The role of immune receptors with inter- and intraspecies diversity in infectious diseases

• Project/Area Number: 16K08839
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kanazawa University (2017-2018); Osaka University (2016)
• Principal Investigator: Hirayasu Kouyuki 金沢大学, 先進予防医学研究センター, 特任准教授 (30585170)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫レセプター / 免疫逃避機構 / 活性化レセプター / 抑制化レセプター / 白血球レセプター複合体 / 感染免疫 / 多様性 / 免疫逃避 / 感染症 / 病原微生物 / 免疫学 / 免疫受容体 / 病原性微生物

Outline of Final Research Achievements

The aim of this study is to clarify the role of immune receptors with inter- and intraspecies diversity in infectious diseases.
In the process of search for interaction between pathogens and host immune receptors, it was found that inhibitory receptor LILRB1 recognized RIFINs expressed on P. falciparum-infected red blood cells. RIFINs inhibited activation of LILRB1-expressing B cells and natural killer (NK) cells. Furthermore, P. falciparum-infected erythrocytes isolated from patients with severe malaria were more likely to interact with LILRB1 than erythrocytes from patients with non-severe malaria, suggesting that LILRB1-RIFIN interaction may be involved in the development of severe malaria.

Academic Significance and Societal Importance of the Research Achievements

マラリアは、マラリア原虫が引き起こす感染症であるが、これまでに有効なワクチンの開発は成功していない。マラリアは感染しても十分な免疫が獲得されないため、マラリア原虫には我々の免疫システムから逃れるメカニズムが存在すると考えられる。本研究によって、マラリア原虫には抑制化レセプターを利用して免疫応答を抑えるという新たなメカニズムが存在し、マラリア重症化に関与していることが明らかとなった。本研究成果は、今後、予防効果の高いマラリアワクチンや治療薬の開発に大きく貢献することが期待される。

