夏賀 健 (ナツガ ケン)
| 医学研究院 専門医学系部門 感覚器病学分野 | 准教授 |
| 附属社会創造数学研究センター | 准教授 |
| 北海道大学病院 | 准教授 |
Last Updated :2025/06/08
■研究者基本情報
メールアドレス
- natsuga
med.hokudai.ac.jp
Researchmap個人ページ
ホームページURL
研究者番号
- 70645457
J-Global ID
■経歴
経歴
- 2021年04月 - 現在
北海道大学, 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） - 2021年02月 - 現在
北海道大学大学院医学研究院皮膚科学分野, 准教授 - 2016年08月 - 2021年02月
北海道大学病院, 皮膚科, 講師 - 2012年09月 - 2016年07月
北海道大学病院皮膚科, Hokkaido University Hospital, 助教 - 2011年04月 - 2012年08月
日本学術振興会, 海外特別研究員 - 2010年09月 - 2012年08月
Cancer Research UK Cambridge Research Institute, 客員研究員 - 2010年04月 - 2010年08月
北海道大学病院, 皮膚科, 客員臨床医師 - 2006年04月 - 2007年03月
北海道大学病院, 皮膚科, 医員 - 2005年04月 - 2006年03月
北海道がんセンター, レジデント - 2003年05月 - 2005年03月
北海道大学医学部付属病院, School of Medicine, 研修医
委員歴
■研究活動情報
受賞
- 2024年08月, 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 - 2024年08月, 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 - 2023年08月, 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 - 2022年08月, Sun Pharma RISING SUN AWARD 2022 日本研究皮膚科学会
夏賀 健 - 2022年08月, 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 - 2021年08月, 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 - 2019年08月, 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 - 2018年03月, マルホ・高木皮膚科学振興財団, 第2回高木賞
夏賀 健 - 2014年02月, 第6回ロート皮膚医学研究賞
夏賀 健 - 2013年02月, 第4回日本研究皮膚科学会きさらぎ賞
夏賀 健 - 2013年02月, 第32回高桑榮松奨学基金奨励賞
夏賀 健 - 2013年01月, 平成24年度フラテ研究奨励賞
夏賀 健 - 2009年12月, 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 - 2009年06月, ESDR-JSID Young Fellow Collegiality Award
夏賀 健 - 2007年, 第106回日本皮膚科学会総会ポスター賞
夏賀 健 - 2006年06月, 平成17年度日本皮膚科学会北海道地方会賞
夏賀 健 - 2005年10月, 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 - 2004年12月, 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 - 2004年02月, 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 - 1998年12月, 北海道大学レーン記念賞
夏賀 健
論文
- 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, 2025年02月25日
研究論文（学術雑誌） - Advanced phasing techniques in congenital skin diseases
Ken Natsuga
The Journal of Dermatology, 2024年12月26日
研究論文（学術雑誌） - 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, 2024年12月12日
研究論文（学術雑誌） - Multiple Acantholytic Acanthomas in Junctional Epidermolysis Bullosa.
Sota Itamoto, Ken Natsuga, Takashi Seo, Shota Takashima, Hideyuki Ujiie
Acta dermato-venereologica, 104, adv42258, 2024年11月19日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2024年11月13日
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, 2024年11月11日, ［査読有り］
研究論文（学術雑誌） - 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, 2024年10月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2024年09月30日, ［査読有り］, ［責任著者］, ［国際誌］
英語 - 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, 2024年09月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2024年09月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2024年07月17日, ［査読有り］, ［国際誌］
英語 - Atypical manifestations of hemangiomas in epidermolysis bullosa.
S Itamoto, K Natsuga, S Takashima, H Ujiie
The Journal of dermatology, 2024年06月14日, ［査読有り］, ［責任著者］, ［国際誌］
英語 - 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, 2024年05月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2024年04月27日, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, 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, 2024年03月14日, ［査読有り］, ［国際誌］
英語 - 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, 2024年02月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2023年12月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - Dermal discoloration due to osmium tetroxide.
Satsuki Naruse, Shota Takashima, Ken Natsuga, Hideyuki Ujiie
Clinical toxicology (Philadelphia, Pa.), 61, 11, 1004, 1005, 2023年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2023年10月27日, ［査読有り］
英語, 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, 2023年09月07日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2023年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2023年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2023年03月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2023年03月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2022年12月30日, ［査読有り］, ［国際誌］
英語 - 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, 2022年12月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2022年10月, ［査読有り］, ［国際誌］
英語 - Apremilast for lithium-associated psoriasis
Joohyung Youh, Hajime Miyazawa, Hiroaki Iwata, Ken Natsuga, Hideyuki Ujiie
Dermatologica Sinica, 2022年07月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2022年06月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2022年06月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2022年04月21日, ［査読有り］, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2022年04月, ［査読有り］, ［筆頭著者, 最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2022年02月07日, ［査読有り］ - Prevention of chemotherapy-induced hair loss by peroxisome proliferator-activated receptor-γ modulation.
