satoru Shinkuma, Wataru Nishie, Hiroshi Shimizu
DERMATOLOGIC CLINICS, 28, 1, 137, +, Jan. 2010, [Peer-reviewed], [Invited], [Lead author, Corresponding author]
English, Scientific journal - Response of Intractable Skin Ulcers in Recessive Dystrophic Epidermolysis Bullosa Patients to an Allogeneic Cultured Dermal Substitute
Ken Natsuga, Daisuke Sawamura, Maki Goto, Erina Homma, Yuka Goto-Ohguchi, Satoru Aoyagi, Masashi Akiyama, Yoshimitsu Kuroyanagi, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 90, 2, 165, 169, 2010, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Localized Linear IgA/IgG Bullous Dermatosis
Satoko Shimizu, Ken Natsuga, Satoru Shinkuma, Chikako Yasui, Kikuo Tsuchiya, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 90, 6, 621, 624, 2010, [Peer-reviewed]
English, Scientific journal - Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation
Kei Ito, Daisuke Sawamura, Maki Goto, Hideki Nakamura, Wataru Nishie, Kaori Sakai, Ken Natsuga, Satoru Shinkuma, Akihiko Shibaki, Jouni Uitto, Christopher P. Denton, Osamu Nakajima, Masashi Akiyama, Hiroshi Shimizu
AMERICAN JOURNAL OF PATHOLOGY, 175, 6, 2508, 2517, Dec. 2009, [Peer-reviewed]
English, Scientific journal - Secondary syphilis mimicking warts in an HIV-positive patient
S. Shinkuma, R. Abe, M. Nishimura, K. Natsuga, Y. Fujita, T. Nomura, W. Nishie, H. Shimizu
Sexually Transmitted Infections, 85, 6, 484, 6, Oct. 2009, [Peer-reviewed]
English - A Novel Humanized Neonatal Autoimmune Blistering Skin Disease Model Induced by Maternally Transferred Antibodies
Wataru Nishie, Daisuke Sawamura, Ken Natsuga, Satoru Shinkuma, Maki Goto, Akihiko Shibaki, Hideyuki Ujiie, Edit Olasz, Kim B. Yancey, Hiroshi Shimizu
JOURNAL OF IMMUNOLOGY, 183, 6, 4088, 4093, Sep. 2009, [Peer-reviewed]
English, Scientific journal - Widespread keratosis follicularis squamosa
Y. Nomura, M. Abe, K. Natsuga, R. Moriuchi, H. Kawasaki, M. Mayuzumi, A. Yasuoka, H. Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 34, 4, 519, 520, Jun. 2009, [Peer-reviewed]
English - Pemphigus foliaceus associated with oesophageal cancer
S. Shinkuma, M. Akiyama, N. Torii-Saito, K. Natsuga, Y. Tateishi, K. Ito, J. Hirota, Y. Shimizu, T. Shichinohe, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 23, 4, 473, 474, Apr. 2009, [Peer-reviewed]
English - Autoantibodies against type XVII collagen C-terminal domain in a patient with bullous pemphigoid associated with psoriasis vulgaris
D. Inokuma, K. Kodama, K. Natsuga, M. Kasai, M. Abe, W. Nishie, R. Abe, T. Hashimoto, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 160, 2, 451, 454, Feb. 2009, [Peer-reviewed]
English - Morphological and genetic analysis of steatocystoma multiplex in an Asian family with pachyonychia congenita type 2 harbouring a KRT17 missense mutation
M. Kanda, K. Natsuga, W. Nishie, M. Akiyama, A. Nagasaki, T. Shimizu, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 160, 2, 465, 468, Feb. 2009, [Peer-reviewed], [Corresponding author]
English - Type XVII collagen is a key player in tooth enamel formation.
Takuya Asaka, Masashi Akiyama, Takanori Domon, Wataru Nishie, Ken Natsuga, Yasuyuki Fujita, Riichiro Abe, Yoshimasa Kitagawa, Hiroshi Shimizu
The American journal of pathology, 174, 1, 91, 100, 1, Jan. 2009, [Peer-reviewed], [International Magazine]
English, Scientific journal, Inherited tooth enamel hypoplasia occurs due to mutations in genes that encode major enamel components. Enamel hypoplasia also has been reported in junctional epidermolysis bullosa, caused by mutations in the genes that encode type XVII collagen (COL17), a component of the epithelial-mesenchymal junction. To elucidate the pathological mechanisms of the enamel hypoplasia that arise from the deficiency of epithelial-mesenchymal junction molecules, such as COL17, we investigated tooth formation in our recently established Col17(-/-) and Col17 rescued mice. Compared with wild-type mice, the incisors of the Col17(-/-) mice exhibited reduced yellow pigmentation, diminished iron deposition, delayed calcification, and markedly irregular enamel prisms, indicating the presence of enamel hypoplasia. The molars of the Col17(-/-) mice demonstrated advanced occlusal wear. These abnormalities were corrected in the Col17 rescued humanized mice. Thus, the Col17(-/-) mice clearly reproduced the enamel hypoplasia in human patients with junctional epidermolysis bullosa. We were able to investigate tooth formation in the Col17(-/-) mice because the Col17(-/-) genotype is not lethal. Col17(-/-) mouse incisors had poorly differentiated ameloblasts that lacked enamel protein-secreting Tomes' processes and reduced mRNA expression of amelogenin, ameloblastin, and of other enamel genes. These findings indicated that COL17 regulates ameloblast differentiation and is essential for normal formation of Tomes' processes. In conclusion, COL17 deficiency disrupts the epithelial-mesenchymal interactions, leading to both defective ameloblast differentiation and enamel malformation. - Cutaneous pemphigus vulgaris with skin features similar to the classic mucocutaneous type: a case report and review of the literature
S. Shinkuma, W. Nishie, A. Shibaki, D. Sawamura, K. Ito, Y. Tsuji-Abe, K. Natsuga, P. T. Chan, M. Amagai, H. Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 33, 6, 724, 728, Nov. 2008, [Peer-reviewed]
English, Scientific journal - Usefulness of thermography techniques for evaluating the disease activity in Kimura's disease
S. Shinkuma, W. Nishie, D. Sawamura, K. Natsuga, S. Aoyagi, H. Shimizu
Clinical and Experimental Dermatology, 33, 6, 768, 771, 6, Nov. 2008, [Peer-reviewed]
English, Scientific journal - Acquired perforating dermatosis appearing as elastosis perforans serpiginosa and perforating folliculitis
R. Abe, S. Murase, Y. Nomura, K. Natsuga, Y. Tateishi, Y. Tomita, Y. Tsuji-Abe, T. Matsumura, H. Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 33, 5, 653, 654, Sep. 2008, [Peer-reviewed]
English - Precursor B-cell lymphoblastic lymphoma presented with intraocular involvement and unusual skin manifestations
Satoru Shinkuma, Ken Natsuga, Masashi Akiyama, Akari Saito, Wataru Saito, Shuichi Ota, Takeshi Kondo, Riichiro Abe, Kazuo Kodama, Hiroshi Shimizu
ANNALS OF HEMATOLOGY, 87, 8, 677, 679, Aug. 2008, [Peer-reviewed]
English - Leukaemic dissemination of Merkel cell carcinoma in a patient with systemic lupus erythematosus
I. Nemoto, K. C. Sato-Matsumura, Y. Fujita, K. Natsuga, H. Ujiie, Y. Tomita, N. Kato, M. Kondo, K. Ohnishi
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 33, 3, 270, 272, May 2008, [Peer-reviewed]
English, Scientific journal - Novel ABCA12 mutations identified in two cases of non-bullous congenital ichthyosiform erythroderma associated with multiple skin malignant neoplasia
Ken Natsuga, Masashi Akiyama, Naoko Kato, Kaori Sakai, Yoriko Sugiyama-Nakagiri, Machiko Nishimura, Hiroo Hata, Masataka Abe, Ken Arita, Yukiko Tsuji-Abe, Takashi Onozuka, Satoru Aoyagi, Kazuo Kodama, Hideyuki Ujiie, Yuki Tomita, Hiroshi Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 127, 11, 2669, 2673, Nov. 2007, [Peer-reviewed], [Lead author]
English - Non-Hodgkin lymphoma preceded by recalcitrant eczema
Ken Natsuga, Riichiro Abe, Hideyuki Ujiie, Akihiko Shibaki, Daisuke Sawamura, Mitsufumi Nishio, Katsuya Fujimoto, Takao Koike, Hiroshi Shimizu
EUROPEAN JOURNAL OF HAEMATOLOGY, 79, 4, 369, 370, Oct. 2007, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Amicrobal pustulosis asssociated with IgA nephropathy and Sjogren's syndrome
Ken Natsuga, Daisuke Sawamura, Erina Homma, Toshifumi Nomura, Masataka Abe, Ryuichi Muramatsu, Toshio Mochizuki, Takao Koike, Hiroshi Shimizu
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 57, 3, 523, 526, Sep. 2007, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Keratoacanthoma developing on nevus sebaceous in a child
Hideyuki Ujiie, Naoko Kato, Ken Natsuga, Yuki Tomita
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 56, 2, S57, S58, Feb. 2007, [Peer-reviewed]
English - Severe cholinergic urticaria successfully treated with scopolamine butylbromide in addition to antihistamines
H Ujiie, T Shimizu, K Natsuga, K Arita, K Tomizawa, H Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 31, 4, 588, 589, Jul. 2006, [Peer-reviewed]
English - Mycosis fungoides bullosa
K Natsuga, T Shimizu, R Abe, K Kodama, H Shimizu
ARCHIVES OF DERMATOLOGY, 142, 6, 793, 795, Jun. 2006, [Peer-reviewed], [Lead author, Corresponding author]
English - Two cases of atypical melanocytic lesions in recessive dystrophic epidermolysis bullosa infants
K Natsuga, M Akiyama, KC Sato-Matsumura, K Tsuchiya, H Shimizu
CLINICAL AND EXPERIMENTAL DERMATOLOGY, 30, 6, 636, 639, Nov. 2005, [Peer-reviewed], [Lead author]
English, Scientific journal - Ultrastructural features of trafficking defects are pronounced in melanocytic nevus in Hermansky-Pudlak syndrome type 1
K Natsuga, M Akiyama, T Shimizu, T Suzuki, S Ito, Y Tomita, J Tanaka, H Shimizu
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 125, 1, 154, 158, Jul. 2005, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal
Other Activities and Achievements
- Skin aging: a perspective.
