長谷 耕二 (ハセ コウジ)

Hase, Koji

写真a

所属(所属キャンパス)

薬学部 薬科学科 生化学講座 (芝共立)

職名

教授

HP

外部リンク

 

研究分野 【 表示 / 非表示

  • 免疫学

  • 消化器内科学

 

著書 【 表示 / 非表示

  • ヒトマイクロバイオーム研究最前線

    長谷 耕二, (株)エヌ・ティー・エス , 2016年03月

    担当範囲: 腸内細菌定着と宿主エピゲノム変化

  • エピジェネティクスキーワード事典

    長谷 耕二, 古澤之裕, 尾畑佑樹, 羊土社, 2013年12月

    担当範囲: 自己免疫・アレルギー疾患とエピジェネティクス

  • 臨床粘膜免疫学

    長谷 耕二, (株)シナジー, 2010年12月

    担当範囲: 粘膜上皮細胞における抗原捕捉と提示

論文 【 表示 / 非表示

  • Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses

    Nagai M., Noguchi R., Takahashi D., Morikawa T., Koshida K., Komiyama S., Ishihara N., Yamada T., Kawamura Y., Muroi K., Hattori K., Kobayashi N., Fujimura Y., Hirota M., Matsumoto R., Aoki R., Tamura-Nakano M., Sugiyama M., Katakai T., Sato S., Takubo K., Dohi T., Hase K.

    Cell (Cell)  178 ( 5 ) 1072 - 1087.e14 2019年08月

    ISSN  00928674

     概要を見る

    © 2019 Elsevier Inc. Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis. Temporary fasting drastically reduces the levels of B cells in Peyer's patches, with germinal center B cells undergoing apoptosis and naive cells migrating to the bone marrow and only egressing upon refeeding.

  • Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis

    Nishida K., Hasegawa A., Yamasaki S., Uchida R., Ohashi W., Kurashima Y., Kunisawa J., Kimura S., Iwanaga T., Watarai H., Hase K., Ogura H., Nakayama M., Kashiwakura J., Okayama Y., Kubo M., Ohara O., Kiyono H., Koseki H., Murakami M., Hirano T.

    Sci. Rep. 9 ( 1 ) 10842 2019年07月

    研究論文(学術雑誌), 共著, 査読有り

     概要を見る

    The Author(s). Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis.

  • Sox8 is essential for M-cell maturation to accelerate IgA response at the early stage after weaning in mice

    Kimura S, Kobayashi N, Nakamura Y, Kanaya T, Takahashi D, Fujiki R, Mutoh M, Obata Y, Iwanaga T, Nakagawa T, Kato N, Sato S, Kaisho T, Ohno H, and *HASE Koji

    J. Exp. Med. 216 ( 4 ) 831 - 846 2019年04月

    研究論文(学術雑誌), 共著, 査読有り,  ISSN  00221007

     概要を見る

    Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. The expression of Sox8 requires activation of RANKL-RelB signaling. Chromatin immunoprecipitation and luciferase assays revealed that Sox8 directly binds the promoter region of Gp2 to increase Gp2 expression, which is the hallmark of functionally mature M cells.Furthermore, genetic deletion of Sox8 causes a marked decrease in the number of mature M cells, resulting in reduced antigen uptake in Peyer's patches. Consequently, juvenile Sox8-deficient mice showed attenuated germinal center reactions and antigen-specific IgA responses. These findings indicate that Sox8 plays an essential role in the development of M cells to establish mucosal immune responses.

  • MZB1 promotes the secretion of J-chain–containing dimeric IgA and is critical for the suppression of gut inflammation

    Xiong E., Li Y., Min Q., Cui C., Liu J., Hong R., Lai N., Wang Y., Sun J., Matsumoto R., Takahashi D., Hase K., Shinkura R., Tsubata T., Wang J.

    Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America)  116 ( 27 ) 13480 - 13489 2019年

    ISSN  00278424

     概要を見る

    © 2019 National Academy of Sciences. All rights reserved. IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.

  • Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

    Yamada T., Hino S., Iijima H., Genda T., Aoki R., Nagata R., Han K., Hirota M., Kinashi Y., Oguchi H., Suda W., Furusawa Y., Fujimura Y., Kunisawa J., Hattori M., Fukushima M., Morita T., Hase K.