Research Products

• [Int'l Joint Research] Univ. of Texas Southwestern Med. Center(米国)
• [Int'l Joint Research] University of Copenhagen/Copenhagen University Hospital(Denmark)
• [Int'l Joint Research] Tanga Research Centre(Tanzania)
• [Int'l Joint Research] Washington University School of Medicine(米国)
• [Journal Article] LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. (2018)
  • Author(s): Deng M, 外30名, Arase H, Xia N, Jiang Y, Collins R, You MJ, Homsi J, Unni N, Lewis C, Chen GQ, Fu YX, Liao XC, An Z, Zheng J, Zhang N, Zhang CC.
  • Journal Title: Nature Volume: 562 Pages: 605-609
  • DOI: 10.1038/s41586-018-0615-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heightened BRAF and BRAF pseudogene expression levels in two Japanese patients with Erdheim-Chester disease (2018)
  • Author(s): Murakami, Yukakoa, Wataya-Kaneda, Mari,*, Kitayama, Kazukoa, Arase, Norikoa,b Murota, Hiroyukia, Hirayasu, Kouyukic, Arase, Hisashib, Katayama, Ichiro
  • Journal Title: Journal of Cutaneous Immunology and Allergy Volume: - Pages: 16-22
  • DOI: 10.1002/cia2.12010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] LILRファミリーを介した宿主病原体相互作用 (2018)
  • Author(s): 平安恒幸、齋藤史路、荒瀬 尚
  • Journal Title: 医学のあゆみ Volume: 265 Pages: 1171-1176
• [Journal Article] 熱帯熱マラリア原虫による免疫逃避機構 (2018)
  • Author(s): 齋藤史路、平安恒幸、荒瀬 尚
  • Journal Title: 臨床免疫・アレルギー科 Volume: 70 Pages: 289-294
  • NAID: 40021674556
• [Journal Article] 細菌の抗体免疫逃避と生体防御 (2018)
  • Author(s): 平安恒幸
  • Journal Title: 臨床免疫・アレルギー科 Volume: 70 Pages: 452-458
• [Journal Article] LILRファミリーを標的とした病原体および腫瘍の免疫逃避機構 (2018)
  • Author(s): 平安恒幸
  • Journal Title: 臨床免疫・アレルギー科 Volume: 71 Pages: 283-287
  • NAID: 40021829191
• [Journal Article] Heightened BRAF and BRAF pseudogene expression levels in two Japanese patients with Erdheim-Chester disease (2018)
  • Author(s): Murakami Y, Wataya-Kaneda M, Kitayama K, Arase N, Murota H, Hirayasu K, Arase H, Katayama I.
  • Journal Title: Journal of Cutaneous Immunology and Allergy Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Leukocyte Immunoglobulin-Like Receptor (LILR) (2018)
  • Author(s): Kouyuki Hirayasu, Hisashi Arase
  • Journal Title: Encyclopedia of Signaling Molecules Second Edition Volume: - Pages: 2854-2861
  • Peer Reviewed
• [Journal Article] 抑制化受容体を標的とした熱帯熱マラリア原虫による免疫逃避機構 (2018)
  • Author(s): 齋藤史路、平安恒幸、荒瀬 尚
  • Journal Title: 実験医学 Volume: 36 Pages: 994-997
• [Journal Article] Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors (2017)
  • Author(s): Saito Fumiji、Hirayasu Kouyuki、Satoh Takeshi、Wang Christian W.、Lusingu John、Arimori Takao、Shida Kyoko、Palacpac Nirianne Marie Q.、Itagaki Sawako、Iwanaga Shiroh、Takashima Eizo、Tsuboi Takafumi、Kohyama Masako、Suenaga Tadahiro、Colonna Marco、Takagi Junichi、Lavstsen Thomas、Horii Toshihiro、Arase Hisashi
  • Journal Title: Nature Volume: 552 Pages: 101-105
  • DOI: 10.1038/nature24994
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myeloperoxidase/HLA Class II Complexes Recognized by Autoantibodies in Microscopic Polyangiitis (2017)
  • Author(s): Hiwa Ryosuke、Ohmura Koichiro、Arase Noriko、Jin Hui、Hirayasu Kouyuki、Kohyama Masako、Suenaga Tadahiro、Saito Fumiji、Terao Chikashi、Atsumi Tatsuya、Iwatani Hirotsugu、Mimori Tsuneyo、Arase Hisashi
  • Journal Title: Arthritis & Rheumatology Volume: 69 Pages: 2069-2080
  • DOI: 10.1002/art.40170
  • Peer Reviewed
• [Journal Article] 熱帯熱マラリア原虫のもつRIFINによる宿主の免疫抑制化受容体を介した免疫からの逃避の機構 (2017)
  • Author(s): 齋藤史路・平安恒幸・荒瀬 尚
  • Journal Title: First Author's Volume: - Pages: 142
  • DOI: 10.7875/first.author.2017.142
  • Peer Reviewed / Open Access
• [Journal Article] 病原微生物の抗体免疫逃避と生体防御 (2017)
  • Author(s): 平安恒幸、荒瀬 尚
  • Journal Title: 感染・炎症・免疫 Volume: 47 Pages: 2-9
• [Journal Article] LILRA2 is an innate immune sensor for microbially cleaved immunoglobulins. (2016)
  • Author(s): Hirayasu K, Saito F, Suenaga T, Shida K, Arase N, Oikawa K, Yamaoka T, Murota H, Chibana H, Nagai H, Nakamura Y, Katayama I, Colonna M, Arase H.
  • Journal Title: Nat Microbiol. Volume: - Pages: 1-1
  • DOI: 10.1038/nmicrobiol.2016.54
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 白血球レセプター複合体の多様性と機能 (2019)
  • Author(s): 平安恒幸
  • Organizer: 第1回日本医学会連合Rising Starリトリート
  • Invited
• [Presentation] RIFINs of Plasmodium falciparum target multiple inhibitory receptors for immune evasion (2019)
  • Author(s): Akihito Sakoguchi, Fumiji Saito, Kouyuki Hirayasu, Kyoko Shida, Masako Kohyama, Tadahiro Suenaga, Shiroh Iwanaga, Toshihiro Horii, Hisashi Arase
