• Research outline
• Research interests
• Staff
• Publications
• Collaborations
• Research Grant List

Research outline

In our laboratory, we focus on immune receptors and their signaling molecules that activate signals via ITAM motifs, and are working to elucidate the physiological functions of these molecules using molecular biological and genetic engineering techniques. By doing so, we aim to discover novel mechanisms involved in the onset and progression of various diseases such as infectious diseases, cancer, and dementia, and to establish a new concept of treatment.

【Recent and selected publications】

• Mitsuyama H et al., Heliyon, 2024
• Iizasa E et al., Nat Commun., 2021.
• Uematsu T et al., Sci Rep., 2015.
• Hara H et al., Nat Commun., 2015.
• Yasukawa S et al., Nat Commun. 2014.
• Hara H et al., Trends in immunol., 2009.
• Hara H et al., J Immunol., 2008.
• Hara H et al., Nat Immunol., 2007.
• Hara H et al., J Exp Med., 2004
• Hara H, et al., Immunity., 2003

Contact

E-mail:

Research interests

• Pattern recognition receptors that recognize pathogenic mycobacteria and the immune evasion mechanisms by those receptors
• βc cytokine receptor signaling
• Functions and applications of novel lipid-inducible macrophages
• Regulation of itch by neuroimmune system
• Regulation of food allergy by immunosuppressive eosinophils

Staff

Professor

Instructor/Lecturer

Instructor/Lecturer

Assistant professor

Publications

Hiromitsu Hara

1. Mitsuyama H, Iizasa E, Kukita A, Toda S, Yoshida H, Inoue H, and Hara H: Deletion of Card9 eliminates the detrimental facets of mycobacterial adjuvants.
   Heliyon. 2024, 10(19):e38139.
2. Iizasa E, Chuma Y, Uematsu T, Kubota M, Kawaguchi H, Umemura M, Toyonaga K, Kiyohara H, Yano I, Colonna M, Sugita M, Matsuzaki G, Yamasaki S, Yoshida H and Hara H: TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation.
   Nat Commun. 2021, 12(1):2299.
3. Kimura D, Miyakoda K, Kimura K, Honma K, Hara H, Yoshida H, and Yui K: IL-27-producing CD4+ T cells regulate protective immunity during infection with malaria parasites.  
   Immunity. 2016, 44:672-682.
4. Uematsu T, Iizasa E-I, Kobayashi N, Yoshida H and Hara H: Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity.
   Sci Rep. 2015, 5:1757.
5. Hara H, Yokosuka T, Hirakawa H, Ishihara C, Yasukawa S, Yamazaki M, Koseki H, Yoshida H and Saito T: Clustering of CARMA1 through SH3-GUK domain interactions is required for its activation of NF-κB signaling.
   Nat Commun. 2015, 6:5555.
6. Yasukawa S, Miyazaki Y, Yoshii C, Nakaya M, Ozaki N, Toda S, Kuroda E, Ishibashi K-I, Yasuda T, Natsuaki Y, Mi-ichi F, Iizasa EI, Nakahara T, Yamazaki M, Kabashima K, Iwakura Y, Takai T, Saito T, Kurosaki T, Malissen B, Ohno N, Furue M, Yoshida H, and Hara H: An ITAM-Syk-CARD9 signaling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells.
   Nat Commun. 2014, 5:3755.
7. Hara H and Saito T: CARD9 vs. CARMA1 in innate and adaptive immunity.
   Trends in immunol. 2009, 30(5): 234-242.
8. Hara H, Ishihara C, Takeuchi A, Xue L, Morris SW, Penninger JM, Yoshida H, Saito T: Cell-type-specific regulation of ITAM-mediated NF-κB activation by adaptors CARMA1 and CARD9.
   J Immunol. 2008, 181(2):918-30.
9. Hara H, Ishihara C, Takeuchi A, Imanishi1 T, Xue L, Morris SW, Inui M, Takai T, Shibuya A, Saijo S, Iwakura Y, Ohno N, Koseki H, Yoshida H, Penninger JM & Saito T: The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors.
   Nat Immunol. 2007, 8(6):619-29.
10. Suzuki N, Suzuki S, Millar DG, Unno M, Hara H, Calzascia T, Yamasaki S, Yokosuka T, Chen NJ, Elford AR, Suzuki J, Takeuchi A, Mirtsos C, Bouchard D, Ohashi PS, Yeh WC, Saito T: A critical role for the innate immune signaling molecule IRAK-4 in T cell activation.
    Science. 2006 Mar 31;311(5769):1927-32
11. Hara H, Bakal C, Wada T, Bouchard D, Rottapel R, Saito T, Penninger JM: The molecular adapter Carma1 controls entry of IκB kinase into the central immune synapse.
    J Exp Med. 2004, 200(9):1167-77.
12. Hara H, Wada T, Bakal C, Kozieradzki I, Suzuki S, Suzuki N, Nghiem M, Griffiths EK, Krawczyk C, Bauer B, D'Acquisto F, Ghosh S, Yeh WC, Baier G, Rottapel R, Penninger JM: The MAGUK family protein CARD11 is essential for lymphocyte activation.
    Immunity. 2003, 18(6):763-75.
13. Hara H, Takeda A, Takeuchi M, Wakeham AC, Itie A, Sasaki M, Mak TW, Yoshimura A, Nomoto K, Yoshida H: The apoptotic protease-activating factor 1-mediated pathway of apoptosis is dispensable for negative selection of thymocytes.
    J Immunol. 2002, 168(5):2288-95.
14. Hara H, Kishihara K, Matsuzaki G, Takimoto H, Tsukiyama T, Tigelaar RE and Nomoto K: Development of dendritic epidermal T cells with a skewed diversity of gamma delta TCRs in Vd1-deficient mice.
    J Immunol. 2000, 165(7):3695-705.