夏賀健, 月刊皮膚科, 7, 2, 2025 - 私の治療 鶏眼(うおのめ)・胼胝(たこ)
夏賀健, 週刊日本医事新報, 5236, 2024 - Diseases Causing Subepidermal Blisters and Their Healing Mechanisms
夏賀健, 西日本皮膚科, 86, 5, 2024 - すぐに役立つ すごく役立つ 皮膚科検査の基本マニュアル 遺伝学的検査・細胞解析 遺伝学的解析の総説
夏賀健, 皮膚病診療, 46, Supplement, 2024 - 皮膚科にも来た再生医療 皮膚科における自家培養表皮
夏賀 健, 日本臨床皮膚科医会雑誌, 41, 1, 030, 032, Jan. 2024
日本臨床皮膚科医会, Japanese - 新・皮膚科セミナリウム 水疱症アップデート 表皮水疱症の水疱形成機構
夏賀 健, 日本皮膚科学会雑誌, 133, 12, 2819, 2823, Nov. 2023
(公社)日本皮膚科学会, Japanese - 重症(旧Herlitz型)接合部型表皮水疱症の1例
横手 銀珠, 石田 倫子, 工藤 恭子, 市山 正子, 高島 翔太, 夏賀 健, 皮膚科の臨床, 65, 1, 69, 73, Jan. 2023
金原出版(株), Japanese - 血管型エーラス・ダンロス症候群の遺伝子治療の可能性 siRNA技術を導入した治療法の研究が進められている
林 周次郎, 夏賀 健, 日本医事新報, 5043, 46, 46, Dec. 2020
(株)日本医事新報社, Japanese - 汎発性疣贅症の新知見について 免疫不全を念頭に診断と治療を進める必要がある
夏賀 健, 新熊 悟, 日本医事新報, 5038, 53, 53, Nov. 2020
(株)日本医事新報社, Japanese - 新・皮膚科セミナリウム 自己免疫性水疱症 難治例への対処 自己免疫性表皮下水疱症 診断・病態の最新の進歩
夏賀 健, 日本皮膚科学会雑誌, 129, 13, 2749, 2754, Dec. 2019
(公社)日本皮膚科学会, Japanese - 【4疾患からみる膠原病のいま】小児線状強皮症に対してシクロスポリン内服が有効であった2例
眞井 翔子, 藤田 靖幸, 夏賀 健, 西江 渉, 小野寺 智洋, 岡 敏明, 清水 宏, 皮膚科の臨床, 61, 12, 1797, 1802, Nov. 2019
金原出版(株), Japanese - 重症汎発性接合部型表皮水疱症の1家系
平岡 美樹子, 今門 純久, 夏賀 健, 秋山 真志, 澤村 大輔, 清水 宏, 日本皮膚科学会雑誌, 129, 12, 2525, 2532, Nov. 2019
(公社)日本皮膚科学会, Japanese - 治療法の再整理とアップデートのために 専門家による私の治療 鶏眼(うおのめ)・胼胝腫(たこ)
夏賀 健, 日本医事新報, 4976, 48, 48, Sep. 2019
(株)日本医事新報社, Japanese - 【内科医のための皮膚疾患アトラス-日常診療における部位別皮疹の診かた-】(Part2)症例 皮疹(皮膚所見)からの診断と治療へのアプローチ<部位別> 全身 全身の水ぶくれと紅斑
夏賀 健, 診断と治療, 107, Suppl., 322, 323, Mar. 2019
(株)診断と治療社, Japanese - 【内科医のための皮膚疾患アトラス-日常診療における部位別皮疹の診かた-】(Part2)症例 皮疹(皮膚所見)からの診断と治療へのアプローチ<部位別> 全身 全身の水ぶくれ
夏賀 健, 診断と治療, 107, Suppl., 324, 325, Mar. 2019
(株)診断と治療社, Japanese - 皮膚加齢における基底膜蛋白の生理学的意義の解明
夏賀 健, コスメトロジー研究報告, 26, 94, 97, Sep. 2018
(公財)コスメトロジー研究振興財団, Japanese - トラニラストが奏効したannular elastolytic giant cell granulomaの1例
藤村 悠, 夏賀 健, 伊東 孝政, 青柳 哲, 清水 宏, 臨床皮膚科, 72, 9, 681, 684, Aug. 2018
(株)医学書院, Japanese - 表皮下水疱症 発症機序/新規治療法の最新の進歩
夏賀 健, 日本皮膚科学会雑誌, 128, 5, 971, 971, May 2018
(公社)日本皮膚科学会, Japanese - 17型コラーゲンは加齢による表皮の過増殖を抑制する
渡邉 美佳, 夏賀 健, 西江 渉, 藤村 悠, 氏家 英之, 尾崎 倫孝, 清水 宏, 日本皮膚科学会雑誌, 128, 4, 607, 607, Apr. 2018
(公社)日本皮膚科学会, Japanese - 陰圧閉鎖療法が奏功したHydroxyurea(HU)による下腿潰瘍の2例
小住 英之, 渡邉 美佳, 夏賀 健, 山口 泰之, 須貝 達朗, 中山 ちひろ, 中里 信一, 新熊 悟, 清水 宏, 日本皮膚科学会雑誌, 128, 4, 607, 607, Apr. 2018
(公社)日本皮膚科学会, Japanese - 脾摘後に自然消退した続発性皮膚B細胞リンパ腫の1例
眞井 翔子, 夏賀 健, 清水 宏, 白鳥 聡一, 高橋 祥公, 日本皮膚科学会雑誌, 128, 4, 608, 608, Apr. 2018
(公社)日本皮膚科学会, Japanese - BNIP3は紫外線から皮膚を保護する際に重要な役割を果たす
森田 遼, 森山 麻里子, 森田 貴士, 丸谷 祐樹, 後藤 ありさ, 松本 諭以子, 夏賀 健, 早川 堯夫, 森山 博由, 日本薬学会年会要旨集, 138年会, 3, 133, 133, Mar. 2018
(公社)日本薬学会, Japanese - BNIP3は紫外線から皮膚を保護する際に重要な役割を果たす
森田遼, 森山麻里子, 森田貴士, 丸谷祐樹, 後藤ありさ, 松本諭以子, 夏賀健, 早川堯夫, 森山博由, 日本薬学会年会要旨集(CD-ROM), 138th, 3, ROMBUNNO.26PA‐am169S, 133, Mar. 2018
(公社)日本薬学会, Japanese - 小児線状強皮症に対してシクロスポリン内服が有効であった3例
眞井 翔子, 藤田 靖幸, 宮内 俊成, 藤村 悠, 夏賀 健, 乃村 俊史, 西江 渉, 清水 宏, 小野寺 智洋, 岡 敏明, 日本皮膚科学会雑誌, 128, 1, 62, 62, Jan. 2018
(公社)日本皮膚科学会, Japanese - Bnip3が誘導するオートファジーは紫外線ストレスから表皮を保護する
丸谷 祐樹, 森山 麻里子, 森田 貴士, 後藤 ありさ, 森田 遼, 松本 諭以子, 夏賀 健, 早川 堯夫, 森山 博由, 生命科学系学会合同年次大会, 2017年度, [1P, 0561], Dec. 2017
生命科学系学会合同年次大会運営事務局, Japanese - 【ヒト化マウスモデル】 自己抗原のヒト化による自己免疫性表皮下水疱症モデル
夏賀 健, 清水 宏, 臨床免疫・アレルギー科, 68, 3, 271, 277, Sep. 2017
(有)科学評論社, Japanese - 皮膚基底膜構築における17型コラーゲン細胞外領域切断の生理機能の解析
西村 真智子, 西江 渉, 新熊 悟, 夏賀 健, 中村 秀樹, 清水 宏, 白藤 宜紀, 岩月 啓氏, 澤村 大輔, 日本皮膚科学会雑誌, 127, 9, 2111, 2111, Aug. 2017
(公社)日本皮膚科学会, Japanese - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF/MS)が診断に有用であったMicrosporum canis感染症の家族例
山口 泰之, 藤田 靖幸, 白戸 貴久, 新熊 悟, 夏賀 健, 乃村 俊史, 清水 宏, 福元 達也, 日本皮膚科学会雑誌, 127, 9, 2115, 2115, Aug. 2017
(公社)日本皮膚科学会, Japanese - 単回使用陰圧治療システムが有効であった壊疽性膿皮症の2例
山口 泰之, 柳 輝希, 佐藤 一正, 葭本 倫大, 平田 悠, 氏家 韻欣, 西村 真智子, 夏賀 健, 清水 宏, 椎谷 千尋, 月永 一郎, 松村 哲理, 日本皮膚科学会雑誌, 127, 9, 2118, 2118, Aug. 2017
(公社)日本皮膚科学会, Japanese - bcl2ファミリー分子BNIP3はオートファジーを介した表皮における形態維持を担う
丸谷 祐樹, 森山 麻里子, 森田 貴士, 中島 佑香, 後藤 ありさ, 森田 遼, 夏賀 健, 早川 堯夫, 森山 博由, 日本薬学会年会要旨集, 137年会, 3, 152, 152, Mar. 2017