K Natsuga
The British journal of dermatology, 186, 1, 14, 15, 2022年01月, ［査読有り］, ［招待有り］, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌） - IgA nephropathy preceded by erythroderma with eosinophilia.
Mina Takatsu, Ken Natsuga, Fumihiko Hattanda, Hideyuki Ujiie
European journal of dermatology : EJD, 32, 1, 127, 129, 2022年01月01日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2022年01月, ［査読有り］, ［国際誌］
英語 - 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, 2021年12月, ［査読有り］, ［招待有り］, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2021年11月17日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2021年08月24日, ［査読有り］, ［筆頭著者］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2021年08月, ［査読有り］, ［国際誌］
英語, 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, 2021年07月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2021年07月05日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2021年06月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2021年06月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2021年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2021年04月, ［査読有り］, ［国際誌］
英語 - 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, 2021年03月03日, ［査読有り］, ［国際誌］
英語 - 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, 2021年03月, ［査読有り］, ［国際誌］
英語 - 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, 2021年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年, ［査読有り］, ［国際誌］
英語, 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, 2021年01月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2020年12月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語 - 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, 2020年10月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2020年10月, ［査読有り］, ［国際誌］
英語 - 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, 2020年08月18日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2020年04月, ［査読有り］, ［国際誌］
英語 - 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, 2020年01月, ［査読有り］, ［国際誌］
英語 - 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, 2019年10月, ［査読有り］, ［招待有り］, ［筆頭著者, 最終著者］, ［国際誌］
英語, 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, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年05月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年03月, ［査読有り］, ［責任著者］, ［国際誌］
英語 - 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, 2019年03月, ［査読有り］, ［国際誌］
英語 - 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, 2019年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年02月01日, ［査読有り］, ［筆頭著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2019年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年12月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2018年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年09月, ［査読有り］, ［国際誌］
英語 - 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, 2018年08月29日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年07月, ［査読有り］, ［責任著者］, ［国際誌］
英語 - 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, 2018年06月, ［査読有り］, ［責任著者］, ［国際誌］
英語 - 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, 2018年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年05月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2018年02月01日, ［査読有り］
英語 - Extensive Eruptive Syringoma After Liver Transplantation.
Takuya Maeda, Ken Natsuga, Wataru Nishie, Kenichiro Yamashita, Hiroshi Shimizu
Acta dermato-venereologica, 98, 1, 119, 120, 2018年01月12日, ［査読有り］, ［責任著者］, ［国際誌］
英語 - 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, 2018年01月01日, ［査読有り］
英語 - 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, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2017年12月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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, 2017年12月01日, ［査読有り］
英語 - 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, 2017年11月01日, ［査読有り］, ［責任著者］
英語 - 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, 2017年11月, ［査読有り］
英語 - 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, 2017年10月, ［査読有り］
英語 - 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, +, 2017年09月, ［査読有り］
英語 - 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, 2017年07月, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌） - 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, 2017年06月, ［査読有り］
英語 - 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, 2017年05月, ［査読有り］
英語 - 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, 2017年02月, ［査読有り］
英語 - 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, 2017年02月, ［査読有り］
英語 - 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, 2016年12月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2016年11月, ［査読有り］
英語 - 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, 2016年11月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2016年11月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2016年10月, ［査読有り］, ［筆頭著者］
英語 - Stem cell markers of skin appendages in human skin tumours
K. Natsuga
BRITISH JOURNAL OF DERMATOLOGY, 175, 3, 459, 459, 2016年09月, ［招待有り］, ［筆頭著者, 最終著者, 責任著者］
英語 - 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, 2016年09月, ［査読有り］
英語 - 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, 2016年07月, ［査読有り］
英語 - 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, 2016年05月, ［査読有り］
英語 - 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, 2016年05月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2016年04月, ［査読有り］, ［責任著者］
英語 - 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, 2016年03月, ［査読有り］, ［責任著者］
英語 - 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, 2016年02月, ［査読有り］
英語, 研究論文（学術雑誌） - 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., 2016年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - 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, 2016年01月, ［査読有り］
英語 - 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, 2016年01月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌） - 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, 2016年01月, ［査読有り］
英語 - 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, 2016年01月, ［査読有り］
英語, 研究論文（学術雑誌） - 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年, ［査読有り］, ［責任著者］