    EBioMedicine (EBioMedicine)  2019年

     概要を見る

    © 2019 Background: The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases; however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin establishes a first-line barrier against pathogens and serves as a niche for microbial growth. Methods: To elucidate relationships among dysbiosis, abnormal mucin utilisation, and microbial metabolic dysfunction, we analysed short-chain fatty acids (SCFAs) and mucin components in stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohn's disease (CD) patients from Japan. Findings: Levels of n-butyrate were significantly lower in stools of both CD and UC patients than in stools of healthy subjects. Correlation analysis identified seven bacterial species positively correlated with n-butyrate levels; the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans serve as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in colonic lamina propria. Microbial utilisation of mucin-associated O-glycans was significantly reduced in n-butyrate-deficient UC patients. Interpretation: Mucin O-glycans facilitate symbiosynthesis of n-butyrate by gut microbiota. Abnormal mucin utilisation may lead to reduced n-butyrate production in UC patients. Fund: Japan Society for the Promotion of Science, Health Labour Sciences Research Grant, AMED-Crest, AMED, Yakult Foundation, Keio Gijuku Academic Development Funds, The Aashi Grass Foundation, and The Canon Foundation.

全件表示 >>

KOARA(リポジトリ)収録論文等 【 表示 / 非表示

総説・解説等 【 表示 / 非表示

  • 腸内エコロジーを支える生物間代謝経路

    山田恭央, 長谷 耕二

    実験医学 36 ( 18 ) 3964 - 3069 2018年11月

    総説・解説(商業誌、新聞、ウェブメディア), 共著

  • 腸内エコロジーの破綻と炎症性腸疾患

    長谷 耕二

    実験医学 36 ( 18 ) 3054 - 3058 2018年11月

    総説・解説(商業誌、新聞、ウェブメディア), 単著

  • M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance.

    長谷 耕二

    Inflamm Regen. 38   15 2018年09月

    総説・解説(学術雑誌), 共著

  • 粘膜免疫組織としての小腸

    長谷 耕二

    消化器病サイエンス 2 ( 3 )  2018年09月

    総説・解説(商業誌、新聞、ウェブメディア), 単著

  • 粘膜面におけるバリア機能と免疫恒常性の維持に果たすM細胞の役割

    石原成美, 小林伸英, 長谷 耕二

    アレルギー 67 ( 3 ) 171 - 187 2018年05月

    総説・解説(商業誌、新聞、ウェブメディア), 共著

全件表示 >>

研究発表 【 表示 / 非表示

  • 飢餓ストレスによるリンパ球の動態制御

    長谷 耕二

    2017年度生命科学系学会合同年次大会 (ConBio2017), 2017年12月, 口頭(招待・特別)

  • 腸内細菌由来の酪酸による全身性自己免応答の制御

    長谷 耕二

    第22回日本食物繊維学会, 2017年11月, 口頭(招待・特別)

  • マイクロバイオータとアレルギー

    長谷 耕二

    第54回小児アレルギー学会, 2017年11月, 口頭(招待・特別)

  • Intestinal microbiota-derived metabolites regulate autoimmunity through epigenetic modifications

    長谷 耕二

    Fujihara Seminar (Tomakomai, Japan) , 2017年09月, 口頭(招待・特別)

  • Microbiota-derived metabolites shape host immunity

    長谷 耕二

    第59回歯科基礎医学会学術大会, 2017年09月, 口頭(招待・特別)

全件表示 >>

競争的資金等の研究課題 【 表示 / 非表示

  • 多変量解析による慢性炎症スパイラル形成機構の解明

    2017年07月
    -
    2020年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 長谷 耕二, 基盤研究(B), 補助金,  代表

  • 腸内代謝産物によるT細胞非依存的IgA産生誘導機構の解明

    2017年04月
    -
    2020年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 長谷 耕二, 基盤研究(B), 補助金,  代表

  • 生物間代謝経路によって制御される脂質クオリティの解析

    2016年04月
    -
    2018年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 長谷 耕二, 新学術領域研究(研究領域提案型), 補助金,  代表

  • 腸管免疫系を構成するTリンパ球のシングルセル解析への挑戦

    2016年04月
    -
    2018年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 長谷 耕二, 挑戦的萌芽研究, 補助金,  代表

受賞 【 表示 / 非表示

  • 第53回ベルツ賞(2等賞)

    2016年11月, べーリンガーインゲルハイム, 宿主-腸内細菌叢相互作用

    受賞区分: その他の賞

  • 第12回日本学術振興会賞

    2016年02月, 粘膜面における免疫制御機構の解明

    受賞区分: その他の賞

 

担当授業科目 【 表示 / 非表示

  • 細胞の機能と構成分子

    2019年度

  • 生化学系アドバンスト実習

    2019年度

  • 生化学実習

    2019年度

  • 免疫学1

    2019年度

  • C10(1)身体をまもる

    2019年度

全件表示 >>