(公社)日本薬学会, Japanese - 【新生児の皮膚病】 (コラム1)出生前診断について
夏賀 健, Visual Dermatology, 16, 3, 276, 277, Feb. 2017
(株)学研メディカル秀潤社, Japanese - 広範囲に皮疹を生じた長島型掌蹠角化症の1例
宮内 俊成, 乃村 俊史, 鈴木 翔多朗, 大口 由香, 山口 泰之, 新熊 悟, 夏賀 健, 藤田 靖幸, 清水 宏, 日本皮膚科学会雑誌, 126, 9, 1725, 1725, Aug. 2016
(公社)日本皮膚科学会, Japanese - 優性栄養障害型表皮水疱症(DDEB)患者に生じた後天性表皮水疱症(EBA)の1例
林 良太, 伊藤 明子, 増井 由紀子, 伊藤 雅章, 阿部 理一郎, 下村 裕, 夏賀 健, 渡邉 美佳, 岩田 浩明, 新熊 悟, 日本皮膚科学会雑誌, 126, 7, 1320, 1320, Jun. 2016
(公社)日本皮膚科学会, Japanese - Herlitz型接合部型表皮水疱症の1例
横山 華英, 木村 有太子, 高森 健二, 須賀 康, 夏賀 健, 西江 渉, 清水 宏, 日本皮膚科学会雑誌, 126, 7, 1321, 1321, Jun. 2016
(公社)日本皮膚科学会, Japanese - 病理学的に乾癬様の変化を呈した菌状息肉症の2例
山口 泰之, 藤田 靖幸, 平田 悠, 西村 真智子, 夏賀 健, 清水 宏, 肥田 時征, 加藤 直子, 日本皮膚科学会雑誌, 126, 7, 1331, 1331, Jun. 2016
(公社)日本皮膚科学会, Japanese - アトピー性皮膚炎/魚鱗癬における細菌叢と抗菌ペプチド
夏賀 健, 日本皮膚科学会雑誌, 126, 5, 793, 793, May 2016
(公社)日本皮膚科学会, Japanese - 表皮細胞の分化・増殖における基底膜の役割
夏賀 健, 日本皮膚科学会雑誌, 126, 5, 841, 841, May 2016
(公社)日本皮膚科学会, Japanese - 広範囲に皮疹を生じた長島型掌蹠角化症の1例
宮内 俊成, 乃村 俊史, 鈴木 翔多朗, 大口 由香, 山口 泰之, 新熊 悟, 夏賀 健, 藤田 靖幸, 清水 宏, 日本皮膚科学会雑誌, 126, 5, 979, 979, May 2016
(公社)日本皮膚科学会, Japanese - 長島型掌蹠角化症の1例
宮内 俊成, 乃村 俊史, 鈴木 翔多朗, 山口 泰之, 夏賀 健, 藤田 靖幸, 清水 宏, 角化症研究会記録集, 30, 78, 82, Mar. 2016
角化症研究会事務局, Japanese - bc12ファミリー分子BNIP3はオートファジーを介して表皮の分化および形態維持を行う
久保 嘉一, 森山 麻里子, 中島 佑香, 後藤 ありさ, 夏賀 健, 早川 堯夫, 森山 博由, 日本薬学会年会要旨集, 136年会, 3, 146, 146, Mar. 2016
(公社)日本薬学会, Japanese - 病理学的に乾癬様の変化を呈した菌状息肉症の2例
山口 泰之, 藤田 靖幸, 平田 悠, 西村 真智子, 夏賀 健, 清水 宏, 肥田 時征, 加藤 直子, 日本皮膚科学会雑誌, 126, 2, 167, 167, Feb. 2016
(公社)日本皮膚科学会, Japanese - 進行性顔面片側萎縮症の1例
堀田 萌子, 藤田 靖幸, 葭本 倫大, 剱持 靖子, 夏賀 健, 冨澤 幸生, 清水 宏, 皮膚科の臨床, 58, 1, 150, 151, Jan. 2016
金原出版(株), Japanese - 水疱性類天疱瘡におけるIgE自己抗体の解析
守内 玲寧, 西江 渉, 氏家 英之, 夏賀 健, 清水 宏, 日本皮膚科学会雑誌, 125, 12, 2301, 2301, Nov. 2015
(公社)日本皮膚科学会, Japanese - Piezogenic pedal papulesの3例
椎谷 千尋, 夏賀 健, 泉 健太郎, 青柳 哲, 清水 宏, 臨床皮膚科, 69, 10, 731, 734, Sep. 2015
(株)医学書院, Japanese - Autoantibodies to parts of type XVII collagen outside of the non-collageneous 16A domain lead to mild bullous pemphigoid due to the non-depletion of autoantigen
H. Iwata, K. Imafuku, K. Izumi, M. Wada, K. Natsuga, H. Ujiie, W. Nishie, H. Shimizu, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 135, S4, S4, Sep. 2015
English, Summary international conference - 角化症と水疱症 その基礎と臨床 水疱症update 2014
夏賀 健, 西日本皮膚科, 77, 3, 281, 281, Jun. 2015
日本皮膚科学会-西部支部, Japanese - 【骨格筋症候群(第2版)-その他の神経筋疾患を含めて-】[上] 筋ジストロフィーおよび膜イオンチャネル異常症 先天性筋ジストロフィー(CMD) 非福山型先天性筋ジストロフィー 表皮水疱症 筋ジストロフィー症候群(プレクチン欠損症)
夏賀 健, 日本臨床, 別冊, 骨格筋症候群(上), 168, 172, May 2015
(株)日本臨床社, Japanese - 進行性顔面片側萎縮症の1例
堀田 萌子, 藤田 靖幸, 葭本 倫大, 剱持 靖子, 夏賀 健, 清水 宏, 冨澤 幸生, 日本皮膚科学会雑誌, 125, 6, 1268, 1269, May 2015
(公社)日本皮膚科学会, Japanese - Piezogenic pedal papulesの3例
椎谷 千尋, 夏賀 健, 泉 健太郎, 青柳 哲, 清水 宏, 日本皮膚科学会雑誌, 125, 6, 1281, 1281, May 2015
(公社)日本皮膚科学会, Japanese - 抗NC16A抗体を有さない軽症の水疱性類天疱瘡の1例
今福 恵輔, 岩田 浩明, 泉 健太郎, 夏賀 健, 氏家 英之, 西江 渉, 清水 宏, 日本皮膚科学会雑誌, 125, 4, 915, 915, Apr. 2015
(公社)日本皮膚科学会, Japanese - 水疱性類天疱瘡自己抗原である17型コラーゲンの異なるエピトープに対する抗体の病原性解析
和田 麻友美, 西江 渉, 氏家 英之, 泉 健太郎, 岩田 浩明, 夏賀 健, 清水 宏, 北川 善政, 北海道歯学雑誌, 35, 2, 188, 188, Mar. 2015
北海道歯学会, Japanese - 進行性顔面片側萎縮症の1例
堀田 萌子, 藤田 靖幸, 葭本 倫大, 剱持 靖子, 夏賀 健, 冨澤 幸生, 清水 宏, 日本皮膚科学会雑誌, 125, 1, 104, 104, Jan. 2015
(公社)日本皮膚科学会, Japanese - 結節性強皮症の1例
中里 信一, 乃村 俊史, 山根 尚子, 新熊 悟, 夏賀 健, 藤田 靖幸, 有田 賢, 竹中 ちひろ, 清水 宏, 日本皮膚科学会雑誌, 125, 1, 104, 104, Jan. 2015
(公社)日本皮膚科学会, Japanese - 中年女性の前腕に生じたelastotic bandsの1例
羽賀 直哉, 阿部 理一郎, 森田 裕介, 藤村 悠, 夏賀 健, 乃村 俊史, 熊切 正信, 清水 宏, 日本皮膚科学会雑誌, 124, 14, 3184, 3184, Dec. 2014
(公社)日本皮膚科学会, Japanese - 鎖骨内金属インプラントによる皮膚潰瘍の1例
北村 真也, 夏賀 健, 今福 恵輔, 本間 英里奈, 山根 尚子, 青柳 哲, 清水 宏, 松村 哲理, 日本皮膚科学会雑誌, 124, 14, 3190, 3190, Dec. 2014
(公社)日本皮膚科学会, Japanese - 50歳代女の前腕に生じたelastotic bandsの1例
羽賀 直哉, 阿部 理一郎, 森田 裕介, 藤村 悠, 夏賀 健, 乃村 俊史, 清水 宏, 熊切 正信, 日本皮膚科学会雑誌, 124, 11, 2134, 2134, Oct. 2014
(公社)日本皮膚科学会, Japanese - Piezogenic pedal papulesの3例
椎谷 千尋, 夏賀 健, 泉 健太郎, 青柳 哲, 清水 宏, 日本皮膚科学会雑誌, 124, 11, 2134, 2134, Oct. 2014
(公社)日本皮膚科学会, Japanese - METAL IMPLANT-INDUCED SKIN ULCER MIMICKING SCROFULODERMA
