Role of MZB1 in the regulation of gut IgA secretion during inflammatory conditions

• Project/Area Number: 20K07547
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Keio University (2022); Tokyo Medical and Dental University (2020-2021)
• Principal Investigator: Wang Ji-Yang 慶應義塾大学, 薬学部(芝共立), 客員教授 (80231041)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IgA / MZB1 / Mucosal inflammation / Colitis / Colorectal cancer / 腸管免疫 / 大腸炎 / 腸内細菌 / 形質細胞 / J鎖 / Ｊ鎖 / 二量体 / Ｂ細胞 / IgA分泌 / 分子シャペロン / 腸管 / 炎症

Outline of Research at the Start

腸管内のIgA（分泌型IgA）は、腸内細菌叢の恒常性維持と腸内での感染防御において重要な役割を担う。分泌型IgAは通常、1分子のJ鎖を含む二量体として腸管の形質細胞から分泌され、腸管内に輸送される。J鎖はIgAの輸送に必須であり、J鎖を含まないIgAは腸管内へ輸送されない。申請者は最近、シャペロン分子MZB1がJ鎖とIgAの結合を効率化し、MZB1欠損マウスでは炎症状態の腸管へのIgA分泌が著しく減少して腸炎が重症化することを見出した。本研究では、炎症時にのみMZB1依存的な腸管へのIgA分泌がおこるメカニズムの解明を通して、腸管でのIgAの産生と分泌の制御機構を解明する。

Outline of Final Research Achievements

The present study investigated the regulatory mechanism of gut IgA secretion and the role of IgA in suppressing colorectal cancer induced by colitis, and obtained the following results: 1) The molecular chaperon MZB1 plays a crucial role in promoting gut IgA secretion by inhibiting the degradation of cytoplasmic IgA in the plasma cell. 2) Single-cell RNA sequencing revealed that IgA+ plasma cells in the gut originated from B-1 cells. 3) MZB1-deficient mice exhibited worsened DSS-induced colitis and an increased incidence of colorectal cancer development. These results indicate that MZB1 is essential for suppressing colitis and inhibiting the progression of colorectal cancer by enhancing gut IgA secretion.

Academic Significance and Societal Importance of the Research Achievements

クローン病や潰瘍性大腸炎といった炎症性腸疾患（Inflammatory Bowel Disease: IBD）は根治困難な慢性腸疾患であり、大腸がんの誘発要因でもあるが、その発症機構は十分に解明されていない。本研究により、腸管へのIgA分泌が炎症抑制のみならず、炎症により誘発される大腸がんの発生をも抑制することが明らかになった。また、IgAを経口投与することにより、腸管炎症を抑制できることも示した。即ち、IgAが大腸炎や大腸がんの予防や治療薬として臨床応用できる可能性が示唆され、医学的・社会的な意義が極めて大きい。

Research Products

• [Journal Article] A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency (2023)
  • Author(s): IRF4 International Consortium、Fornes Oriol、Jia Alicia、Kuehn Hye Sun、Min Qing、Pannicke Ulrich、Schleussner Nikolai、Thouenon Romane、Yu Zhijia
  • Journal Title: Science Immunology Volume: 8 Issue: 79
  • DOI: 10.1126/sciimmunol.ade7953
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway (2022)
  • Author(s): Wang Ying、Liu Jun、Akatsu Chizuru、Zhang Runyun、Zhang Hai、Zhu Han、Liu Kangwei、Zhu Han-Ying、Min Qing、Meng Xin、Cui Chaoqun、Tang Yue、Yu Meiping、Li Yaxuan、Feng Xiaoqian、Wei Hao、Wen Zichao、Ji Sihan、Weigert Martin G.、Tsubata Takeshi、Wang Ji-Yang
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 36
  • DOI: 10.1073/pnas.2205629119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene (2022)
  • Author(s): Wang Wenjie、Min Qing、Lai Nannan、Csomos Krisztian、Wang Ying、Liu Luyao、Meng Xin、Sun Jinqiao、Hou Jia、Ying Wenjing、Zhou Qinhua、Sun Bijun、Hui Xiaoying、Ujhazi Boglarka、Gordon Sumai、Buchbinder David、Schuetz Catharina、Butte Manish、Walter Jolan E.、Wang Xiaochuan、Wang Ji-Yang
  • Journal Title: Frontiers in Immunology Volume: 13
  • DOI: 10.3389/fimmu.2022.890073
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glia maturation factor-γ is involved in S1P-induced marginal zone B-cell chemotaxis and optimal IgM production to type II T-independent antigen (2022)
  • Author(s): Li Y, Tang Y, Liu J, Meng X, Wang Y, Min Q, Hong R, Tsubata T, Hase K, Wang JY.
  • Journal Title: International Immunology Volume: 34 Issue: 1 Pages: 35-43
  • DOI: 10.1093/intimm/dxab097
  • Peer Reviewed
• [Journal Article] RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production. (2021)
  • Author(s): Min Q, Meng X, Zhou Q, Wang Y, Li Y, Lai N, Xiong E, Wang W, Yasuda S, Yu M, Zhang H, Sun J, Wang X, Wang JY.
  • Journal Title: JCI Insight Volume: 6 Issue: 19
  • DOI: 10.1172/jci.insight.148887
  • Peer Reviewed
• [Journal Article] Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis. (2021)
  • Author(s): Wei H, Wang JY
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 5 Pages: 2284-2284
  • DOI: 10.3390/ijms22052284
  • Peer Reviewed
• [Journal Article] CTLA-4 expression by B-1a B cells is essential for immune tolerance (2021)
  • Author(s): Yang Yang、Li Xiao、Ma Zhihai、Wang Chunlin、Yang Qunying et al
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 525-525
  • DOI: 10.1038/s41467-020-20874-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SAMHD 1‐mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination (2020)
  • Author(s): Husain Afzal、Xu Jianliang、Fujii Hodaka、Nakata Mikiyo、Kobayashi Maki、Wang Ji‐Yang、Rehwinkel Jan、Honjo Tasuku、Begum Nasim A
  • Journal Title: The EMBO Journal Volume: 39 Issue: 15
  • DOI: 10.15252/embj.2019102931
  • Peer Reviewed / Open Access
• [Journal Article] Effective and safe treatment of a novel IL2RA deficiency with rapamycin (2020)
  • Author(s): Lai Nannan、Liu Luyao、Lin Li、Cui Chaoqun、Wang Ying、Min Qing、Xiong Ermeng、Wang Wenjie、Ying Wenjing、Zhou Qinhua、Hou Jia、Sun Jinqiao、Wang Ji-Yang、Wang Xiaochuan
  • Journal Title: The Journal of Allergy and Clinical Immunology: In Practice Volume: 8 Issue: 3 Pages: 1132-1135.e4
  • DOI: 10.1016/j.jaip.2019.09.027
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct roles of BCNP1 in B-cell development and activation (2019)
  • Author(s): Hong Rongjian、Lai Nannan、Xiong Ermeng、Ouchida Rika、Sun Jiping、Zhou Yang、Tang Yue、Hikida Masaki、Tsubata Takeshi、Tagawa Masatoshi、Wang Yanqing、Wang Ji-Yang
  • Journal Title: International Immunology Volume: 32 Issue: 1 Pages: 17-26
  • DOI: 10.1093/intimm/dxz055
  • Peer Reviewed / Int'l Joint Research