論文 - 足立　剛也

Survey on patients with undiagnosed diseases in Japan: Potential patient numbers benefiting from Japan's initiative on rare and undiagnosed diseases (IRUD)

Adachi T., Imanishi N., Ogawa Y., Furusawa Y., Izumida Y., Izumi Y., Suematsu M.

Orphanet Journal of Rare Diseases （Orphanet Journal of Rare Diseases）  13 （ 1 ） 208 - 208 2018年11月

査読有り

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Background: There is now an international partnership to establish global programs for patients with rare and undiagnosed diseases, involving interdisciplinary expert panels and phenotype-driven genetic analyses utilizing next-generation sequencing and analytics. Whereas it is crucial to have data such as the actual number of undiagnosed patients, to help inform the implementation plan with such programs, there have been no systematic studies to quantitate the numbers of patients principally because of the inherent difficulty in most health systems to identify patients whose condition has not yet been diagnosed and coded. Our national experience with a rare disease program, Nan-Byo which was established in 1972, and the more recently expanded Initiative on Rare and Undiagnosed Diseases (IRUD), provided a unique opportunity to design a cross-sectional study to ascertain the undiagnosed patients in Japan based on the IRUD referral criteria. Results: Two rounds of online surveys were performed: one survey targeting physicians affiliated with general hospitals (GH) and family clinics (FC) (the response rate: 30.6% (242/792)) and one nationwide survey targeting university hospitals (UH) in Japan (47.1% (839/1781)). A high percentage of doctors needing IRUD was seen in pediatrics at GH, FC, while there was a clear demand for IRUD in most departments at UH. We calculated the number of undiagnosed patients in Japan, as the "percentage of doctors needing IRUD" × "number of patients who would be referred to IRUD per doctor needing IRUD (cases/person)" × "total number of doctors in the relevant facilities in Japan (persons)", resulting in 3681 cases in pediatrics/pediatric surgery and 33,703 cases in other departments, for a total of 37,384 cases. Conclusions: Our study revealed the extant demand for IRUD in most departments and 37,000+ potential patients with undiagnosed diseases in the Japanese health system. These data inform the establishment of an equitable, sustainable, efficient and effective outpatient-based IRUD. These findings would serve as a valuable reference for undiagnosed diseases programs in different international jurisdictions and for countries and regions who also share vision(s) for societal implementation that help to advance international efforts to support patients with rare diseases who are direly waiting for diagnosis, subsequent treatment and care.

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Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome

Iriki H., Ouchi T., Ito H., Sawada M., Mukai M., Nomura H., Baba Y., Adachi T., Funakoshi T., Amagai M., Takahashi H.

Journal of Dermatology （Journal of Dermatology）  45 （ 6 ） 738 - 741 2018年06月

査読有り,  ISSN  03852407

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The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.

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Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells

Kitashima D.Y., Kobayashi T., Woodring T., Idouchi K., Doebel T., Voisin B., Adachi T., Ouchi T., Takahashi H., Nishifuji K., Kaplan D.H., Clausen B.E., Amagai M., Nagao K.

EBioMedicine （EBioMedicine）  27   293 - 303 2018年01月

査読有り,  ISSN  2352-3964

　概要を見る

Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

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Japan’s initiative on rare and undiagnosed diseases (IRUD): towards an end to the diagnostic odyssey

Takeya Adachi, Kazuo Kawamura, Yoshihiko Furusawa, Yuji Nishizaki, Noriaki Imanishi, Senkei Umehara, Kazuo Izumi, Makoto Suematsu

European Journal of Human Genetics （Springer Nature）  25 （ 9 ） 1025 - 1028 2017年09月

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Japan has been facing challenges relating to specifically defined rare diseases, called Nan-Byo in Japanese (literally 'difficult'+'illness'), and has already taken measures for them since 1972. This governmental support has surely benefited Nan-Byo patients; however, those suffering from medically unidentified conditions do not fall into this scheme and thus still confront difficulty in obtaining an examination, a diagnosis, and a treatment. To identify such rare and often undiagnosed diseases, we must integrate systematic diagnosis by medical experts with phenotypic and genetic data matching. Thus, in collaboration with Nan-Byo researchers and the Japanese universal healthcare system, the Japan Agency for Medical Research and Development launched the Initiative on Rare and Undiagnosed Diseases (IRUD) in 2015. IRUD is an ambitious challenge to construct a comprehensive medical network and an internationally compatible data-sharing framework. Synergizing with existing next-generation sequencing capabilities and other infrastructure, the nationwide medical research consortium has successfully grown to accept more than 2000 undiagnosed registrants by December 2016. We also aim at expanding the concept of microattribution throughout the initiative; that is, proper credit as collaborators shall be given to local primary care physicians, nurses and paramedics, patients, their family members, and those supporting the affected individuals whenever appropriate. As it shares many challenges among similar global efforts, IRUD's future successes and lessons learned will significantly contribute to ongoing international endeavors, involving players in basic research, applied research, and societal implementation.