Shinya Kitamura, Ken Natsuga, Keisuke Imafuku, Erina Homma, Naoko Yamane, Satoru Aoyagi, Tetsuri Matsumura, Hiroshi Shimizu, JOURNAL OF DERMATOLOGY, 41, 6, 6, Oct. 2014
English, Summary international conference - 膿疱性乾癬と抗ラミニンγ1類天疱瘡を合併した1例
藤村 悠, 夏賀 健, 濱出 洋平, 野村 友希子, 清水 宏, 加来 洋, 村松 隆一, 日本皮膚科学会雑誌, 124, 10, 1936, 1936, Sep. 2014
(公社)日本皮膚科学会, Japanese - 鎖骨内金属インプラントによる皮膚潰瘍の1例
北村 真也, 夏賀 健, 今福 恵輔, 本間 英里奈, 山根 尚子, 青柳 哲, 清水 宏, 松村 哲理, 日本皮膚科学会雑誌, 124, 10, 1941, 1941, Sep. 2014
(公社)日本皮膚科学会, Japanese - 血清中に抗デスモコリン3IgG抗体を検出した増殖性天疱瘡の1例
守内 玲寧, 菊地 一博, 伊東 孝政, 清水 聡子, 村松 隆一, 夏賀 健, 清水 宏, 日本皮膚科学会雑誌, 124, 10, 1942, 1942, Sep. 2014
(公社)日本皮膚科学会, Japanese - 抗デスモグレイン自己抗体を認めた口腔扁平上苔癬の2例
村松 憲, 西江 渉, 夏賀 健, 藤田 靖幸, 岩田 浩明, 清水 宏, 山田 珠希, 山下 映美, 浅香 卓哉, 日本皮膚科学会雑誌, 124, 10, 1946, 1946, Sep. 2014
(公社)日本皮膚科学会, Japanese - Plasmin but not neutrophil elastase nor MMP9 primarily cleaves the juxtamembranous NC16A domain of collagen XVII
W. Nishie, W. Mayumi, K. Natsuga, K. Izumi, H. Shimizu, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 134, S13, S13, Sep. 2014
English, Summary international conference - トラニラストが奏効したannular elastolytic giant cell granulomaの1例
藤村 悠, 夏賀 健, 伊東 孝政, 青柳 哲, 清水 宏, 日本皮膚科学会雑誌, 124, 5, 984, 984, Apr. 2014
(公社)日本皮膚科学会, Japanese - 形質細胞性口唇炎と日光口唇炎のダーモスコピー所見の検討
伊東 孝政, 夏賀 健, 谷村 心太郎, 青柳 哲, 清水 宏, 日本皮膚科学会雑誌, 124, 4, 775, 775, Apr. 2014
(公社)日本皮膚科学会, Japanese - ケラチン9遺伝子変異を認めたepidermolytic palmoplantar keratodermaの1例
高島 翔太, 乃村 俊史, 鈴木 翔多朗, 藤村 悠, 中里 信一, 夏賀 健, 佐藤 英嗣, 阿部 理一郎, 清水 宏, 日本皮膚科学会雑誌, 124, 4, 792, 792, Apr. 2014
(公社)日本皮膚科学会, Japanese - 自己抗原の枯渇を標的とした水疱性類天疱瘡の新規治療法開発
夏賀 健, 日本皮膚科学会雑誌, 124, 4, 866, 866, Apr. 2014
(公社)日本皮膚科学会, Japanese - The role of decreased skin tension in the pathogenesis of bullous pemphigoid: a newly proposed hypothesis
Hans I-Chen Harn, Chao-Kai Hsu, Michael Hughes, Ken Natsuga, Hiroshi Shimizu, Julia Yu-Yun Lee, Ming-Jer Tang, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 134, 4, 1178, 1178, Apr. 2014
English, Summary international conference - Pathogenetic mechanisms in autoimmune skin fragility
Ken Natsuga, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 134, 4, 1171, 1171, Apr. 2014
English, Summary international conference - 肛門周囲に限局した水疱性類天疱瘡の1例
山本 洋平, 阿部 理一郎, 中里 信一, 夏賀 健, 乃村 俊史, 西江 渉, 清水 宏, 日本皮膚科学会雑誌, 123, 8, 1548, 1548, Jul. 2013
(公社)日本皮膚科学会, Japanese - 形質細胞性口唇炎と日光口唇炎のダーモスコピー所見の検討
伊東 孝政, 夏賀 健, 谷村 心太郎, 青柳 哲, 清水 宏, 日本皮膚科学会雑誌, 123, 8, 1548, 1548, Jul. 2013
(公社)日本皮膚科学会, Japanese - トラニラストが奏効したannular elastolytic giant cell granulomaの1例
藤村 悠, 夏賀 健, 伊東 孝政, 青柳 哲, 清水 宏, 日本皮膚科学会雑誌, 123, 8, 1550, 1550, Jul. 2013
(公社)日本皮膚科学会, Japanese - Skin barrier defect allows more abundant microbiota in skin and induces skin inflammation and the expression of antimicrobial peptides independently of microbiota
K. Natsuga, S. Cipolat, F. M. Watt, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 133, S192, S192, May 2013
English, Summary international conference - Essential role of collagen XVII in basement membrane formation and keratinocyte migration
M. Nishimura, W. Nishie, Y. Shirafuji, S. Shinkuma, K. Natsuga, H. Nakamura, D. Sawamura, K. Iwatsuki, H. Shimizu, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 133, S151, S151, May 2013
English, Summary international conference - アトピー性皮膚炎および先天性表皮水疱症として経過観察されていたKindler症候群の2例
神谷 浩二, 白藤 宜紀, 青山 裕美, 岩月 啓氏, 新熊 悟, 夏賀 健, 中村 秀樹, 西江 渉, 清水 宏, 日本皮膚科学会雑誌, 123, 4, 456, 456, Apr. 2013
(公社)日本皮膚科学会, Japanese - ケラチン5のコイル1A領域N末端部にミスセンス変異を生じた単純型表皮水疱症
新熊 悟, 西江 渉, 夏賀 健, 氏家 英之, 中村 秀樹, 清水 宏, Jacyk Witold, 秋山 真志, 日本皮膚科学会雑誌, 123, 4, 461, 461, Apr. 2013
(公社)日本皮膚科学会, Japanese - Exophiala speciesによるPhaeohyphomycosisの1例
宮内 俊成, 阿部 理一郎, 柴 景子, 村田 純子, 山根 尚子, 夏賀 健, 亀井 克彦, 清水 宏, 日本皮膚科学会雑誌, 123, 5, 989, 989, Apr. 2013
(公社)日本皮膚科学会, Japanese - 毛包系腫瘍の多発を認めたKID症候群の1例
小田 裕次郎, 古結 英樹, 成田 幸代, 瀬戸山 充, 神田 真聡, 夏賀 健, 秋山 真志, 角化症研究会記録集, 27, 68, 71, Mar. 2013
