TAKAHASHI Hayato

写真a

Affiliation

School of Medicine, Department of Dermatology (Shinanomachi)

Position

Associate Professor

Academic Background 【 Display / hide

  • 1994.04
    -
    2000.03

    慶應義塾大学, 医学部

    University, Graduated

  • 2002.04
    -
    2006.03

    慶應義塾大学大学院, 医学研究科, 内科系皮膚科学

    Graduate School, Withdrawal after completion of doctoral course requirements, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), 慶應義塾大学, Coursework, 2009.01

    Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris.

Licenses and Qualifications 【 Display / hide

  • 医師免許, 2000.04

  • 日本皮膚科学会認定皮膚科専門医, 2007.10

 

Research Areas 【 Display / hide

  • Life Science / Dermatology

  • Life Science / Immunology

Research Keywords 【 Display / hide

  • Desmoglein

  • Pemphigus

  • Interface dermatitis

  • Drug eruption

  • Food allergy

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Books 【 Display / hide

  • 眼疾患アトラスシリーズ 第3巻『外眼部アトラス』

    高橋勇人, 総合医学社, 2019.10

    Scope: 丹毒,  Contact page: 108-109

  • 皮膚科のくすりの使い方

    高橋勇人, じほう, 2019.08

    Scope: 薬疹,  Contact page: 141-144

  • 私の治療2019-20年度

    高橋勇人, 日本医事新報社, 2019.07

    Scope: 天疱瘡,  Contact page: 877-878

  • ガイドライン外来診療 2019

    高橋勇人, 日経メディカル開発, 2019.03

    Scope: 薬疹,  Contact page: 329-334

  • 皮膚症状110症例でみる内科疾患

    高橋勇人, 日本医事新報社, 2018.09

    Scope: 悪性リンパ腫③ 腫瘍随伴性天疱瘡,  Contact page: 22-23

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Papers 【 Display / hide

  • Intravenous Ig Regulates Anti-Desmoglein 3 IgG Production in B220<sup>–</sup> Antibody-Producing Cells in Mice with Pemphigus Vulgaris

    Kase Y., Takahashi H., Ito H., Kamata A., Amagai M., Yamagami J.

    Journal of Investigative Dermatology (Journal of Investigative Dermatology)  142 ( 7 ) 1786 - 1792.e3 2022.07

    ISSN  0022202X

     View Summary

    Intravenous Ig (IVIG) is a treatment option for intractable cases of pemphigus vulgaris (PV), an autoimmune blistering disease caused by autoantibodies against desmoglein 3 (DSG3). To investigate the efficacy of IVIG on autoantibody secretion, we produced PV model mice by adoptive transfer of immunized Dsg3−/− splenocytes to Rag2−/− mice. We found that circulating anti-DSG3 IgG ELISA titer decreased in PV model mice after 5 days of treatment with IVIG compared with PBS-treated mice, whereas the F(ab’)2 fragment did not suppress the anti-DSG3 IgG titer. enzyme-linked immunospot assay revealed that IVIG treatment reduced the frequency of anti-DSG3 antibody–secreting cells in the spleen but not in lymph nodes and bone marrow. Moreover, this reduction was observed only in the splenic B220− fraction but not in the B220+ fraction. Furthermore, IVIG decreased the serum levels of anti-DSG3 IgG, even after a significant reduction of its titer, owing to antibody-mediated CD20+ B cell depletion. In addition, IVIG suppressed anti-DSG3 IgG production in B220−CD138+ plasma cells derived from PV model mice ex vivo. These results indicate that IVIG reduced autoantibody production in B220− cells containing plasma cells in PV model mice, and this function may indicate one of the mechanisms of action of IVIG on PV.

  • Risk of Progression to Autoimmune Disease in Severe Drug Eruption: Risk Factors and the Factor-Guided Stratification

    Mizukawa Y., Aoyama Y., Takahashi H., Takahashi R., Shiohara T.

    Journal of Investigative Dermatology (Journal of Investigative Dermatology)  142 ( 3 ) 960 - 968.e9 2022.03

    ISSN  0022202X

     View Summary

    The identification of risk factors is key not only to uncover the pathogenesis of autoimmune disease but also to predict progression to autoimmune disease. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is likely the best prototypic example for analyzing the sequential events. We conducted a retrospective study of 55 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms followed up for the possibility of later development of autoimmune disease ∼18 years after resolution. Nine patients progressed to autoimmune sequelae regardless of treatment. The generation of autoantibodies was preceded by 8 years in eight of the nine patients. The combination of increases in lymphocyte counts, severe liver damage, a rebound increase in globulin, persistent reactivations of Epstein‒Barr virus and human herpesvirus-6, and low IL-2 and IL-4 at the acute/subacute phases were significant risk factors for the future development of autoimmune disease. On the basis of these factors, we established a scoring system that can identify high-risk patients. When stratified these patients into three risk categories (low/intermediate/high), occurrence of autoimmune disease was exclusively detected in the high group. Our data represent a scoring system to identify patients at high risk of developing autoimmune disease, although a larger study is required to validate the scoring system.

  • IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3-Specific B Cell Receptor Knock-in Mouse

    Nomura H., Wada N., Takahashi H., Kase Y., Yamagami J., Egami S., Iriki H., Mukai M., Kamata A., Ito H., Fujii H., Ishikura T., Koseki H., Watanabe T., Yamada T., Ohara O., Koyasu S., Amagai M.

    Journal of Immunology (Journal of Immunology)  208 ( 3 ) 582 - 593 2022.02

    ISSN  00221767

     View Summary

    Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2-/- mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b-/- and Fcgr2b1/mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.

  • Analysis of clinical characteristics, prognosis and antibody pathogenicity of pemphigus patients positive for anti-desmoglein IgG autoantibodies in remission: a retrospective cohort study

    Zhao W.L., Ishii K., Egami S., Xu Z., Funakoshi T., Takahashi H., Tanikawa A., Ishiko A., Amagai M., Yamagami J.

    Journal of the European Academy of Dermatology and Venereology (Journal of the European Academy of Dermatology and Venereology)  36 ( 2 ) 271 - 278 2022.02

    ISSN  09269959

     View Summary

    Background: The detection of serum anti-desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that anti-Dsg autoantibodies remain detectable in some patients without active pemphigus lesions. Objectives: To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti-Dsg IgG autoantibodies in remission. Methods: We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay. Results: When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti-Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (P = 0.885) and rate of relapse (P = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (P = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti-Dsg antibodies in active phase and remission showed similar pathogenicity. Conclusions: This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.

  • Diagnostic utility of the basophil activation test in natto-induced hypersensitivity

    Fukuda R., Ouchi T., Asahina Y., Shiiya C., Takeuchi S., Yasuda-Sekiguchi F., Iriki H., Kouno M., Takahashi S., Tanikawa A., Amagai M., Takahashi H.

    Allergology International (Allergology International)  71 ( 1 ) 125 - 130 2022.01

    ISSN  13238930

     View Summary

    Background: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. Methods: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. Results: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. Conclusions: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

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Presentations 【 Display / hide

  • IL-27 is crucial in anti-desmoglein 3 autoantibody production in pemphigus vulgaris mouse model

    Kamata A, Takahashi H, Yoshida H, Yamagami J, Amagai M

    48th Annual Meeting of the Japanese Society for Immunology (Hamamatsu, Japan) , 

    2019.12

  • Blockade of pathogenic immunoglobulin class-switch is a tolerogenic process to prevent pemphigus development in desmoglein 3-sepecific B cell receptor knock-in mouse

    Nomura H, Takahashi H, Yamagami J, Fujii H, Koseki H, Watanabe T, Ohara O, Koyasu S, Amagai M

    48th Annual Meeting of The Japanese Society for Immunology (Hamamatsu, Japan) , 

    2019.12

  • The clinical utility of basophil activation test in diagnosis of hypersensitivity due to fermented soybeans,natto

    Fukuda R, Ouchi T, Shiiya C, Yasuda-Sekiguchi F, Kouno M, Takahashi S, Amagai M, Takahashi H

    EAACI Allegy School on Food Allergy (Paris, France) , 

    2019.12

  • 薬疹 経過中に自己抗体が出現した薬剤性過敏症症候群および疑い例の検討

    椎谷千尋, 大内健嗣, 舩越建, 天谷雅行, 高橋勇人

    第49回日本皮膚免疫アレルギー学会総会学術大会 (横浜) , 

    2019.11

  • Evaluation on cytokine and transcriptional factor impacts on cholesterol 25-hydroxylase induction in CD4+ T cells

    Takahashi H, Isami K, Amagai M

    44th Annual Meeting of the Japanese Society for Investigative Dermatology (Aomori, Japan) , 

    2019.11

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • [基盤研究A] 病態に直結するT細胞レパトアの制御を目指した、新たな免疫制御機構の同定と解析