英語, 研究論文（学術雑誌） - 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, 2016年01月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2016年01月, ［査読有り］
英語 - 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年, ［査読有り］
英語 - 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, 2015年09月, ［査読有り］, ［責任著者］
英語 - 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, 2015年09月, ［査読有り］
英語 - 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, 2015年05月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2015年04月, ［査読有り］
英語 - 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, 2015年04月, ［査読有り］
英語, 研究論文（学術雑誌） - Plectin-related skin diseases
Ken Natsuga
JOURNAL OF DERMATOLOGICAL SCIENCE, 77, 3, 139, 145, 2015年03月, ［査読有り］, ［招待有り］, ［筆頭著者, 最終著者, 責任著者］
英語 - 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, 2015年02月, ［査読有り］
英語 - 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, 2014年11月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2014年10月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2014年08月, ［査読有り］
英語 - A recurrent ‘hot spot’ glycine substitution mutation, G2043R in COL7A1, induces dominant dystrophic epidermolysis bullosa associated with intracytoplasmic accumulation of pro-collagen VII
Nishie W, Natsuga K, Nakamura H, Ito T, Toyonaga E, Sato H, Shimizu H
Journal of Dermatological Science, 75, 1, 69, 71, 2014年07月, ［査読有り］
英語 - 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, 2014年06月, ［査読有り］, ［責任著者］
英語 - 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, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌） - Epidermal Barriers
Ken Natsuga
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 4, 4, a018218, 2014年04月, ［査読有り］, ［招待有り］, ［筆頭著者, 最終著者, 責任著者］
英語, 研究論文（学術雑誌） - Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors.
Donati G, Proserpio V, Lichtenberger BM, Natsuga K, Sinclair R, Fujiwara H, Watt FM
Proceedings of the National Academy of Sciences of the United States of America, 111, 15, E1501, E1509, 2014年04月, ［査読有り］
英語, 研究論文（学術雑誌） - 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年, ［査読有り］, ［責任著者］
英語 - 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, 2013年07月, ［査読有り］
英語 - 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年, ［査読有り］
英語, 研究論文（学術雑誌） - 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年, ［査読有り］
英語 - The β9 loop domain of PA-PLA1α has a crucial role in autosomal recessive woolly hair/hypotrichosis.
Shinkuma S, Inoue A, Aoki J, Nishie W, Natsuga K, Ujiie H, Nomura T, Abe R, Akiyama M, Shimizu H
The Journal of investigative dermatology, 132, 8, 2093, 2095, 2012年08月, ［査読有り］
英語 - 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, 2012年06月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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, 2012年05月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2012年04月, ［査読有り］, ［筆頭著者, 責任著者］
英語 - 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, 2011年10月, ［査読有り］, ［責任著者］
英語 - 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, 2011年09月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - Malignant skin tumours in patients with inherited ichthyosis
K. Natsuga, M. Akiyama, H. Shimizu
BRITISH JOURNAL OF DERMATOLOGY, 165, 2, 263, 268, 2011年08月, ［査読有り］, ［筆頭著者, 責任著者］
英語 - 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, 2011年05月, ［査読有り］, ［国際誌］
英語, 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, 2011年04月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2011年02月, ［査読有り］
英語 - 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, 2011年02月, ［査読有り］
英語 - 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, 2011年01月, ［査読有り］, ［筆頭著者, 責任著者］
英語 - 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, 2011年01月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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, 2010年12月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2010年11月, ［査読有り］, ［筆頭著者, 責任著者］
英語 - 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, 2010年10月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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, 2010年08月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2010年05月, ［査読有り］
英語, 研究論文（学術雑誌） - Epidermolysis Bullosa in Japan
Satoru Shinkuma, Ken Natsuga, Wataru Nishie, Hiroshi Shimizu
DERMATOLOGIC CLINICS, 28, 2, 431, +, 2010年04月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2010年03月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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, 2010年03月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌） - Animal Models of Epidermolysis Bullosa
Ken Natsuga, Satoru Shinkuma, Wataru Nishie, Hiroshi Shimizu
DERMATOLOGIC CLINICS, 28, 1, 137, +, 2010年01月, ［査読有り］, ［招待有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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年, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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年, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2009年12月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2009年10月, ［査読有り］
英語 - 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, 2009年09月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2009年06月, ［査読有り］
英語 - 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, 2009年04月, ［査読有り］
英語 - 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, 2009年02月, ［査読有り］
英語 - 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, 2009年02月, ［査読有り］, ［責任著者］
英語 - 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, 2009年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, 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, 2008年11月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2008年11月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2008年09月, ［査読有り］
英語 - 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, 2008年08月, ［査読有り］
英語 - 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, 2008年05月, ［査読有り］
英語, 研究論文（学術雑誌） - 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, 2007年11月, ［査読有り］, ［筆頭著者］
英語 - 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, 2007年10月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - Amicrobial pustulosis associated with IgA nephropathy and Sjögren's syndrome.