和文総説（in Japanese）

1. 原博満：結核菌による宿主自然免疫応答の制御。
   生化学95(5):1-5 (2023).
2. 原博満：アレルギー性接触皮膚炎感作にかかわる自然免疫活性化機構.
   日本皮膚免疫アレルギー学会雑誌. 2(2) : 272-280 (2019)
3. 原博満：CBMシグナリングの異常によるリンパ球恒常性の破綻と疾患の発症。
   実験医学（増刊）「臓器連関による生体恒常性に破綻と疾患」（羊土社）37 (7): 1118-1126 (2019).
4. 豊永憲司、飯笹英一、原博満：ITAM/ITIM共役受容体によるパターン認識と自然免疫応答。
   臨床免疫・アレルギー科 66 (3):274-282 (2016) .
5. 原博満：Carma1クラスターによる抗原受容体シグナルの制御。
   臨床免疫・アレルギー科 64(4):398-403 (2015)
6. 原博満、安川晋輔：接触アレルゲンによる自然免疫活性化機構。
   感染炎症免疫 43 (4):285-95 (2013).
7. 原博満：CARMA1，BCL10，CARD9とNF-κBの活性化。
   臨床免疫・アレルギー科 54(3):378-383 (2010) .
8. 原博満：CARMA1（CARD11）によるNK細胞活性化の制御。 
   臨床免疫・アレルギー科 53 (2): 133-139 (2010).
9. 原博満：リンパ系細胞と骨髄系細胞におけるNF-kB活性化，MAPK活性化誘導アダプターの相違。
   臨床免疫・アレルギー科 49(3): 357-364 (2008).
10. 原博満：抗原レセプターを介したNF-kB活性化経路。
    実験医学 23:2052-2056(2005)   