角化症研究会事務局, Japanese - Antibodies to pathogenic epitopes on type X VII collagen cause skin fragility in a complement-dependent and -independent manner
夏賀 健, 西江 渉, 新熊 悟, 氏家 英之, 西村 真知子, 澤村 大輔, 清水 宏, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 6, 262, 262, 01 Nov. 2012
Japanese - Chemical Carcinogenesis in Mice With a Defective Epidermal Barrier - Exploring the Connection Between Skin Barrier and Cancer Susceptibility
S. Cipolat, K. Natsuga, L. M. Sevilla, R. Nachat, F. M. Watt, EUROPEAN JOURNAL OF CANCER, 48, S170, S170, Jul. 2012
English, Summary international conference - 肛囲に限局したlinear IgA/IgG bullous dermatosisの1例
清水 聡子, 夏賀 健, 新熊 悟, 安居 千賀子, 土屋 喜久夫, 清水 宏, 日本皮膚科学会雑誌, 122, 4, 1210, 1210, Apr. 2012
(公社)日本皮膚科学会, Japanese - 抗BP230抗体陽性pemphigoid nodularisの1例
新熊 悟, 猪熊 大輔, 夏賀 健, 氏家 英之, 西江 渉, 清水 宏, 日本皮膚科学会雑誌, 122, 3, 625, 625, Mar. 2012
(公社)日本皮膚科学会, Japanese - 肛囲に限局したlinear IgA/IgG bullous dermatosisの1例
清水 聡子, 安居 千賀子, 林 韻欣, 土屋 喜久夫, 夏賀 健, 新熊 悟, 清水 宏, 日本皮膚科学会雑誌, 122, 2, 379, 379, Feb. 2012
(公社)日本皮膚科学会, Japanese - 常染色体劣性乏毛症患者に高頻度に認められたLIPH founder変異とその機能解析
新熊 悟, 秋山 真志, 夏賀 健, 乃村 俊史, 有田 賢, 西江 渉, 清水 宏, 井上 飛鳥, 青木 淳賢, 日本皮膚科学会雑誌, 122, 2, 379, 379, Feb. 2012
(公社)日本皮膚科学会, Japanese - 劣性栄養障害型表皮水疱症患者における遺伝子型-表現型の相互関係の解析
新熊 悟, 西江 渉, 夏賀 健, 伊藤 圭, 中村 秀樹, 清水 宏, 日本皮膚科学会雑誌, 122, 2, 381, 381, Feb. 2012
(公社)日本皮膚科学会, Japanese - 日本人に生じたDuhring疱疹状皮膚炎における表皮トランスグルタミナーゼ(eTG)抗体価の検討
新熊 悟, 阿部 理一郎, 林 欣宇, 夏賀 健, 氏家 英之, 西江 渉, 清水 宏, 大田 光仁, 土屋 喜久夫, 福本 隆也, 浅田 秀夫, 日本皮膚科学会雑誌, 122, 2, 383, 383, Feb. 2012
(公社)日本皮膚科学会, Japanese - 最近経験した先天性表皮水疱症の2例
木村 亜矢子, 神戸 直智, 松江 弘之, 夏賀 健, 清水 宏, 日本皮膚科学会雑誌, 122, 2, 435, 435, Feb. 2012
(公社)日本皮膚科学会, Japanese - 【橋本公二コネクション-薬疹・水疱症・そして皮膚科医人生-】 (Part2)水疱症関連 (case 07)非Herlitz型接合部型表皮水疱症
松本 圭子, 橋本 公二, 薬師寺 直喜, 西江 渉, 夏賀 健, 中村 秀樹, 清水 宏, Visual Dermatology, 11, 2, 165, 167, Jan. 2012
(株)学研メディカル秀潤社, Japanese - 複数の表皮基底膜構成蛋白に対する自己抗体を認めた自己免疫性水疱症の1例
菊地 一博, 佐藤 英嗣, 夏賀 健, 梶田 哲, 日本皮膚科学会雑誌, 122, 1, 54, 54, Jan. 2012
(公社)日本皮膚科学会, Japanese - プレクチンの発現様式の違いによって2種類の表皮水疱症の臨床型が決定される
夏賀 健, 西江 渉, 秋山 志, 新熊 悟, 中村 秀樹, 長崎 暁理, 澤村 大輔, 清水 宏, Has Cristina, Bruckner-Tuderman Leena, 大内 健嗣, 石河 晃, 平子 善章, 尾張部 克志, 日本皮膚科学会雑誌, 122, 1, 57, 57, Jan. 2012
(公社)日本皮膚科学会, Japanese - 担癌患者に生じた自己免疫性水疱症の1例
守内 玲寧, 阿部 理一郎, 夏賀 健, 乃村 俊史, 清水 宏, 三田村 卓, 櫻木 範明, 橋本 隆, 日本皮膚科学会雑誌, 121, 14, 3355, 3355, Dec. 2011
(公社)日本皮膚科学会, Japanese - 先天性爪甲硬厚症2型におけるKRT17遺伝子変異検索
神田 真聡, 夏賀 健, 西江 渉, 秋山 真志, 長崎 暁理, 清水 宏, 清水 忠道, 日本皮膚科学会雑誌, 121, 14, 3357, 3357, Dec. 2011
(公社)日本皮膚科学会, Japanese - 自己免疫性表皮下水疱症の診断
夏賀 健, 札幌社会保険総合病院医誌, 20, 2, 48, 52, Dec. 2011
(独)地域医療機能推進機構札幌北辰病院, Japanese - 先天性表皮水疱症の1例
澤井 孝宏, 川見 健也, 清原 隆宏, 熊切 正信, 夏賀 健, 谷岡 未樹, 清水 宏, 日本皮膚科学会雑誌, 121, 5, 906, 906, Apr. 2011
(公社)日本皮膚科学会, Japanese - 先天性魚鱗癬様紅皮症、葉状魚鱗癬の病因 ABCA12遺伝子変異とTGM1遺伝子変異
坂井 香織, 秋山 真志, 柳 輝希, 夏賀 健, 清水 宏, 角化症研究会記録集, 25, 52, 54, Mar. 2011
角化症研究会事務局, Japanese - 【新入医局員最初の一歩 目で見てわかる皮膚の科学】 (Part2)ミクロ検査の実際 遺伝子検査の実際
夏賀 健, 秋山 真志, Visual Dermatology, 10, 4, 394, 397, Mar. 2011
(株)学研メディカル秀潤社, Japanese - VII型コラーゲンとラミニン332に対する自己抗体を認めた小児表皮下水疱症の1例
林 欣宇, 柳 輝希, 秋山 真志, 飯谷 麻里, 守内 玲寧, 夏賀 健, 新熊 悟, 猪熊 大輔, 有田 賢, 清水 宏, 日本皮膚科学会雑誌, 121, 3, 585, 585, Mar. 2011
(公社)日本皮膚科学会, Japanese - クロベタゾールプロピオン酸エステル軟膏外用が奏効した高齢者水疱性類天疱瘡の一例
新熊 悟, 松村 和子, 夏賀 健, 札幌社会保険総合病院医誌, 19, 2, 53, 57, Dec. 2010
(独)地域医療機能推進機構札幌北辰病院, Japanese - アトピー性皮膚炎との鑑別を要したKindler症候群の一例
白藤 宜紀, 青山 裕美, 岩月 啓氏, 梅村 茂夫, 新熊 悟, 夏賀 健, 中村 秀樹, 西江 渉, 清水 宏, Journal of Environmental Dermatology and Cutaneous Allergology, 4, 5, 437, 437, Nov. 2010
(一社)日本皮膚アレルギー・接触皮膚炎学会, Japanese - Erratum: Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice (Proceedings of the National Academy of Sciences of the United States of America (2010) 107, (14345-14350) DOI: 10.10
Yasuyuki Fujita, Riichiro Abe, Daisuke Inokuma, Mikako Sasaki, Daichi Hoshina, Ken Natsuga, Wataru Nishie, James R. McMillan, Hideki Nakamura, Tadamichi Shimizu, Masashi Akiyama, Daisuke Sawamura, Hiroshi Shimizu, Proceedings of the National Academy of Sciences of the United States of America, 107, 14514, 10 Aug. 2010 - 複数の表皮基底膜構成蛋白に対する自己抗体を認めた自己免疫性水疱症の1例