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A Single-Center Open-Label Single-Arm Study Evaluating Efficacy and Safety of Skin Adhesive Epinexus<sup>TM</sup> in Surgical Patients

Kazuo Kishi, Noriko Aramaki-Hattori, Yoshiaki Sakamoto, Keisuke Okabe, Tetsu Hayashida, Maiko Takahashi, Yuko Kitagawa, Masataka Saito, Takeya Adachi, Aki Honda, Hiromitsu Jinno

Modern Plastic Surgery （Scientific Research Publishing, Inc,）  07 （ 04 ） 31 - 38 2017年

査読有り,  ISSN  2164-5213

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Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

Gareth Baynam, Faye Bowman, Karla Lister, Caroline E Walker, Nicholas Pachter, Jack Goldblatt, Kym M Boycott, William A Gahl, Kenjiro Kosaki, Takeya Adachi, Ken Ishii, Trinity Mahede, Fiona McKenzie, Sharron Townshend, Jennie Slee, Cathy Kiraly-Borri, Anand Vasudevan, Anne Hawkins, Stephanie Broley, Lyn Schofield, Hedwig Verhoef, Tudor Groza, Andreas Zankl, Peter N Robinson, Melissa Haendel, Michael Brudno, John S Mattick, Marcel E Dinger, Tony Roscioli, Mark J Cowley, Annie Olry, Marc Hanauer, Fowzan S Alkuraya, Domenica Taruscio, Manuel Posada de la Paz, Hanns Lochmüller, Kate Bushby, Rachel Thompson, Victoria Hedley, Paul Lasko, Kym Mina, John Beilby, Cynthia Tifft, Mark Davis, Nigel G Laing, Daria Julkowska, Yann Le Cam, Sharon F Terry, Petra Kaufmann, Iiro Eerola, Irene Norstedt, Ana Rath, Makoto Suematsu, Stephen C Groft, Christopher P Austin, Ruxandra Draghia-Akli, Tarun S Weeramanthri, Caron Molster, Hugh J S Dawkins

Advances in experimental medicine and biology （Springer International Publishing）  1031   55 - 94 2017年

査読有り,  ISSN  0065-2598

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Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.

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Skin-infiltrating CD4+ lymphoma cells depend on hair follicle-derived IL-7

Takeya Adachi, Tetsuro Kobayashi, Eiji Sugihara, Keitaro Fukuda, Manabu Ohyama, Hideyuki Saya, Taketo Yamada, Masayuki Amagai, Keisuke Nagao

Journal of Dermatological Science （Elsevier {BV}）  84 （ 1 ） e60 2016年10月

査読有り,  ISSN  0923-1811

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Case of isolated epidermolytic acanthoma: Genetic and immunohistochemical analysis

Takeya Adachi, Keiji Tanese, Takeshi Ouchi, Satomi Igawa, Hajime Nakano, Akira Ishiko

The Journal of Dermatology （Wiley-Blackwell）  43 （ 8 ） 974 - 975 2016年03月

査読有り,  ISSN  0385-2407

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Hair follicle–derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma

Takeya Adachi, Tetsuro Kobayashi, Eiji Sugihara, Taketo Yamada, Koichi Ikuta, Stefania Pittaluga, Hideyuki Saya, Masayuki Amagai, Keisuke Nagao

Nature Medicine （Springer Nature）  21 （ 11 ） 1272 - 1279 2015年10月

査読有り,  ISSN  1078-8956

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The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4(+) and CD8(+) skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8(+) TRM cells, and IL-7 for CD8(+) and CD4(+) TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4(+) TRM lymphoma cell localization depended on the presence of hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.

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Postherpetic Wolf's isotopic response: possible contribution of resident memory T cells to the pathogenesis of lichenoid reaction

M. Ise, K. Tanese, T. Adachi, W. Du, M. Amagai, M. Ohyama

British Journal of Dermatology （Wiley-Blackwell）  173 （ 5 ） 1331 - 1334 2015年10月

査読有り,  ISSN  0007-0963

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Toxic epidermal necrolysis in the absence of circulating T cells: A possible role for resident memory T cells

Hisato Iriki, Takeya Adachi, Mariko Mori, Keiji Tanese, Takeru Funakoshi, Daiki Karigane, Takayuki Shimizu, Shinichiro Okamoto, Keisuke Nagao

Journal of the American Academy of Dermatology （Elsevier {BV}）  71 （ 5 ） e214 - e216 2014年11月

査読有り,  ISSN  0190-9622

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Hapten-induced lymphadenosis benigna cutis secondary to squaric acid dibutylester sensitization for alopecia areata

Takeya Adachi, Takeshi Ouchi, Tamotsu Ebihara, Manabu Ohyama

The Journal of Dermatology （Wiley-Blackwell）  41 （ 2 ） 182 - 183 2014年01月

査読有り,  ISSN  0385-2407

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Comparison of basophil activation test and lymphocyte transformation test as diagnostic assays for drug hypersensitivity

Takeya Adachi, Hayato Takahashi, Takeru Funakoshi, Hiroyuki Hirai, Akihiko Hashiguchi, Masayuki Amagai, Keisuke Nagao