Daiji Sakata

1. Kunimura K, Akiyoshi S, Uruno T, Matsubara K, Sakata D, Morino K, Hirotani K, Fukui Y: DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis.
   J Allergy Clin Immunol., 151(6), 1585-1594.e9, 2023.
2. Morino K, Kunimura K, Sugiura Y, Izumi Y, Matsubara K, Akiyoshi S, Maeda R, Hirotani K, Sakata D, Mizuno S, Takahashi S, Bamba T, Uruno T, Fukui Y: Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.
   Front Immunol., 17;14:1131146, 2023.
3. Tatsuguchi T, Uruno T, Sugiura Y, Oisaki K, Takaya D, Sakata D, Izumi Y, Togo T, Hattori Y, Kunimura K, Sakurai T, Honma T, Bamba T, Nakamura M, Kanai M, Suematsu M, Fukui Y: Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.
   Biochem Biophys Res Commun., 18;609:183-188, 2022.
4. Tatsuguchi T, Uruno T, Sugiura Y, Sakata D, Izumi Y, Sakurai T, Hattori Y, Oki E, Kubota N, Nishimoto K, Oyama M, Kunimura K, Ohki T, Bamba T, Tahara H, Sakamoto M, Nakamura M, Suematsu M, Fukui Y: Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.
   Int Immunol., 34(5), 277-289, 2022.
5. Matsubara K, Kunimura K, Yamane N, Aihara R, Sakurai T, Sakata D, Uruno T, Fukui Y: DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells.
   Biochem Biophys Res Commun., 24;559:135-140, 2021.
6. Kamikaseda Y, Uruno T, Kunimura K, Harada A, Saiki K, Oisaki K, Sakata D, Nakahara T, Kido-Nakahara M, Kanai M, Nakamura S, Ohkawa Y, Furue M, Fukui Y: Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound.
   J Allergy Clin Immunol., 148(2):633-638, 2021.
7. Sakurai T, Kukimoto-Miino M, Kunimura K, Yamane N, Sakata D, Aihara R, Yasuda T, Yokoyama S, Shirozu M, Fukui Y, Uruno T, Furue M, Fukui Y: A conserved PI(4, 5)P2-binding domain is critical for immune regulatory function of DOCK8.
   Life Sci. Alliance., 11;4(4):e202000873, 2021.
8. Aihara R, Kunimura K, Watanabe M, Uruno T, Yamane N, Sakurai T, Sakata D, Nishimura F, Fukui Y: DOCK8 controls survival of group 3 innate lymphoid cells in the gut through Cdc42 activation.
   Int Immunol., 1;33(3):149-160, 2020.
9. Kunimura K, Sakata D, Tun X, Uruno T, Ushijima M, Katakai T, Shiraishi A, Aihara R, Kamikaseda Y, Matsubara K, Kanegane H, Sawa S, Eberl G, Ohga S, Yoshikai Y, Fukui Y: S100A Protein Is Essential for the Development of Mature Microfold Cells in Peyer’s Patches.
   Cell Rep., 29(9), 2823-2834.e7, 2019.
10. Sakata D, Uruno T, Matsubara K, Andoh T, Yamamura K, Magoshi Y, Kunimura K, Kamikaseda Y, Furue M, Fukui Y: Selective role of neurokinin B in IL-31-induced itch response in mice.
    J Allergy Clin Immunol., 144(4), 1130-1133.e8, 2019.

Jun Kasamatsu

1. Wang WL*, Kasamatsu J*, Joshita S*, Gilfillan S, Di Luccia B, Panda SK, Kim DH, Desai P, Bando JK, Huang SC, Yomogida K, Hoshino H, Fukushima M, Jacobsen EA, Van Dyken SJ, Ruedl C, Cella M, Colonna M (*共同筆頭著者): The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4⁺ eosinophils unique to the small intestine.
   Proc Natl Acad Sci U S A., 7;119(23):e2204557119, 2022.
2. Tashiro R, Niizuma K, Kasamatsu J, Okuyama Y, Rashad S, Kikuchi A, Fujimura M, Kure S, Ishii N, Tominaga T: Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation.