菊地 一博, 佐藤 英嗣, 夏賀 健, 梶田 哲, 西日本皮膚科, 72, 3, 300, 300, Jun. 2010
日本皮膚科学会-西部支部, Japanese - 筋ジストロフィー型単純型表皮水疱症の1例
大内 健嗣, 舩越 建, 谷川 瑛子, 小堺 有史, 夏賀 健, 秋山 真志, 石河 晃, 日本小児皮膚科学会雑誌, 29, 1, 43, 48, May 2010
日本小児皮膚科学会, Japanese - 先天性表皮水疱症の遺伝カウンセリング
笠井 靖代, 渡邊 理子, 有馬 香織, 今井 庸子, 窪田 祥吾, 杉本 充弘, 夏賀 健, 清水 宏, 日本遺伝カウンセリング学会誌, 31, 1, 62, 62, Apr. 2010
日本遺伝カウンセリング学会, Japanese - 高頻度に認められるLIPH founder変異を有した常染色体劣性乏毛症の4家系
新熊 悟, 秋山 真志, 夏賀 健, 乃村 俊史, 有田 賢, 西江 渉, 清水 宏, 日本皮膚科学会雑誌, 120, 3, 688, 688, Mar. 2010
(公社)日本皮膚科学会, Japanese - KRT17変異を持つ先天性爪甲厚硬症2型1家系における多発性脂腺嚢腫の遺伝学的・組織学的検討
神田 真聡, 夏賀 健, 西江 渉, 秋山 真志, 長崎 暁理, 清水 忠道, 清水 宏, 日本小児皮膚科学会雑誌, 28, 2, 198, 198, Nov. 2009
日本小児皮膚科学会, Japanese - 筋ジストロフィー合併型単純型表皮水疱症の1例
大内 健嗣, 舩越 建, 谷川 瑛子, 石河 晃, 小堺 有史, 夏賀 健, 秋山 真志, 日本小児皮膚科学会雑誌, 28, 2, 199, 199, Nov. 2009
日本小児皮膚科学会, Japanese - 先天性厚硬爪甲症と多発性脂腺嚢腫
神田 真聡, 夏賀 健, 秋山 真志, 清水 宏, 日本小児皮膚科学会雑誌, 28, 2, 211,3, 213,3, Nov. 2009
日本小児皮膚科学会, Japanese - 担癌患者に生じた自己免疫性水疱症の1例
守内 玲寧, 阿部 理一郎, 夏賀 健, 乃村 俊史, 清水 宏, 三田村 卓, 櫻木 範明, 橋本 隆, 日本皮膚科学会雑誌, 119, 2, 210, 210, Feb. 2009
(公社)日本皮膚科学会, Japanese - Speckled lentiginous nevus上に生じた悪性黒色腫の1例
後藤 由香, 青柳 哲, 夏賀 健, 秦 洋郎, 猪熊 大輔, 澤村 大輔, 清水 宏, 月永 一郎, 深澤 雄一郎, 日本皮膚科学会雑誌, 119, 1, 58, 58, Jan. 2009
(公社)日本皮膚科学会, Japanese - Perforating dermatosisの1例
村瀬 修平, 阿部 理一郎, 野村 友希子, 夏賀 健, 立石 八寿貴, 冨田 幸希, 清水 宏, 松村 哲理, 日本皮膚科学会雑誌, 119, 1, 60, 60, Jan. 2009
(公社)日本皮膚科学会, Japanese - Amicrobial pustulosis associated with autoimmune diseases
夏賀 健, 澤村 大輔, 本間 英里奈, 乃村 俊史, 安部 将隆, 清水 宏, 村松 隆一, 日本皮膚科学会雑誌, 119, 1, 62, 62, Jan. 2009
(公社)日本皮膚科学会, Japanese - 北海道がんセンターにおける過去13年間の悪性黒色腫87例の検討
山根 尚子, 加藤 直子, 大澤 倫子, 柳 輝希, 皆川 英彦, 舟山 恵美, 夏賀 健, 日本皮膚科学会雑誌, 119, 1, 66, 66, Jan. 2009
(公社)日本皮膚科学会, Japanese - 複数の皮膚悪性腫瘍に罹患し、ABCA12遺伝子の新規変異が同定された非水疱型先天性魚鱗癬様紅皮症の2例
夏賀 健, 秋山 真志, 坂井 香織, 中桐 頼子, 西村 真智子, 安倍 将隆, 有田 賢, 阿部 由紀子, 小野塚 貴, 青柳 哲, 秦 洋郎, 小玉 和郎, 清水 宏, 加藤 直子, 氏家 英之, 冨田 幸希, 日本皮膚科学会雑誌, 119, 1, 71, 71, Jan. 2009
(公社)日本皮膚科学会, Japanese - Anaplastic large cell lymphoma(ALCL)の1例
山根 尚子, 加藤 直子, 柳 輝希, 大澤 倫子, 夏賀 健, 氏家 英之, 富田 幸希, 日本皮膚科学会雑誌, 119, 1, 73, 73, Jan. 2009
(公社)日本皮膚科学会, Japanese - 皮膚に単発したInfantile myofibromatosisの1例
菊地 一博, 阿部 理一郎, 新熊 悟, 濱坂 恵理香, 夏賀 健, 秦 洋郎, 立石 八寿貴, 柴田 雅彦, 冨田 幸希, 阿部 由紀子, 青柳 哲, 清水 宏, 向井 万起男, 日本皮膚科学会雑誌, 119, 1, 75, 76, Jan. 2009
(公社)日本皮膚科学会, Japanese - 全身の膿疱
小玉 和郎, 夏賀 健, 本間 英里奈, 乃村 俊史, 清水 宏, 澤村 大輔, 日本皮膚科学会雑誌, 118, 10, 1985, 1985, Sep. 2008
(公社)日本皮膚科学会, Japanese - 北海道がんセンターにおける過去14年間の悪性黒色腫90例の検討
山根 尚子, 加藤 直子, 大澤 倫子, 柳 輝希, 伊藤 幹, 西村 真智子, 皆川 英彦, 舟山 恵美, 林 利彦, 夏賀 健, 日本皮膚科学会雑誌, 118, 10, 2024, 2024, Sep. 2008
(公社)日本皮膚科学会, Japanese - 非水疱型先天性魚鱗癬様紅皮症(NBCIE)患者に生じた悪性黒色腫と末梢T細胞性リンパ腫(PTCL)
夏賀 健, 加藤 直子, 氏家 英之, 冨田 幸希, 日本皮膚科学会雑誌, 118, 7, 1278, 1279, Jun. 2008
(公社)日本皮膚科学会, Japanese - 免疫グロブリン大量静注療法が著効した水疱性類天疱瘡の1例
新熊 悟, 阿部 由紀子, 冨田 幸希, 夏賀 健, 氏家 英之, 阿部 理一郎, 秋山 真志, 清水 宏, 日本皮膚科学会雑誌, 118, 5, 933, 937, Apr. 2008
(公社)日本皮膚科学会, Japanese - Speckled lentiginous nevus上に生じた悪性黒色腫の1例
後藤 由香, 青柳 哲, 夏賀 健, 秦 洋郎, 猪熊 大輔, 澤村 大輔, 月永 一郎, 深澤 雄一郎, 清水 宏, 臨床皮膚科, 62, 1, 62, 65, Jan. 2008
(株)医学書院, Japanese - Case report: A case of malignant melanoma on a speckled lentiginous nevus
後藤 由香, 青柳 哲, 夏賀 健, 臨床皮膚科, 62, 1, 62, 65, Jan. 2008
医学書院, Japanese - 免疫グロブリン大量静注療法が著効した水疱性類天疱瘡の1例
新熊 悟, 阿部 由紀子, 冨田 幸希, 夏賀 健, 氏家 英之, 阿部 理一郎, 秋山 真志, 清水 宏, 皮膚の科学, 6, 3, 319, 319, Jun. 2007
日本皮膚科学会-大阪地方会・京滋地方会, Japanese - 特異な角化性局面を契機にHIV感染症と診断した1例
新熊 悟, 阿部 理一郎, 西村 真智子, 夏賀 健, 西江 渉, 浜坂 幸吉, 清水 宏, 日本皮膚科学会雑誌, 117, 4, 710, 710, Mar. 2007
(公社)日本皮膚科学会, Japanese - Ultrastructural observations in a pigmented nevus in Hermansky-Pudlak syndrome (HPS) type 1: abnormal melanosome formation in nevus cells is of significant diagnostic value
K Natsuga, M Akiyama, T Shimizu, T Suzuki, S Ito, Y Tomita, J Tanaka, H Shimizu, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 123, 5, A93, A93, Nov. 2004
English, Summary international conference
Lectures, oral presentations, etc.
