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

2022 Fiscal Year Final Research Report

• 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
• Keywords: IgA / MZB1 / Mucosal inflammation / Colitis / Colorectal cancer

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.

Free Research Field

免疫学

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。