Natsuga K, Sawamura D, Homma E, Nomura T, Abe M, Muramatsu R, Mochizuki T, Koike T, Shimizu H
Journal of the American Academy of Dermatology, 57, 3, 523, 526, 2007年09月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌） - 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, 2007年02月, ［査読有り］
英語 - 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, 2006年07月, ［査読有り］
英語 - Mycosis fungoides bullosa
K Natsuga, T Shimizu, R Abe, K Kodama, H Shimizu
ARCHIVES OF DERMATOLOGY, 142, 6, 793, 795, 2006年06月, ［査読有り］, ［筆頭著者, 責任著者］
英語 - 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, 2005年11月, ［査読有り］, ［筆頭著者］
英語, 研究論文（学術雑誌） - 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, 2005年07月, ［査読有り］, ［筆頭著者, 責任著者］
英語, 研究論文（学術雑誌）
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(公社)日本皮膚科学会, 日本語 - 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, 2018年04月
(公社)日本皮膚科学会, 日本語 - 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, 2018年04月
(公社)日本皮膚科学会, 日本語 - 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, 2018年04月
(公社)日本皮膚科学会, 日本語 - 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, 2018年03月
(公社)日本薬学会, 日本語 - 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, 2018年03月
(公社)日本薬学会, 日本語 - 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, 2018年01月
(公社)日本皮膚科学会, 日本語 - 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], 2017年12月
生命科学系学会合同年次大会運営事務局, 日本語 - 【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, 2017年09月
(有)科学評論社, 日本語 - 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, 2017年08月
(公社)日本皮膚科学会, 日本語 - 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, 2017年08月
(公社)日本皮膚科学会, 日本語 - 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, 2017年08月
(公社)日本皮膚科学会, 日本語 - 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, 2017年03月
(公社)日本薬学会, 日本語 - 【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, 2017年02月
(株)学研メディカル秀潤社, 日本語 - 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, 2016年08月
(公社)日本皮膚科学会, 日本語 - 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, 2016年06月
(公社)日本皮膚科学会, 日本語 - 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, 2016年06月
(公社)日本皮膚科学会, 日本語 - 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, 2016年06月
(公社)日本皮膚科学会, 日本語 - 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, 2016年05月
(公社)日本皮膚科学会, 日本語 - 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, 2016年05月
(公社)日本皮膚科学会, 日本語 - 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, 2016年05月
(公社)日本皮膚科学会, 日本語 - 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, 2016年03月
角化症研究会事務局, 日本語 - 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, 2016年03月
(公社)日本薬学会, 日本語 - 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, 2016年02月
(公社)日本皮膚科学会, 日本語 - 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, 2016年01月
金原出版(株), 日本語 - 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, 2015年11月
(公社)日本皮膚科学会, 日本語 - 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, 2015年09月
(株)医学書院, 日本語 - 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, 2015年09月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2015年06月
日本皮膚科学会-西部支部, 日本語 - 【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, 2015年05月
(株)日本臨床社, 日本語 - 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, 2015年05月