- Deciphering Epidermal Behaviors to Understand Skin Diseases
Ken Natsuga
The 48th Annual Meeting of the Japanese Society for Investigative Dermatology, Dec. 2024, Invited oral presentation
[Invited] - Revertant mosaicism
Ken Natsuga
EB Clinet Conference 2024, Oct. 2024
[Invited] - Revertant mosaicism therapy for EB
Ken Natsuga
International Epidermolysis Bullosa Symposium, Aug. 2023, English, Invited oral presentation
[Invited] - Evaluation of revertant mosaicism in EB
Ken Natsuga
International EB Symposium, May 2023, English, Invited oral presentation
[Invited] - Physiology and pathology of the cutaneous basement membrane zone
Ken Natsuga
The 47th Annual Meeting of the Japanese Society for Investigative Dermatology, Dec. 2022, English, Invited oral presentation
[Invited] - Biology of the cutaneous basement membrane zone: the state of the art
Ken Natsuga
The 48th Annual Meeting of the Taiwanese Dermatological Association (TDA), Nov. 2022, English, Invited oral presentation
[Invited] - Bursting the Bubble: Advances in the Diagnosis of Bullous Diseases
Ken Natsuga
4th Annual Meeting of Dermatopathology, Oct. 2022, English, Invited oral presentation
[Invited] - Revertant mosaicism in EB
Ken Natsuga
International epidermolysis bullosa workshop, Aug. 2022, English, Invited oral presentation
[Invited] - Diagnosis and treatment for genodermatosis in Japan
Ken Natsuga
2021 SATU Joint Research/SDGs Seminar, Aug. 2021, English, Invited oral presentation
[Invited] - EB care and research in Japan
Ken Natsuga
International epidermolysis bullosa workshop, Jan. 2021, English, Invited oral presentation
[Invited] - Epidermolysis bullosa: implications for stem cells and wound healing.
Ken Natsuga
JSID Asian Kisaragi-Juku 2020, Dec. 2020, English, Invited oral presentation
[Invited] - Epidermal responses to physical stimuli
Ken Natsuga
Japan-Singapore International Skin Conference 2019, Apr. 2019, English, Invited oral presentation
[Invited] - Organization of the Basement Membrane Zone: Implications for Epidermolysis Bullosa.
Ken Natsuga
115th Annual Meeting of the Japanese Dermatological Association (JDA), Jun. 2016, English, Invited oral presentation
[Invited] - Organization of the Basement Membrane Zone: Implications for Bullous Pemphigoid and Epidermolysis Bullosa.
Ken Natsuga
72nd annual meeting of the American Academy of Dermatology, Mar. 2014, English, Invited oral presentation
[Invited] - Pathogenetic mechanisms in autoimmune skin fragility.
Ken Natsuga
40th annual SCUR meeting/ 6th joint meeting of SCUR and SSSR, May 2013, English, Invited oral presentation
[Invited]
Affiliated academic society
Research Themes
- 表皮水疱症におけるリバータントスキンの診断法確立
Apr. 2024 - Mar. 2027
夏賀 健、高島翔太
日本医療研究開発機構 難治性疾患実用化研究事業 - 表皮水疱症の創傷治癒遅延因子の同定とその克服
科学研究費助成事業 基盤研究(B)
01 Apr. 2023 - 31 Mar. 2026
夏賀 健
日本学術振興会, 基盤研究(B), 北海道大学, 23H02928 - 加齢に着目した皮膚の免疫自己寛容破綻機序の解明
科学研究費助成事業 基盤研究(B)
01 Apr. 2021 - 31 Mar. 2024
氏家 英之, 柳 輝希, 泉 健太郎, 夏賀 健, 岩田 浩明
免疫系の老化、すなわち免疫老化によって自己免疫疾患のリスクが増加することが知られているが、詳細な機序の大部分は不明である。水疱性類天疱瘡（BP）は表皮基底膜部に存在するBP180やBP230に対する自己抗体によって生じる自己免疫性水疱症で、高齢者に好発する。我々は最近、一部の高齢マウスは表皮基底膜部に対する自己抗体を自然産生していることを発見した。本研究の目的は、BPをモデル疾患として“加齢に伴う免疫自己寛容の破綻機序を解明する”ことである。
まず、高齢マウスが産生する抗基底膜部自己抗体の標的抗原を同定するため、BP180、ラミニンγ1、ラミニンγ2、ラミニンβ3、ラミニンα3の各リコンビナントタンパクを作成した。高齢マウス（70週齢以上）の血清を採取し、作成したリコンビナントタンパクを基質としてウエスタンブロットを施行した。BP180リコンビナントタンパクを基質としたウエスタンブロット法で、約半数の高齢マウス血清中に抗BP180 IgM抗体が検出された。ラミニンγ1、ラミニンγ2、ラミニンβ3、ラミニンα3を基質としたウエスタンブロット法は陰性だった。
次に、加齢に伴いB細胞が抗基底膜部自己抗体を産生する機序を、制御性T細胞(Treg)とAge-associate B cells（ABCs）に着目して検討した。Treg欠損マウスでは野生型マウスに比較して、脾臓におけるABCsが増加していた。
また、薬剤投与により高齢マウスに病原性自己抗体を誘導できるかどうかを、近年BPの発症誘因として注目されているDPP-4阻害薬と抗PD-1抗体に着目して検討している。現在、高齢マウスにこれらの薬剤を投与中だが、今のところBP自己抗体の有意な誘導は見られていない。
日本学術振興会, 基盤研究(B), 北海道大学, 21H02938 - エピトープスプレディング現象に着目した水疱性類天疱瘡の病態解明
科学研究費助成事業 基盤研究(B)
01 Apr. 2020 - 31 Mar. 2023
西江 渉, 岩田 浩明, 泉 健太郎, 氏家 英之, 夏賀 健
2020年度は、18名の水疱性類天疱瘡患者（DPP4阻害薬内服中の症例を含む）末梢血単核球中のB細胞をEBウイルスを用い形質転換した。樹立したLymphoblastoid cell lineの培養上清を用い、水疱性類天疱瘡抗原であるBP180タンパクへの自己抗体の反応性をELISA法で確認したところ、全ての患者さん由来細胞でIgGクラス自己抗体の反応性は確認できなかった。しかし、6名のLymphoblastoid cell line培養上清に坑BP180 IgMクラス自己抗体を確認したため、形質転換した細胞群から単一あるいはポリクローナルな状態での、坑BP180自己抗体産生細胞の採取をFACSソーティングで試みた。その結果、坑BP180自己抗体産生細胞数が極めて少なかったことと、蛍光標識BP180タンパクが細胞表面に結合した後のエンドサイトーシスに伴う蛍光の減弱のため、細胞の単離は上手くいかなかった。そこで、pH耐性緑色蛍光タンパクであるGamillusを融合したBP180タンパクを作製し、再度FACSソーティングを行うこととした。細胞を単離したのち、次世代シークエンサーによる自己抗体可変領域のアミノ酸配列の解読と、リコンビナント坑BP180自己抗体の作製、そしてマウスへ投与し病原性の確認を計画しそれぞれの予備実験を開始していたが、今後の研究を遂行できなくなったため、2021年以降の交付申請は辞退することにした。
日本学術振興会, 基盤研究(B), 北海道大学, 20H03700 - 表皮水疱症の治療最適化戦略
難治性疾患実用化研究事業
Apr. 2018 - Mar. 2021
夏賀 健
日本医療研究開発機構, Principal investigator, Competitive research funding - Novel bullous pemphigoid models induced by breaking tolerance to autoantigens.
