Does IL-21 produced in Peyer's patch regulate the affinity of IgA and food allergy?

• Project/Area Number: 18K05478
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 38050:Food sciences-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Hashiguchi Masaaki 獨協医科大学, 医学部, 准教授 (20372443)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: IgA / パイエル板 / IL-21

Outline of Final Research Achievements

IgA is at least partly induced in Peyer’s patches (PPs), which are secondary lymphoid tissues and scatteredly located in the small intestine (SI). However, the precise mechanisms have not been clarified yet. Establishing hybridomas from naive murine PPs revealed the major specificity against double stranded DNA in IgA. The IgA was induced by the intestinal microbes and in PPs, but was independent of CD4+ T cells. IgA positively regulate intestinal bacteria via an antigen-independent manner. TGF-beta induced IgA secretion from naive B cells, but was not enough for the induction of surface IgA. The additional IL-21 and IL-5 upregulate surface IgA+ B cell frequency. The blocking of IL-21R signaling abrogated GC B cell frequency and IgA+ B cells in PPs. PPs were required for oral antigen-specific IgA in the intestine. These results suggest that PPs are required for anti-dsDNA and anti-diet protein IgAs, and that IL-21 and IL-5 coordinately induce IgA.

Academic Significance and Societal Importance of the Research Achievements

腸管で産生されるIgA抗体については、一部は腸内細菌に結合するなど、特異性などが徐々に明らかにされつつあるが、詳細な解析は行われてきていなかった。本研究の結果は、IgA抗体の特異性を明らかにしたことにより全体像が見え、解析の方向性を定める点で、重要な知見となったと考える。また、IgA抗体産生誘導機構の一部が明らかとなり、今後の解析の上で重要な知見となったと考える。

Research Products

• [Journal Article] IL-21 and IL-5 coordinately induce surface IgA+ cells (2020)
  • Author(s): Hashiguchi Masaaki、Kashiwakura Yuji、Kanno Yumiko、Kojima Hidefumi、Kobata Tetsuji
  • Journal Title: Immunology Letters Volume: 224 Pages: 21-27
  • DOI: 10.1016/j.imlet.2020.05.004
  • Peer Reviewed
• [Journal Article] Peyer’s patches contain abundant isotype-switched B cells with activated phenotypes and are inductive sites for T-independent anti-DNA IgA (2019)
  • Author(s): Hashiguchi, M., Kashiwakura, Y., Kojima, H., Kanno, Y., Kobata, T.
  • Journal Title: Immunol. Lett. Volume: 211 Pages: 53-59
  • DOI: 10.1016/j.imlet.2019.05.015
  • Peer Reviewed
• [Presentation] RORalpha is crucial for the survival of IgA+ plasma cells but not B220+ IgA+ cells (2019)
  • Author(s): Hashiguchi, M., Kashiwakura, Y., Kanno, Y., Kojima, H., Kobata, T.
  • Organizer: 第48回日本免疫学会総会・学術集会
• [Presentation] IL-21 and CD4+ T cells are required for Peyer’s patch germinal center formation but not for intestinal IgA in homeostatic condition (2018)
  • Author(s): Hashiguchi, M., Kashiwakura, Y., Kanno, Y., Kojima, H., Kobata, T.
  • Organizer: 第47回日本免疫学会総会・学術集会