   J Cell Physiol., 236(11):7554-7564, 2021.
3. Sato K, Yamamoto H, Nomura T, Kasamatsu J, Miyasaka T, Tanno D, Matsumoto I, Kagesawa T, Miyahara A, Zong T, Oniyama A, Kawamura K, Yokoyama R, Kitai Y, Ishizuka S, Kanno E, Tanno H, Suda H, Morita M, Yamamoto M, Iwakura Y, Ishii K, Kawakami K: Production of IL-17A at Innate Immune Phase Leads to Decreased Th1 Immune Response and Attenuated Host Defense against Infection with Cryptococcus deneoformans.
   J Immunol., 1;205(3):686-698, 2020.
4. Kasamatsu J, Deng M, Azuma M, Funami K, Shime H, Oshiumi H, Matsumoto M, Kasahara M, Seya T: Double-stranded RNA analog and type I interferon regulate expression of Trem paired receptors in murine myeloid cells.
   BMC Immunol., 3;17(1):9, 2016.
5. Kasamatsu J, Takahashi S, Azuma M, Matsumoto M, Morii-Sakai A, Imamura M, Teshima T, Takahashi A, Hirohashi Y, Torigoe T, Sato N, Seya T. PolyI:C and mouse survivin artificially embedding human 2B peptide induce a CD4+ T cell response to autologous survivin in HLA-A*2402 transgenic mice.
   Immunobiology, 220(1):74-82, 2015
6. Kasamatsu J, Azuma M, Oshiumi H, Morioka Y, Okabe M, Ebihara T, Matsumoto M, Seya T: INAM plays a critical role in IFN-γ production by NK cells interacting with polyinosinic-polycytidylic acid-stimulated accessory cells.
   J Immunol., 15;193(10):5199-207, 2014.
7. Kanda R, Sutoh Y, Kasamatsu J, Maenaka K, Kasahara M, Ose T: Crystal structure of the lamprey variable lymphocyte receptor C reveals an unusual feature in its N-terminal capping module.
   PLoS One, 23;9(1):e85875, 2014.
8. Kasamatsu J: Evolution of innate and adaptive immune systems in jawless vertebrates.
   Microbiol Immunol., 57(1):1-12, 2013.
9. Ebihara T, Azuma M, Oshiumi H, Kasamatsu J, Iwabuchi K, Matsumoto K, Saito H, Taniguchi T, Matsumoto M, Seya T: Identification of a polyI:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation.
   J Exp Med., 22;207(12):2675-87, 2010.
10. Kasamatsu J*, Sutoh Y*, Fugo K, Otsuka N, Iwabuchi K, Kasahara M (*共同筆頭著者): Identification of a third variable lymphocyte receptor in the lamprey.
    Proc Natl Acad Sci U S A., 10;107(32):14304-8, 2010.
11. Kasamatsu J, Oshiumi H, Matsumoto M, Kasahara M, Seya T: Phylogenetic and expression analysis of lamprey toll-like receptors.
    Dev Comp Immunol., 34(8):855-65, 2010.
12. Kasamatsu J, Suzuki T, Ishijima J, Matsuda Y, Kasahara M: Two variable lymphocyte receptor genes of the inshore hagfish are located far apart on the same chromosome.
    Immunogenetics, 59(4):329-31, 2007.
13. Kim HM, Oh SC, Lim KJ, Kasamatsu J, Heo JY, Park BS, Lee H, Yoo OJ, Kasahara M, Lee JO: Structural diversity of the hagfish variable lymphocyte receptors.
    J Biol Chem., 2;282(9):6726-32, 2007.
14. Pancer Z, Saha NR, Kasamatsu J, Suzuki T, Amemiya CT, Kasahara M, Cooper MD: Variable lymphocyte receptors in hagfish. 
    Proc Natl Acad Sci U S A., 28;102(26):9224-9, 2005.
15. Kasamatsu J, Watanabe Y, Hanzawa N: Genetic Variability of MHC Class II Beta 1 Genes in Far Eastern Dace,Tribolodon hakonensis. 
    Mar Biotechnol., 6 S398-S403, 2004.