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
01 Apr. 2016 - 31 Mar. 2019
Nishie Wataru, IZUMI kentaro, TOYONAGA ellen
The aim of this study is to develop bullous pemphigoid models for elucidating the pathomechanisms and producing novel therapies. We have established several novel bullous pemphigoid models by immunizing recombinant collagen XVII (COL17) proteins. Notably, monoclonal antibodies derived from the immunized mice disclosed that epitopes and subclasses of the monoclonal antibodies were associated with phenotypes of skin disease.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 16H05365 - Establishment of cicatricial alopecia animal models
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
01 Apr. 2016 - 31 Mar. 2019
Nakamura Hideki
Cicatricial alopecia is a type of hair loss characterized by loss of hair follicles and surrounding fibrosis. The aim of this study was to elucidate the mechanism of cicatricial alopecia by analyzing the hair follicles in the blistered skin of mice in detail. A major finding was a delay in hair follicle development/cycling at the re-epithelialized wounds after blistering. At the same time, infiltration of inflammatory cells was poor at the site where several layers of epithelization were completed, and there was no difference compared to the intact site. Taken together, these results indicate that the early stage of cicatricial alopecia involves less inflammation, with the proliferation of epithelial cells required for hair follicle growth directed toward re-epithelialization.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 16K10120 - Dynamics of epithelial stem cells upon wounding
Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
Apr. 2017 - Mar. 2019
Natsuga Ken, Watanabe Mika, Fujimura Yu
In wounds in which the epidermis was selectively removed, there was 1 -3 reepithelialization at 24 hours after wounding as visible through HE staining. The basal layer of the epidermis expressing α6 integrin was present at this point, and cells in the re-epithelialized layer were stained with pan-cytokeratin. Loricrin staining, showing differentiation into epidermal granular layer, was not seen 48 hours after wound creation but was confirmed 72 hours later. HE staining also shows no granular layer at 48 hours after wounding, but at 72 hours after wounding, the final reepithelialization is complete. Lineage tracing also revealed that daughter cells of hair follicle upper stem cells are involved in wound reepithelialization.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, Principal investigator, Competitive research funding, 17K16317 - Pathogenesis of bullous pemphigoid: a study using class-switched monoclonal antibodies.
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
01 Apr. 2016 - 31 Mar. 2018
Nishie Wataru
Bullous pemphigoid (BP) is an autoimmune blistering skin disease, in which autoantibodies target collagen XVII (COL17) in the skin. Here we produced recombinant monoclonal antibodies (mAb) directing COL17 with different isotypes including IgG1, IgG2a, IgA and IgE. These mAbs have identical variable regions. Passive transfer of these mAbs into mice induced activation of complements when IgG2a but not IgG1 mAbs were injected. However, there was no clinical differences were observed in complement-activating and complement-non-activating recipient mice. These results suggest that activation of complements is not enough to induce blistering skin disease in mice.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 16K15539 - Treatment of epidermolysis bullosa with revertant keratinocyte-derived iPS cells
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
01 Apr. 2015 - 31 Mar. 2018
Fujita Yasuyuki, MATSUMURA WAKANA, NAKAYAMA CHIHIRO
Cell-based therapies such as allogeneic mesenchymal stem/stromal cells (MSCs) transplantation for recessive dystrophic epidermolysis bullosa (RDEB) were explored. However, some hurdles exist to come over in current MSC-based therapies; limited proliferation and limited cell survival. To solve these problems, we focused on keratinocyte-derived induced pluripotent stem cells (iPSCs). Keratinocytes from intact areas of patients might have revertant mosaicism where the pathogenic mutations are spontaneously corrected. In this study, we succeeded to develop MSCs from keratinocytes-derived iPSCs (KC-iPSC-MSCs) of normal human and a RDEB patient. Keratinocytes-derived iPSCs (KC-iPSCs) were cultured with activin A, BIO and BMP4 to induct mesoderm lineage, and then cultured with bFGF and EGF. In 14 days, spindle-shaped cells
appeared which showed mesenchymal differentiation. Furthermore, the intravenous injection of the KC-iPSC-MSCs into wounded mice induced human type VII collagen.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 15K09753 - Prevention of autoantigen depletion for bullous pemphigoid treatment
Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
Apr. 2015 - Mar. 2017
Natsuga Ken, Watanabe Mika, Fujimura Yu
Immune system works against external pathogens such as viruses and bacteria. Once immune system does not function well, it targets our body cells. This phenomenon is called "autoimmunity". Bullous pemphigoid, an autoimmune disease in which skin attachment molecules are targeted, shows skin blisters on the whole body. We analyzed how skin cells respond to the treatment with antibodies against skin. As a result, the expression levels of molecules associated with intracellular trafficking were increased.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Hokkaido University, Principal investigator, Competitive research funding, 15K19668 - Induction of tolerance to bullous pemphigoid autoantigen by oral administration of antigenic peptides.
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
01 Apr. 2015 - 31 Mar. 2016
Nishie Wataru, NATSUGA KEN
Bullous pemphigoid (BP) is the major autoimmune blistering disease in which autoantibodies mainly target NC16A domain of collagen XVII (COL17). BP may be fatal because majority of patients are treated with systemic immmune suppressive drugs; thus, disease-specific therapies are required. In this study, we aimed at the fact that BP autoantibodies mainly target NC16A domain, and hypothesized that oral treatment with NC16A peptides may induce tolerance to COL17. We showed that oral treatment of NC16A peptides can suppress development of autoantibodies directing COL17 in mice, although statistical significance was not achieved. However, this finding must be very helpful to establish novel disaese-specific therapies for BP in the near future.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 15K15409 - Elucidating roles of plasmin in blister formation of bullous pemphigoid
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
01 Apr. 2013 - 31 Mar. 2016
Nakamura Hideki, NISHIE Wataru, NATSUGA Ken, SHIMIZU Hiroshi
Bullous pemphigoid (BP) is an autoimmune blistering disease. The aim of this study is to address the pathogenic roles of plasmin, a protease present in blister fluids of BP, which is known to cleave COL17. We first identified cleavage sites of COL17 by plasmin, and based on this data, cleavage site-specific antibodies were generated. The antibodies revealed that COL17 is actually cleaved by plasmin in lesional skin of certain numbers of BP patients.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 25461661 - Production of a novel blistering disease model by regulating expression of collagen XVII
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
01 Apr. 2012 - 31 Mar. 2016
Nishie Wataru, UJIIE HIDEYUKI, SHINKUMA SATORU, NATSUGA KEN
Collagen XVII (COL17) is a hemidesmosomal molecule which keeps adhesion between the epidermis and dermis. Loss of CO17 expression due to mutation in the COL17A1 leads to blistering disease, epidermolysis bullosa (EB); in addition, autoimmunity to COL17 results in autoimmune blistering disorder bullous pemphigoid (BP). The purpose of this study is to produce a novel blistering model by regulating COL17 expression based on Tet-on system. Transgenic mice carrying human COL17 cDNA driven under the CMV promoter with Tet response element and Tet transactivator sequences driven under the K14 promoter were produced. Upon oral administration of doxycycline (DOX), the Tg mice started to express human COL17 in basal keratinocytes, following by production of IgG autoantibodies directing human COL17. The Tg mice must be useful tool for elucidating pathogenesis of EB and BP, as well as for establishing therapies for these orphan diseases.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 24390274 - Generation of mosaic model of epidermolysis bullosa by inactivation of X chromosome.
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
01 Apr. 2014 - 31 Mar. 2015
NISHIE Wataru, NATSUGA Ken
The popups of this study is to generate a mosaic model of epidermolysis bullosa by inactivation of X chromosome. We have generated transgenic (Tg) mice with tetracycline response plasmid expressing human type XVII collagen (COL17) cDNA, and then crossed with the Tg mice expressing reverse tetracycline transactivator driven under keratin 14 promoter on X-chromosome. When primary keratinocytes from the double Tg mice were treated with doxycycline in culture, increased human COL17 gene expression was observed; however, COL17 protein expression was not induced. These results indicate that it may be challenging for this method to obtain mice with high inducible level of COL17, which is needed to be improved.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 26670516 - Modulation of skin microbiota through basememt membrane
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
01 Apr. 2013 - 31 Mar. 2014
SHIMIZU Hiroshi, NISHIE Wataru, NATSUGA Ken
Skin microbiota of mice deficient for skin basement membrane protein (BMZ-deficient mice) were analyzed. At P1, BMZ-deficient mice had less abundant skin microbiota compared with the control group mice while the quantity of skin bacteria was comparable between BMZ-deficient mice and the control mice at P4. Visualization of skin microbiota using FISH methods revealed that bacterial signals were located mainly in the cornified layers of BMZ-deficient mice and the control mice. The specificity of the probe to detect bacterial signals was confirmed by the negative FISH signals using a probe reacting with fungal species which are not found in skin. Further analyses will be done on microbiota of adult BMZ-deficient mice skin and human epidermolysis bullosa patients' skin.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 25670494