Clinical and Translational Allergy （Springer Nature）  4 （ Suppl 3 ） P30 2014年

査読有り,  ISSN  2045-7022

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Rheumatoid neutrophilic dermatosisの1例　関節リウマチの病勢との関連について

足立 剛也, 崎山 とも, 大内 健嗣, 高江 雄二郎, 安岡 秀剛, 谷川 瑛子

臨床皮膚科 （(株)医学書院）  67 （ 7 ） 501 - 505 2013年06月

ISSN  0021-4973

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55歳,女性.7年前より抗リウマチ薬およびメトトレキサートで関節リウマチ(rheumatoid arthritis:RA)を治療中であった.発熱と関節炎の増悪を認め,同時に四肢伸側に爪甲大までの浸潤性紅斑が出現した.病理組織学的に,真皮全層の好中球を主体とする稠密な炎症細胞浸潤であり,血管炎の所見は認めなかった.Rheumatoid neutrophilic dermatosis(RND)と診断し,エタネルセプト投与でRAの諸症状(発熱,関節炎)の軽快とともに皮疹の消退を認めた.RNDはRAに伴う稀な皮疹である.その発症機序は不明だが,過去の報告例よりコントロール不良のRA患者に多く発症し,その症状軽快に伴って消退する傾向が認められた.RNDはRAの病勢を反映し,その評価に有用である可能性が示唆された.(著者抄録)

Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin

Keisuke Nagao, Tetsuro Kobayashi, Kazuyo Moro, Manabu Ohyama, Takeya Adachi, Daniela Y Kitashima, Satoshi Ueha, Keisuke Horiuchi, Hideaki Tanizaki, Kenji Kabashima, Akiharu Kubo, Young-hun Cho, Björn E Clausen, Kouji Matsushima, Makoto Suematsu, Glaucia C Furtado, Sergio A Lira, Joshua M Farber, Mark C Udey, Masayuki Amagai

Nature Immunology （Springer Nature）  13 （ 8 ） 744 - 752 2012年06月

査読有り,  ISSN  1529-2908

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Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

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骨吸収を伴った小児口唇の線状強皮症の1例

足立 剛也, 宮本 樹里亜, 大内 健嗣, 大山 学, 海老原 全, 角田 和之, 天谷 雅行

臨床皮膚科 （(株)医学書院）  66 （ 4 ） 311 - 315 2012年04月

ISSN  0021-4973

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12歳,女児.初診2年前より下口唇に白色調の色調変化を認め,次第に病変が線状に拡大し,白色調も増強してきた.初診時,下口唇正中右側の赤唇部に,軽度に陥凹する線状の白色萎縮性病変を認め,白唇部から下顎の一部にも病変が及んでいた.また,同部位の延長線上の歯肉にも萎縮を伴っており,歯槽骨の一部にも吸収像がみられ,歯の動揺を伴った.病理組織所見では,表皮に著変なく,真皮浅層の浮腫と真皮全層にわたる膠原線維の膨化,均質化を認めた.硬化性萎縮性苔癬との鑑別が問題となったが,小児期の発症で,骨病変を合併したことより,線状強皮症と診断した.小児口唇の線状強皮症はきわめて稀であり,成長障害,機能障害をきたすこともあるため注意が必要である.文献的考察を加えて報告する.(著者抄録)

Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome

Takeshi Ouchi, Akiharu Kubo, Mariko Yokouchi, Takeya Adachi, Tetsuro Kobayashi, Daniela Y. Kitashima, Hideki Fujii, Björn E. Clausen, Shigeo Koyasu, Masayuki Amagai, Keisuke Nagao

The Journal of Experimental Medicine （Rockefeller University Press）  208 （ 13 ） 2607 - 2613 2011年

査読有り,  ISSN  0022-1007

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Epidermal Langerhans cells (LCs) extend dendrites through tight junctions (TJs) to survey the skin surface, but their immunological contribution in vivo remains elusive. We show that LCs were essential for inducing IgG(1) responses to patch-immunized ovalbumin in mice that lacked skin dendritic cell subsets. The significance of LC-induced humoral responses was demonstrated in a mouse model of staphylococcal scalded skin syndrome (SSSS), a severe blistering disease in which the desmosomal protein Dsg1 (desmoglein1) is cleaved by Staphylococcus aureus-derived exfoliative toxin (ET). Importantly, ET did not penetrate TJs, and patch immunization did not alter epidermal integrity. Nevertheless, neutralizing anti-ET IgG(1) was induced after patch immunization and abolished upon LC depletion, indicating that antigen capture through TJs by LCs induced humoral immunity. Strikingly, the ET-patched mice were protected from developing SSSS after intraperitoneal ET challenge, whereas LC-depleted mice were susceptible to SSSS, demonstrating a vital role for LC-induced IgG(1) in systemic defense against circulating toxin in vivo. Therefore, LCs elicit humoral immunity to antigens that have not yet violated the epidermal barrier, providing preemptive immunity against potentially pathogenic skin microbes. Targeting this immunological process confers protection with minimal invasiveness and should have a marked impact on future strategies for development of percutaneous vaccines.

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