和文総説 (in Japanese)

1. 笠松 純, 川上 和義: クリプトコックス感染における防御免疫応答とその破綻。
   日本医真菌学会雑誌 63(3) 47-58, 2022.
2. 笠松 純, 瀬谷 司, 笠原 正典: 病原体認識戦略の進化。
   臨床免疫・アレルギー科, 56(1), 113-121, 2010.
3. 笠松 純, 笠原 正典: 高次機能形成の比較ゲノム：抗原認識戦略の多様性 -免疫系の比較ゲノム解析から学ぶ-。
   比較ゲノム学から読み解く生命システム 基本概念から最新ゲノム情報まで, 87-96, 2007.
4. 笠松 純, 笠原 正典: Variable lymphocyte receptorの構造と機能。
   Annual Review 免疫 2007, 53-61, 中外医学社, 2006.
5. 笠松 純, 笠原 正典: 高次機能形成の比較ゲノム：適応免疫系の起源と多様性.
   細胞工学, 25(3), 298-303, 2006.

Shin-Ei Matsumoto

1. Eriko Kuramoto, Ayano Kitawaki, Takakazu Yagi, Hiroshi Kono, Shin-Ei Matsumoto, Hiromitsu Hara, Yasumasa Ohyagi, Haruki Iwai, Atsushi Yamanaka, Tetsuya Goto: Development of a system to analyze oral frailty associated with Alzheimer's disease using a mouse model.
   Frontiers in Aging Neuroscience  14:935033 (2022)
2. Tsukasa Fujiki, Shin-Ei Matsumoto, Yoshinori Katakura: Age-related functional decline of human B cells.
   Cytotechnology  74(2): 319-327 (2022)
3. Tetsuo Hayashi, Shotaro Shimonaka, Montasir Elahi, Shin-Ei Matsumoto, Koichi Ishiguro, Masashi Takahashi, Nobutaka Hattori, Yumiko Motoi: Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer's Disease Brain Extract in Mouse Brains.
   Journal of Alzheimer’s Disease  79: 1701-1711 (2021)
4. Shotaro Shimonaka, Shin-Ei Matsumoto, Montasir Elahi, Koichi Ishiguro, Masato Hasegawa, Nobutaka Hattori, Yumiko Motoi: Asparagine residue 368 is involved in Alzheimer’s disease tau strain-specific aggregation.
   Journal of Biological Chemistry  295(41): 13996-14014 (2020)
5. Tetsuya Goto, Eriko Kuramoto, Ashis Dhar, Rachel P-H Wang, Haruka Seki, Haruki Iwai, Atsushi Yamanaka, Shin-Ei Matsumoto, Hiromitsu Hara, Makoto Michikawa, Yasumasa Oyagi, Wai K Leung, Raymond C-C Chang: Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer’s Disease in 3xTg-AD Model Mice.
   Journal of Alzheimer’s Disease  76(4):1443-1459 (2020)
6. Nakayama S, Shimonaka S, Elahi M, Nishioka K, Oji Y, Matsumoto SE, Li Y, Yoshino H, Mogushi K, Hatano T, Sato T, Ikura T, Ito N, Motoi Y, Hattori N: Tau aggregation and seeding analyses of two novel MAPT variants found in patients with motor neuron disease and progressive parkinsonism.
   Neurobiology of aging  2019, 84: 240.e13-240.e22
7. Yuko Hara,Yumiko Motoi,Keigo Hikishima,Hiroshi Mizuma,Hirotaka Onoe,Shin-Ei Matsumoto,Montasir Elahi,Hideyuki Okano,Shigeki Aoki,Nobutaka Hattori: Involvement of the Septo-Hippocampal Cholinergic Pathway in Association with Septal Acetylcholinesterase Upregulation in a Mouse Model of Tauopathy
   CURRENT ALZHEIMER RESEARCH 14(1) 94-103 2017
8. Montasir Elahi, Zafrul Hassan, Yumiko Motoi, Shin-Ei Matsumoto, Koichi Ishiguro, and Nobutaka Hattori: Region-specific vulnerability to oxidative stress, neuroinflammation, and tau hyperphosphorylation in experimental diabetes mellitus mice.
   J Alzheimers Dis. 2016, 51(4) 1209-1224
9. Montasir Elahi, Yumiko Motoi, Shin-Ei Matsumoto, Zafrul Hassan, Koichi Ishiguro, and Nobutaka Hattori: Short-term treadmill exercise increased tau insolubility and neuroinflammation in tauopathy model mice
   Neurosci Lett. 2016, 610: 207-212
10. Shin-Ei Matsumoto, Yumiko Motoi, Koichi Ishiguro, Takeshi Tabira, Fuyuki Kametani, Masato Hasegawa, and Nobutaka Hattori: The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: implications of prion-like properties.
    Hum Mol Genet. 2015, 24(22): 6403-6416
11. Kosuke Tomimatsu, Shin-Ei Matsumoto, Hayato Tanaka, Makiko Yamashita, Hidekazu Nakanishi, Kiichiro Teruya, Saiko Kazuno, Tomoya Kinjo, Takeki Hamasaki, Ken-ichi Kusumoto, Shigeru Kabayama, Yoshinori Katakura and Sanetaka Shirahata: A rapid screening and production method using a novel mammalian cell display to isolate human monoclonal antibodies.
    Biochem Biophys Res Commun. 2013, 441(1): 59-64
12. Gakuro Harada, Shin-Ei Matsumoto, Makiko Yamashita, Kaoru Fujii, Sanetaka Shirahata and Yoshinori Katakura: In vitro immunization of Epstein-Barr virus-immortalized B cells augments antigen-specific antibody production.
    Cytotechnology. 2013, 65(6): 979-983
13. Satomi Shiota, Hidenori Takekawa, Shin-Ei Matsumoto, Kazuya Takeda, Fariz Nurwidya, Yasuko Yoshioka, Fumiaki Takahashi, Nobutaka Hattori, Takeshi Tabira, Hideki Mochizuki and Kazuhisa Takahashi: Chronic Intermittent Hypoxia/Reoxygenation Facilitate Amyloid-β Generation in Mice.
    J Alzheimers Dis. 2013, 37(2): 325-333
14. Kohei Shimada, Yumiko Motoi, Koichi Ishiguro, Taiki Kambe, Shin-Ei Matsumoto, Masako Itaya, Miyuki Kunichika, Hideo Mori, Atsuko Shinohara, Momoko Chiba, Yoshikuni Mizuno, Takashi Ueno, and Nobutaka Hattori: Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: Implications of autophagy promotion.
    Neurobiol Dis. 2012, 46(1): 101-108
15. Tohru Hasegawa, Masayoshi Ichiba, Shin-Ei Matsumoto, Koji Kasanuki, Taku Hatano, Hiroshige Fujishiro, Eizo Iseki, Nobutaka Hattori, Tatsuo Yamada, and Takeshi Tabira: Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer’s disease patients.
    J Alzheimers Dis. 2012, 31(1): 59-64