Mechanism s regulating the gene rearrangements in immune system

• Project/Area Number: 18390084
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: SHIMIZU Akira Kyoto University, Graduate School of Medicine, Professor (00162694)
• Co-Investigator(Kenkyū-buntansha): SUGAI Manabu Kyoto University, Graduate School of Medicine, Lecturer (90303891)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥15,370,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2007: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2006: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: immunoglobulin gene / class switching / transcriptional regulation / Id2 / SIP / histone acetylation / Pax5 / Bcl6 / Bc16

Research Abstract

The most unque character in acquired immunity is that genes encoding receptors for antigen undergo rearrangements by DNA recombination to acquire and expand their function in the immune-competent lymphocytes. Furthermore these rearrangements determine the differentiation stage of the lymphocyte. The antigen receptor genes are completed by the rearrangements of variable regions, and this enables the receptors to bind specifically to the antigen. by this, each individual lymphocyte can recognize a specific antigen and thus immune system as whole can recognize a wide variety of antigens. In addition, antibodies act as effecter to eliminate or neutralize antigens. To expand such effecter function of antibody according to the route through which the antigens invade, the constant region genes of its heavy chain also rearrange during activation of B lymphocyte (class switch recombination, CSR).
In this study, we tried to elucidate the molecular mechanisms controlling the rearrangements per se and target gene specificity by analyzing transcription factors involved in the rearrangement process. We found that the transcription factors, Pax5, E2A, SIP, NF_KB, IRF4, and Runx1-3 are involved and important in the specific regulation of target gene selection and expression of AID gene that is essential for CSR. These factors together with Id2 form epigenetic regulatory circuits downstream to TFG-β signal. We also found that expression of these factors is affected by the micro-environment formed by a dynamic reorganization and neogenesis of the secondary and tertiary lymphoid tissues, and in some case these factors showed a redundant function but in other case they Showed opposite function. Such mechanism increases the complexity of the regulation.
In addition, using a combination of stimuli we established an efficient method to induce CSR specifically to IgA in vitro that has been very difficult up to now.