(公社)日本皮膚科学会, 日本語 - 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, 2015年05月
(公社)日本皮膚科学会, 日本語 - 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, 2015年04月
(公社)日本皮膚科学会, 日本語 - 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, 2015年03月
北海道歯学会, 日本語 - 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, 2015年01月
(公社)日本皮膚科学会, 日本語 - 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, 2015年01月
(公社)日本皮膚科学会, 日本語 - 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, 2014年12月
(公社)日本皮膚科学会, 日本語 - 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, 2014年12月
(公社)日本皮膚科学会, 日本語 - 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, 2014年10月
(公社)日本皮膚科学会, 日本語 - 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, 2014年10月
(公社)日本皮膚科学会, 日本語 - 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, 2014年10月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2014年09月
(公社)日本皮膚科学会, 日本語 - 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, 2014年09月
(公社)日本皮膚科学会, 日本語 - 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, 2014年09月
(公社)日本皮膚科学会, 日本語 - 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, 2014年09月
(公社)日本皮膚科学会, 日本語 - 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, 2014年09月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2014年04月
(公社)日本皮膚科学会, 日本語 - 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, 2014年04月
(公社)日本皮膚科学会, 日本語 - 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, 2014年04月
(公社)日本皮膚科学会, 日本語 - 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, 2014年04月
(公社)日本皮膚科学会, 日本語 - 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, 2014年04月
英語, 研究発表ペーパー・要旨（国際会議） - Pathogenetic mechanisms in autoimmune skin fragility
Ken Natsuga, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 134, 4, 1171, 1171, 2014年04月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2013年07月
(公社)日本皮膚科学会, 日本語 - 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, 2013年07月
(公社)日本皮膚科学会, 日本語 - 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, 2013年07月
(公社)日本皮膚科学会, 日本語 - 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, 2013年05月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2013年05月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2013年04月
(公社)日本皮膚科学会, 日本語 - 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, 2013年04月
(公社)日本皮膚科学会, 日本語 - 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, 2013年04月
(公社)日本皮膚科学会, 日本語 - 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, 2013年03月
角化症研究会事務局, 日本語 - 17型コラーゲンの水疱性類天疱瘡病原エピトープに対する抗体は, 補体に依存する経路と依存しない経路で皮膚を脆弱にさせる
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, 2012年11月01日
日本語 - 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, 2012年07月
英語, 研究発表ペーパー・要旨（国際会議） - 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, 2012年04月
(公社)日本皮膚科学会, 日本語 - 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, 2012年03月
(公社)日本皮膚科学会, 日本語 - 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, 2012年02月
(公社)日本皮膚科学会, 日本語 - 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, 2012年02月
(公社)日本皮膚科学会, 日本語 - 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, 2012年02月
(公社)日本皮膚科学会, 日本語 - 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, 2012年02月
(公社)日本皮膚科学会, 日本語 - 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, 2012年02月