    2019.04
    -
    2023.03

    基盤研究A, Research grant, Principal investigator

  • [慶應義塾・学事振興資金(個人研究 特B)]天疱瘡自己抗原に対する末梢性免疫寛容機構の解明

    2018.04
    -
    2019.03

    慶應義塾学事振興資金, No Setting

  • [革新的先端研究開発支援事業] PRIME 新規T細胞サブセットを規定するコレルテロール代謝酵素の機能解析と疾患制御への応用

    2016
    -
    2019

    AMED(国立研究開発法人日本医療研究開発機構)-PRIME, No Setting

  • [免疫アレルギー疾患等実用化研究事業 免疫アレルギー疾患実用化研究分野] 重症薬疹サンプルの選定、採取およびウィルス叢と疾患発症との関連性解析

    2015
    -
    Present

    AMED(国立研究開発法人日本医療研究開発機構), Coinvestigator(s)

  • Molecular mechanism of skin inflammation induced by desmoglein 3-specific T cells

    2014.04
    -
    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

     View Summary

    Interface dermatitis is a pathological feature which is commonly observed in a variety of skin diseases including lichen plans, severe drug adverse reaction, graft-versus-host disease, paraneoplastic pemphigus and so on. The molecular mechanism that leads to interface dermatitis has not been understood. In this project, we took advantage of genetically engineered mice and discovered that T-bet and Stat1, crucial transcriptional factors in T cell differentiation, are keys in development of interface dermatitis. On the other hand, we also sought to establish a novel concept in the field of Immunology in this project. Through investigating genes which are specifically induced by interleukin (IL)-27, we found that cholesterol metabolizing enzyme is induced by IL-27 and the function contributes to immune regulation. Our results are promisingly expected to be useful to invent a new treatment for skin inflammatory diseases in the future.

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Works 【 Display / hide

  • International League of Dermatological Societies-Newsletter「ILDS 2015 Young Dermatologist International Achievement Award(YDIAA) Winners」

    Hayato Takahashi

    2015.12

    Other

  • 慶應義塾医学部新聞「デスモグレイン3反応性T細胞による新規自己免疫性皮膚炎モデルの確立」

    高橋勇人

    2012.11

    Other

  • 慶應義塾医学部新聞「日本皮膚科学会 皆見省吾記念賞受賞」

    高橋勇人

    2012.07

    Other

Intellectual Property Rights, etc. 【 Display / hide

  • 自己免疫疾患における自己抗体産生を抑制するシグナル阻害自己免疫疾患治療剤

    Date applied: 特願2019-214253  2019.11 

    Joint

  • 25−ヒドロキシコレステロールを有効成分として含有してなる、活性化されたT細胞及び/又はB細胞に選択的な細胞死誘導剤又は細胞死促進剤

    Date applied: 特許出願2016-111556  2016.06 

    Patent, Joint

Awards 【 Display / hide

  • Young Dermatologist International Achievement Award 2015

    2015.06, International League of Dermatological Societies

  • 三四会奨励賞受賞

    2012.11

     View Description

    第92回慶應医学会総会(於新棟11階大会議室)にて

  • 平成24年度皆見省吾記念賞

    2012.06

     View Description

    第111回日本皮膚科学会総会(於京都)にて

 

Courses Taught 【 Display / hide

  • LECTURE SERIES, DERMATOLOGY

    2022

  • LECTURE SERIES, DERMATOLOGY

    2021

  • LECTURE SERIES, DERMATOLOGY

    2020

  • LECTURE SERIES, DERMATOLOGY

    2019

Courses Previously Taught 【 Display / hide

  • 皮膚科学

    学校法人慶應義塾大学

    2018.04
    -
    2019.03

  • 皮膚科学講義「皮膚の免疫・アレルギー・薬疹」2017/12/01

    Keio University

    2017.04
    -
    2018.03

  • 皮膚科学講義「アレルギー性皮膚疾患・薬疹」2016/11/24

    Keio University

    2016.04
    -
    2017.03

  • 皮膚科学講義「アレルギー性皮膚疾患・ 薬疹」2015/11/24

    Keio University

    2015.04
    -
    2016.03

  • 皮膚科学講義「アレルギー性皮膚疾患・ 薬疹」2014/11/26

    Keio University

    2014.04
    -
    2015.03

 

Memberships in Academic Societies 【 Display / hide

  • 日本炎症再生医学会, 

    2017
    -
    Present
  • 日本免疫学会, 

    2012
    -
    Present
  • 日本研究皮膚科学会, 

    2005
    -
    Present
  • 日本皮膚科学会, 

    2000
    -
    Present

Committee Experiences 【 Display / hide

  • 2017
    -
    Present

    日本研究皮膚科学会 ISID開設準備委員会 委員

  • 2017
    -
    2020

    日本研究皮膚科学会 推薦員会 委員

  • 2014
    -
    2017

    日本研究皮膚科学会 若手セミナー委員会 委員