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Leukocyte Immunoglobulin-Like Receptor (LILR)にみる微生物と宿主の攻防 (2018)
  • Author(s): 平安 恒幸
  • Organizer: 第91回日本細菌学会総会
  • Invited
• [Presentation] Prothrombin complexed with HLA class II molecules is an autoantibody target in antiphospholipid syndrome (2017)
  • Author(s): Satoko Morikami, Kenji Tanimura, Noriko Arase, Kouyuki Hirayasu, Tadahiro Suenaga, Masako Kohyama, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Antiphospholipid antibody recognizes β2GPI complexed with HLA class II molecules via its domain V (2017)
  • Author(s): Yuki Sasagawa, Kenji Tanimura, Hui Jin, Noriko Arase, Tadahiro Suenaga, Masako Kohyama, Kouyuki Hirayasu, Satoko Morikami, Yasuhiko Ebina, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Antigen-specific immune regulation mediated by TCR-like antibodies (2017)
  • Author(s): Kazuki Kishida, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Chemical compounds that specifically inhibit aberrant MHC class II expression (2017)
  • Author(s): Yuta Shimizu, Kyoko Shida, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors (2017)
  • Author(s): Fumiji Saito, Kouyuki Hirayasu, Takeshi Satoh, Christian W. Wang, John Lusingu, Shiroh Iwanaga, Takafumi Tsuboi, Marco Colonna, Junichi Takagi, Thomas Lavstsen, Toshihiro Horii, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Crucial role of CD74 in hematopoietic cell differentiation (2017)
  • Author(s): Tatsuya Shishido, Masako Kohyama, Kouyuki Hirayasu, Tadahiro Suenaga, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Host-pathogen interaction through LILR and KIR receptor families (2017)
  • Author(s): Kouyuki Hirayasu
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2 (2017)
  • Author(s): Kouyuki Hirayasu
  • Organizer: Cytokines 2017 in Kanazawa, Japan
• [Presentation] Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2 (2016)
  • Author(s): Kouyuki Hirayasu, Fumiji Saito, Tadahiro Suenaga, Kyoko Shida, Noriko Arase, Keita Oikawa, ToshifumiYamaoka, Hiroyuki Murota, Hiroji Chibana, Ichiro Nakagawa, Tomoko Kubori, Hiroki Nagai, Yuji Nakamaru, Ichiro Katayama, Marco Colonna, Hisashi Arase
  • Organizer: 第45日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄）
  • Year and Date: 2016-12-05
• [Presentation] Induction of autoantibody by neo-self TSH receptor / MHC class II complexes (2016)
  • Author(s): Hui Jin, Noriko Arase, Sumiko Matsuoka, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Takehiko Sasazuki and Hisashi Arase
  • Organizer: 第45日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄）
  • Year and Date: 2016-12-05
• [Presentation] 細菌の抗体免疫逃避を検出する新たな免疫システム (2016)
  • Author(s): 平安恒幸
  • Organizer: 第69回日本細菌学会関西支部総会・学術講演会
  • Place of Presentation: 大阪市立大学 田中記念館（大阪）
  • Year and Date: 2016-11-19
  • Invited
• [Presentation] HLA クラス I 認識受容体群 LILR の新展開 - 病原微生物によって壊された抗体を認識 する生体防御機構 - (2016)
  • Author(s): 平安 恒幸, 齋藤 史路, 末永 忠広, 信田 京子, 荒瀬 規子, 及川 敬太, 山岡 俊文, 室田 浩之, 知花 博治, 中川 一路, 久堀 智子, 永井 宏樹, 中丸 裕爾, 片山 一朗, Marco Colonna, 荒瀬 尚
  • Organizer: 第25回日本組織適合性学会大会
  • Place of Presentation: 北海道大学（北海道）
  • Year and Date: 2016-10-22
• [Presentation] Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2 (2016)
  • Author(s): Hirayasu K, Saito F, Suenaga T, Shida K, Arase N, Oikawa K, Yamaoka T, Murota H, Chibana H, Nakagawa I, Kubori T, Nagai H, Nakamaru Y, Katayama I, Colonna M, Arase H
  • Organizer: 16th Annual Meeting of the Society for Natural Immunity
  • Place of Presentation: Taormina, Italy
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2 (2016)
  • Author(s): Hirayasu K, Saito F, Suenaga T, Shida K, Arase N, Oikawa K, Yamaoka T, Murota H, Chibana H, Nakagawa I, Kubori T, Nagai H, Nakamaru Y, Katayama I, Colonna M, Arase H
  • Organizer: 15th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Away Island, Japan
  • Year and Date: 2016-09-06
  • Int'l Joint Research
• [Remarks] マラリアの重症化メカニズムを解明(荒瀬グループがNature誌に発表)
  • URL: http://www.ifrec.osaka-u.ac.jp/jpn/research/20171130-0252.htm
• [Remarks] 熱帯熱マラリア原虫のもつRIFINによる宿主の免疫抑制化受容体を介した免疫からの逃避の機構
  • URL: http://first.lifesciencedb.jp/archives/17623
• [Remarks] 大阪大学免疫学フロンティア研究センター免疫化学研究室ホームページ
  • URL: http://immchem.biken.osaka-u.ac.jp
• [Patent(Industrial Property Rights)] マラリア治療薬、マラリアの治療方法、マラリア治療用候補物質のスクリーニング方法、マラリア重症化マーカー、マラリアの重症化の危険度を試験する方法および試験試薬 (2017)
  • Inventor(s): 平安史路、平安恒幸、荒瀬尚
  • Industrial Property Rights Holder: 国立大学法人大阪大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-228226
  • Filing Date: 2017