(公社)日本皮膚科学会, 日本語 - 【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, 2012年01月
(株)学研メディカル秀潤社, 日本語 - 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, 2012年01月
(公社)日本皮膚科学会, 日本語 - 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, 2012年01月
(公社)日本皮膚科学会, 日本語 - 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, 2011年12月
(公社)日本皮膚科学会, 日本語 - 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, 2011年12月
(公社)日本皮膚科学会, 日本語 - 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, 2011年12月
(独)地域医療機能推進機構札幌北辰病院, 日本語 - 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, 2011年04月
(公社)日本皮膚科学会, 日本語 - 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, 2011年03月
角化症研究会事務局, 日本語 - 【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, 2011年03月
(株)学研メディカル秀潤社, 日本語 - 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, 2011年03月
(公社)日本皮膚科学会, 日本語 - 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, 2010年12月
(独)地域医療機能推進機構札幌北辰病院, 日本語 - 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, 2010年11月
(一社)日本皮膚アレルギー・接触皮膚炎学会, 日本語 - 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, 2010年08月10日 - 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, 2010年06月
日本皮膚科学会-西部支部, 日本語 - 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, 2010年05月
日本小児皮膚科学会, 日本語 - 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, 2010年04月
日本遺伝カウンセリング学会, 日本語 - 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, 2010年03月
(公社)日本皮膚科学会, 日本語 - 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, 2009年11月
日本小児皮膚科学会, 日本語 - 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, 2009年11月
日本小児皮膚科学会, 日本語 - 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, 2009年02月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2009年01月
(公社)日本皮膚科学会, 日本語 - 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, 2008年09月
(公社)日本皮膚科学会, 日本語 - 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, 2008年09月
(公社)日本皮膚科学会, 日本語 - 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, 2008年06月
(公社)日本皮膚科学会, 日本語 - 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, 2008年04月
(公社)日本皮膚科学会, 日本語 - 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, 2008年01月
(株)医学書院, 日本語 - 症例報告 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, 臨床皮膚科, 62, 1, 62, 65, 2008年01月
医学書院, 日本語 - 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, 2007年06月
日本皮膚科学会-大阪地方会・京滋地方会, 日本語 - 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, 2007年03月
(公社)日本皮膚科学会, 日本語 - 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, 2004年11月
英語, 研究発表ペーパー・要旨（国際会議）
講演・口頭発表等
- Deciphering Epidermal Behaviors to Understand Skin Diseases
Ken Natsuga
The 48th Annual Meeting of the Japanese Society for Investigative Dermatology, 2024年12月, 口頭発表（招待・特別）
［招待講演］ - Revertant mosaicism
Ken Natsuga
EB Clinet Conference 2024, 2024年10月
［招待講演］ - Revertant mosaicism therapy for EB
Ken Natsuga
International Epidermolysis Bullosa Symposium, 2023年08月, 英語, 口頭発表（招待・特別）
［招待講演］ - Evaluation of revertant mosaicism in EB
Ken Natsuga
International EB Symposium, 2023年05月, 英語, 口頭発表（招待・特別）
［招待講演］ - Physiology and pathology of the cutaneous basement membrane zone
Ken Natsuga
The 47th Annual Meeting of the Japanese Society for Investigative Dermatology, 2022年12月, 英語, 口頭発表（招待・特別）
［招待講演］ - Biology of the cutaneous basement membrane zone: the state of the art
Ken Natsuga