Research Products

• [Journal Article] Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H^+/K^+-ATPase-reactive TCR transgenic mouse. (2007)
  • Author(s): Katakai, T., et. al.
  • Journal Title: J. Immunol. 119・12 Pages: 7858-7867
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H^+/K^+-ATPase-reactive TCR transgenic mouse. (2007)
  • Author(s): Katakai, T. and Shimizu, A.
  • Journal Title: Cur. Immunol. Rev 3・4 Pages: 251-257
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IL-21 induces inhibitor of differentiation 2(ld2) and leads to complete abrogation of anaphylaxis in mica (2007)
  • Author(s): Kishida, T., Hiromura, Y., Shin-Ya, M., Asada, H., Kuriyama, H., Sugai, M., Shimizu, A., Yokota, Y., Hama, T., Imariishi, J., Hisa, Y., Mazda, O
  • Journal Title: J. Immunol 179 Pages: 8554-8561
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The network of fibroblastic reticular cells in the lymph node : functional framework for immune surveillance (2007)
  • Author(s): Katakai, T., Shimizu, A
  • Journal Title: Curr. Immunol. Rev 3 Pages: 251-257
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rudiment incisors survive and erupt as supernumerary teeth as a result of USAG-1 abrogation. (2007)
  • Author(s): Murashima-Suginami, A., et. al.
  • Journal Title: Biochem. Biophys. Res. Comm. 359 Pages: 549-555
  • Peer Reviewed
• [Journal Article] IL-21 induces inhibitor of differentiation 2 (Id2) and leads to complete abrogation of anaphylaxis in mice. (2007)
  • Author(s): Kishida, T., et. al.
  • Journal Title: J. Immunol. 179 Pages: 8554-8561
  • Peer Reviewed
• [Journal Article] The network of fibroblastic reticular cells in the lymph node: functional framework for immune surveillance. (2007)
  • Author(s): Katakai, T. and Shimizu, A.
  • Journal Title: Cur. Immunol. Rev. 3 Pages: 251-257
• [Journal Article] Plasma ghrelin levels in healthy elderly volunteers: the levels of acylated ghrelin in elderly females correlate positively with serum IGF-1 levels and bowel movement frequency and negatively with systolic blood pressure. (2006)
  • Author(s): Akamizu, T., et. al.
  • Journal Title: J. Endocrinol 188・2 Pages: 333-344
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A transmwmbrane chemokine, CXC chemokine ligand 16, expressed by lymph node fibroblastic reticular cells has the potential to regulate T cell migration and adhesion. (2006)
  • Author(s): Hara, T., et. al.
  • Journal Title: Int Immunol 188・2 Pages: 301-311
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Enhanced anti-fibrotic activity of plasmid DNA expressing small interference RNA for TGF-β type II receptor for a mouse model of obstructive nephropathy by cationized gelatin prepared from different amine compounds. (2006)
  • Author(s): Kushibiki, T., et. al.
  • Journal Title: J. Control. Release 110・3 Pages: 610-617
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] IL-21 induces inhibitor of differentiation 2(Id2)and leads to complete abrogation of anapbylaxis in mice. (2006)
  • Author(s): Kishida, T., et. al.
  • Journal Title: J. Immunol. 117・11 Pages: 8554-8561
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Plasma ghrelin levels in healthy elderly volunteers : the levels of acylated ghrelin in elderly females correlate positively with serum IGF-1 levels and bowel movement frequency and negatively with systolic blood pressure (2006)
  • Author(s): Akamizu, T., Murayama, T., Teramukai, S., Miura, K., Bando, I., Irako, T., Iwakura, H., Ariyasu, H., Hosoda, H., Tada, H., matsuyama, A., Kojima, S., Wada, T., Wakatsuki, Y., Mitsubayashi, K., Kawakita, T., Shimizu. A., Fukushima, M., Yokode, M., Kangawa, K
  • Journal Title: J. Endocrinol 188 Pages: 333-344
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A transmwmbrane chemokine, CXC chemokine ligand 16, expressed by lymph node fibroblastic reticular cells has the potential to regulate T cell migration and adhesion (2006)
  • Author(s): Hara, T., Katakai, T., Lee, J.-H., Nambu, Y., Nakajima-Nagata, N., Gonda, H., Sugai, M., Shimizu, A
  • Journal Title: Intemat. Immunol 18 Pages: 301-311
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] C Enhanced anti-fibrotic activity of plasmid DNA expressing small interference RNA for TGF-β type II receptor for a mouse model of obstructive nephropathy by cationized gelatin prepared from different amine compounds (2006)
  • Author(s): Kushibiki, T., Nagata-Nakajima, N., Sugai, M., Shimizu, A., Tabata, Y
  • Journal Title: J. Control. Release 110 Pages: 610-617
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spontaneous large-scale lymphoid neogenesis and balanced autoirpmunity versus tolerance in the stomach of H^+/K^+- ATPase-reactive TCR transgenic mouse (2006)
  • Author(s): Katakai, T., Nomura, T., Gonda, H., Sugai, M., Agata, Y., Nishio, A., Masuda, T., Sakappchi, S., Shimizu, A
  • Journal Title: J. Immunol 177 Pages: 7858-7867
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Plasma ghrelin levels in healthy elderly volunteers : the levels of acylated ghrelin in elderly females correlate positively with serum IGF-1 levels and bowel movement frequency and negatively with systolic blood pressure. (2006)
  • Author(s): Akamizu, T. et al.
  • Journal Title: J. Endocrinol 188・2 Pages: 333-344
• [Journal Article] A transmwmbrane chemokine, CXC chemokine ligand 16, expressed by lymph node fibroblastic reticular cells has the potential to regulate T cell migration and adhesion. (2006)
  • Author(s): Hara, T. et al.
  • Journal Title: Int Immunol. 18・2 Pages: 301-311
• [Journal Article] Enhanced anti-fibrotic activity of plasmid DNA expressing small interference RNA for TGF-β type II receptor for a mouse model of obstructive nephropathy by cationized gelatin prepared from different amine compounds. (2006)
  • Author(s): Kushibiki, T. et al.
  • Journal Title: J. Control. Release. 110・3 Pages: 610-617
• [Journal Article] Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H^+/K^+-ATPase-reactive TCR transgenic mouse. (2006)
  • Author(s): Katakai, T. et al.
  • Journal Title: J. Immunol. 117・11 Pages: 7858-7867
• [Presentation] Control of B cell differentiation and immune response by Id2 (2006)
  • Author(s): Sugai, M. and Shimizu, A.
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2006-12-12
  • Description: 「研究成果報告書概要(和文)」より