The 48th Annual Meeting of the Taiwanese Dermatological Association (TDA), 2022年11月, 英語, 口頭発表（招待・特別）
［招待講演］ - Bursting the Bubble: Advances in the Diagnosis of Bullous Diseases
Ken Natsuga
4th Annual Meeting of Dermatopathology, 2022年10月, 英語, 口頭発表（招待・特別）
［招待講演］ - Revertant mosaicism in EB
Ken Natsuga
International epidermolysis bullosa workshop, 2022年08月, 英語, 口頭発表（招待・特別）
［招待講演］ - Diagnosis and treatment for genodermatosis in Japan
Ken Natsuga
2021 SATU Joint Research/SDGs Seminar, 2021年08月, 英語, 口頭発表（招待・特別）
［招待講演］ - EB care and research in Japan
Ken Natsuga
International epidermolysis bullosa workshop, 2021年01月, 英語, 口頭発表（招待・特別）
［招待講演］ - Epidermolysis bullosa: implications for stem cells and wound healing.
Ken Natsuga
JSID Asian Kisaragi-Juku 2020, 2020年12月, 英語, 口頭発表（招待・特別）
［招待講演］ - Epidermal responses to physical stimuli
Ken Natsuga
Japan-Singapore International Skin Conference 2019, 2019年04月, 英語, 口頭発表（招待・特別）
［招待講演］ - Organization of the Basement Membrane Zone: Implications for Epidermolysis Bullosa.
Ken Natsuga
115th Annual Meeting of the Japanese Dermatological Association (JDA), 2016年06月, 英語, 口頭発表（招待・特別）
［招待講演］ - Organization of the Basement Membrane Zone: Implications for Bullous Pemphigoid and Epidermolysis Bullosa.
Ken Natsuga
72nd annual meeting of the American Academy of Dermatology, 2014年03月, 英語, 口頭発表（招待・特別）
［招待講演］ - Pathogenetic mechanisms in autoimmune skin fragility.
Ken Natsuga
40th annual SCUR meeting/ 6th joint meeting of SCUR and SSSR, 2013年05月, 英語, 口頭発表（招待・特別）
［招待講演］
共同研究・競争的資金等の研究課題
- 表皮水疱症におけるリバータントスキンの診断法確立
2024年04月 - 2027年03月
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)
2023年04月01日 - 2026年03月31日
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)
2021年04月01日 - 2024年03月31日
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)
2020年04月01日 - 2023年03月31日
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
2018年04月 - 2021年03月
夏賀 健
日本医療研究開発機構, 研究代表者, 競争的資金 - 免疫寛容が破綻し発症する画期的水疱性類天疱瘡モデルの作成と応用
科学研究費助成事業 基盤研究(B)
2016年04月01日 - 2019年03月31日
西江 渉, 岩田 浩明, 氏家 英之, 夏賀 健, 泉 健太郎, 豊永 愛恋
本研究は、免疫寛容の破綻によって発症する水疱性類天疱瘡モデルを作製し、病態解明と新規治療法開発へ応用することを目的としている。水疱性類天疱瘡の患者自己抗体が標的とする自己抗原である17型コラーゲン（COL17）のリコンビナントタンパクを作製し各種マウスへ免疫し、水疱性類天疱瘡のモデルを作製した。免疫したマウスからモノクローナル自己抗体を作製し解析したところ、抗体がCOL17上の標的とする部位および抗体のクラスは、皮膚症状と相関することを初めて明らかにした。
日本学術振興会, 基盤研究(B), 北海道大学, 16H05365 - 水疱形成による瘢痕型脱毛症の新規モデル作製と病態解明
科学研究費助成事業 基盤研究(C)
2016年04月01日 - 2019年03月31日
中村 秀樹, 清水 宏, 西江 渉, 夏賀 健
瘢痕型脱毛症は、毛包の減少と周囲の線維化を特徴とする脱毛の一種である。本研究では、マウス背部皮膚への水疱形成によって、その後に続発する毛包への変化を詳細に解析することで、瘢痕型脱毛症の発症機序を解明することを目的に行った。主要な成果として、水疱形成後に再上皮化した創傷部位では、毛包の発達/周期が遅延することが明らかとなった。これとともに、数層の上皮化が完了した部位に関して、炎症細胞の浸潤は乏しく、正常部位と比較して差はなかった。これらの結果を総合すると、水疱形成にともなう脱毛の初期段階では、毛包の成長に必要な上皮細胞の増殖が再上皮化反応へと向けられ、炎症の関与は乏しいことが解明された。
日本学術振興会, 基盤研究(C), 北海道大学, 16K10120 - 創傷治癒における上皮系幹細胞のダイナミクス
若手研究（B）
2017年04月 - 2019年03月
夏賀 健
表皮を選択的に除去した創傷においては、HE染色において創傷作成24時間後には1-3層の上皮化が見られた。α6インテグリンを発現する表皮基底層はこの時点で認められており、再上皮化した層の細胞は汎ケラチンで染色された。表皮顆粒層への分化を示すロリクリンの染色は創傷作成48時間後でみられないが、72時間後には確認された。HE染色でも創傷作成48時間後で顆粒層がみられないものの、72時間後には認められるため、この時点で最終的な上皮化が完了する。また、lineage tracingで毛包上部幹細胞の娘細胞が創傷の上皮化に関与することが解明された。
日本学術振興会, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 17K16317 - クラススイッチ導入モノクローナル抗体を用いた水疱性類天疱瘡の病態機序の解明
科学研究費助成事業 挑戦的萌芽研究
2016年04月01日 - 2018年03月31日
西江 渉, 夏賀 健
水疱性類天疱瘡（BP）は、皮膚の基底膜構成分子のひとつである17型コラーゲン（COL17）を自己抗体が標的とする自己免疫疾患である。本研究では、IgM型抗COL17モノクローナル抗体（mAb）産生ハイブリドーマを用い、同一の可変領域を持ち、IgMからIgG1, IgG2a, IgA, IgEへクラススイッチしたmAbをそれぞれ作製した。各mAbを新生仔マウスへ投与したところ、投与抗体は皮膚基底膜部へ沈着し、IgG2a投与マウスでは活性化した補体の沈着も認めた。しかし投与抗体のサブクラスによる表現型の違いは認めず、補体が活性化しても水疱形成には至らない可能性を示唆した。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 16K15539 - 復帰変異モザイクを応用したiPS細胞による表皮水疱症の治療
科学研究費助成事業 基盤研究(C)
2015年04月01日 - 2018年03月31日
藤田 靖幸, 清水 宏, 乃村 俊史, 夏賀 健, 松村 若菜, 中山 ちひろ
表皮水疱症患者において後天的に一部皮膚で遺伝子異常が修復される現象（復帰変異モザイク）が観察される。このような部位の皮膚から正常蛋白を産生する角化細胞を採取し、iPS細胞を樹立した上で間葉系幹細胞（MSC）へ分化・培養させ、病変部皮膚へ投与することで、大量の自己由来正常細胞を投与する根本的治療が可能になると考えた。本研究では基礎的検討として、1)表皮水疱症および健常人角化細胞からのiPS細胞の樹立 2)復帰変異モザイクiPS細胞の検索 3) 角化細胞由来iPS細胞から誘導されたMSC(KC-iPSC-MSC)の検証 4) KC-iPS-MSCの皮膚基底膜蛋白の発現検討 を行った。
日本学術振興会, 基盤研究(C), 北海道大学, 15K09753 - 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
若手研究（B）
2015年04月 - 2017年03月
夏賀 健
免疫とは、ウイルスや細菌などの外敵から自分を守るしくみである。しかし、免疫がひとたび異常になると、自分の細胞を攻撃するようになってしまう。この現象は自己免疫と呼ばれている。水疱性類天疱瘡は、皮膚の接着因子に対する自己免疫によって、全身の皮膚に水ぶくれができてしまう疾患である。本研究では、皮膚に対する抗体を皮膚細胞に投与した際、どのような変化が起きるかを網羅的に解析した。結果として、細胞内輸送に関わる分子が増加していることがわかった。
日本学術振興会, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 15K19668 - 経口免疫寛容を応用した水疱性類天疱瘡自己抗体の産生制御
科学研究費助成事業 挑戦的萌芽研究
2015年04月01日 - 2016年03月31日
西江 渉, 夏賀 健
水疱性類天疱瘡(BP)は高齢者に好発する自己免疫性水疱症で、主な標的抗原は表皮真皮境界部に存在する17型コラーゲン(COL17)である。BPでは免疫抑制剤の全身投与が一般的だが、重症化すると死に至る症例も稀でない。従って副作用の少ない疾患特異的な治療法開発が必須である。本研究では、BPの患者自己抗体の多くがCOL17のNC16A領域（77アミノ酸）を標的とする点に着目し、NC16A領域ペプチドをマウスへ経口投与した。その結果、抗原ペプチドの経口投与によって抗COL17の自己抗体産生が抑制される傾向が確認された。本研究結果は、将来、BPに対する新規治療法開発へ応用されることが期待できる。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 15K15409 - プラスミンをターゲットとした水疱性類天疱瘡の発症機序解明
科学研究費助成事業 基盤研究(C)
2013年04月01日 - 2016年03月31日
中村 秀樹, 西江 渉, 夏賀 健, 清水 宏
本研究の目的は、自己免疫性水疱症のなかで最も患者数の多い水疱性類天疱瘡（Bullous pemphigoid, BP）の水疱形成機序を解明し、診断と新規治療法開発へ応用することである。BPでは多数の水疱を生じるが、患者水疱内容液にはBP患者自己抗体の標的となるCOL17を切断可能なプラスミンが豊富に存在する。本研究では、プラスミンによるCOL17の切断部位を同定し、切断されたCOL17の切断部を特異的に認識する抗体を作製した。その結果、一部のBP患者皮膚では、実際にプラスミンによってCOL17が切断されていることを明らかにした。
日本学術振興会, 基盤研究(C), 北海道大学, 25461661 - １７型コラーゲン発現制御による画期的水疱症モデルの作成と応用
科学研究費助成事業 基盤研究(B)
2012年04月01日 - 2016年03月31日
西江 渉, 氏家 英之, 新熊 悟, 夏賀 健
ヘミデスモゾーム構成分子の一つであるXVII型コラーゲン（COL17）は表皮真皮間接合に重要で、遺伝子異常に伴い発現が欠損すると表皮水疱症（EB）の一型を発症する。また後天的にCOL17に対し自己免疫応答を生じると、自己免疫水疱症である水疱性類天疱瘡（BP）を発症する。本研究では、Tet-onシステムを応用し、ドキシサイクリン（DOX）投与によりヒトCOL17の発現を制御可能な遺伝子改変（Tg）マウスを作製した。TgマウスへDOXを経口投与すると、ヒトCOL17が皮膚で新たに発現し、抗ヒトCOL17抗体を生じた。本モデルは、EBやBPの病態解明と治療法開発に有用であると期待できる。
日本学術振興会, 基盤研究(B), 北海道大学, 24390274 - X染色体の不活化を応用した表皮水疱症モザイクモデルの作製
科学研究費助成事業 挑戦的萌芽研究
2014年04月01日 - 2015年03月31日
西江 渉, 夏賀 健
本研究の目的は、X染色体の不活化を応用した表皮水疱症のモザイクモデル作製を試みることである。テトラサイクリン応答配列を有するプロモーター下でヒトXVII型コラーゲン（COL17）遺伝子cDNAを発現するマウスを作製し、X染色体上でK14プロモーター下でリバーステトラサイクリン発現制御因子を発現するマウスと交配しダブルトランスジェニックマウスを作製した。マウス表皮培養細胞へドキシサイクリンを投与するとCOL17遺伝子の発現は誘導できたがタンパクレベルでの発現には至らなかった。本手法によるモザイクモデル作製には、いかに高い発現効率を有する個体を作製できるかが課題であることが明らかとなった。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 26670516 - 基底膜による皮膚細菌叢の制御機構の解明
科学研究費助成事業 挑戦的萌芽研究
2013年04月01日 - 2014年03月31日
清水 宏, 西江 渉, 夏賀 健
皮膚基底膜蛋白欠損マウスの皮膚細菌叢を解析した。生後1日目の段階では、対照群のマウスでむしろ皮膚細菌量が多く、生後4日目では皮膚基底膜蛋白欠損マウスとその対照群の皮膚細菌量が同等であることが確認された。FISH法を用いた皮膚細菌叢の可視化実験では、皮膚基底膜蛋白欠損マウスとその対照群ともに主に表皮の角層において細菌叢が確認された。陰性コントロールとして用いた、皮膚に存在しない真菌のプローブによるFISH法ではシグナルを認めなかった。今後は、長期生存する皮膚基底膜蛋白欠損マウスの皮膚や表皮水疱症患者皮膚を用いてさらに皮膚細菌叢の解析を進める必要がある。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 25670494
