Mechanisms of the induction of A:T mutations in the germinal center B cells

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590445
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: WANG Jiyang 独立行政法人理化学研究所, 免疫多様性研究チーム, チームリーダー (80231041)
• Co-Investigator(Kenkyū-buntansha): OUCHIDA Rika 独立行政法人理化学研究所, 免疫多様性研究チーム, 研究員 (80391887)
• Project Period (FY): 2010 – 2012
• Keywords: 胚中心B細胞 / 抗体遺伝子 / 体細胞変異 / ミスマッチ修復 / 細胞分裂

Research Abstract

The activation-induced cytidine deaminase converts cytosine to uracil and generates a U:G lesion on DNA, which obviously can cause mutations at the C:G pair. However, half of the mutations in the germinal center B cells occur at the non-damaged A:T pair. In the present study, we found that the induction of A:T mutations is an intrinsic property of the germinal center B cells and is independent of target gene location but requires rapid cell division.

Research Products

• [Journal Article] FcμR (Toso/Faim3) is not an inhibitor of Fas-mediated cell death in mouse T and B cells (2013)
  • Author(s): Ouchida, R., Mori, H., Ohno, H. and Wang, J.-Y.
  • Journal Title: Blood Volume: 121 Pages: 2368-2370
  • DOI: doi:10.1182/blood-2012-12-470906
  • Peer Reviewed
• [Journal Article] High levels of AID cause strand bias of mutations at A versus T in Burkitt's lymphoma cells (2013)
  • Author(s): Kano, C. and Wang, J.-Y.
  • Journal Title: Mol. Immunol. Volume: 54 Pages: 397-402
  • DOI: doi:10.1016/j.molimm.2013.01.005
  • Peer Reviewed
• [Journal Article] ADAR1 induces adenosine-targeted DNA mutations in senescent Bcl6-deficient cells (2013)
  • Author(s): Tsuruoka, N., Arima, M., Yoshida, N., Okada, S., Sakamoto, A., Hatano, M., Satake, H., Arguni, E., Wang, J.-Y., Yang, J.-H., Nishikura, K., Sekiya, S., Shozu, M. and Tokuhisa, T.
  • Journal Title: J. Biol. Chem. Volume: 288 Pages: 826-836
  • DOI: doi:10.1074/jbc.M112.365718
  • Peer Reviewed
• [Journal Article] Analysis of Ig gene hypermutation in Ung~<-/->Polh^<-/-> mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions (2013)
  • Author(s): Li, S., Zhao, Y. and Wang, J.-Y.
  • Journal Title: Mol. Immunol. Volume: 53 Pages: 214-217
  • DOI: doi:10.1016/j.molimm.2012.08.009
  • Peer Reviewed
• [Journal Article] Critical role of the IgM Fc receptor in IgM homeostasis, B cell survival and humoral immune responses (2012)
  • Author(s): Ouchida, R., Mori, H., Hase, K., Takatsu, H., Kurosaki, T., Tokuhisa, T., Ohno, H. and Wang, J.-Y.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 109 Pages: E2699-2706
  • DOI: doi:10.1073/pnas.1210706109
  • Peer Reviewed
• [Journal Article] A novel mechanism for the autonomous termination of pre-B cell receptor expression via induction of lysosomal-associated protein transmembrane 5 (2012)
  • Author(s): Kawano, Y., Ouchida, R., Wang, J.-Y., Yoshikawa, S., Yamamoto, M., Kitamura, D. and Karasuyama, H.
  • Journal Title: Mol. Cell. Biol. Volume: 32 Pages: 4462-4471
  • DOI: doi:10.1128/MCB.00531-12
  • Peer Reviewed
• [Journal Article] LAPTM5 is a positive regulator of pro-inflammatory signaling pathways in macrophages (2012)
  • Author(s): Glowacka, W.K., Alberts, P., Ouchida, R., Wang, J.-Y. and Rotin, D.
  • Journal Title: J. Biol. Chem. Volume: 287 Pages: 27691-27702
  • DOI: doi:10.1074/jbc.M112.355917
  • Peer Reviewed
• [Journal Article] HSP90α deficiency does not affect Ig gene hypermutation and class switch but causes enhanced MHC class II antigen presentation (2012)
  • Author(s): Li, Y., Li, S., Hoshino, M., Ishikawa, R., Kajiwara, C., Gao, X., Zhao, Y., Ishido, S., Udono, H. and Wang, J.-Y.
  • Journal Title: Int. Immunol. Volume: 24 Pages: 751-758
  • DOI: doi:10.1093/intimm/dxs076
  • Peer Reviewed
• [Journal Article] CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema (2012)
  • Author(s): Shigeta, A., Tada, Y., Wang, J.-Y., Ishizaki, S., Tuyusaki, J., Yamauchi, K., Kasahara, Y., Iesato, K., Tanabe, N., Takiguchi, Y., Sakamoto, A., Tokuhisa, T., Shibuya, K., Hiroshima, K., West, J. and Tatsumi, K.
  • Journal Title: American Journal of Physiology Volume: 303 Pages: L141-151
  • DOI: doi:10.1152/ajplung.00337.2011.
  • Peer Reviewed
• [Journal Article] Analysis of mice deficient in both REV1 catalytic activity and POLH reveals an unexpected role for POLH in the generation of C to G and G to C transversions during Ig gene hypermutation (2012)
  • Author(s): Kano, C., Hanaoka, F. and Wang, J.-Y.
  • Journal Title: Int. Immunol. Volume: 24 Pages: 169-174
  • DOI: doi:10.1093/intimm/dxr109
  • Peer Reviewed
• [Journal Article] Hsp90 contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells (2011)
  • Author(s): Imai, T., Kato, Y., Kajiwara, C., Mizukami, S., Ishige, I., Ichiyanagi, T., Hikida, M., Wang, J.-Y. and Udono, H.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Pages: 16363-16368
  • DOI: doi:10.1073/pnas.1108372108
  • Peer Reviewed
• [Journal Article] Comparison of two POLQ mutants reveals that a polymerase-inactive POLQ retains significant function in tolerance to etoposide and γ-irradiation in mouse B cells (2011)
  • Author(s): Li, Y., Gao, X. and Wang, J.-Y.
  • Journal Title: Genes Cells Volume: 16 Pages: 973-983
  • DOI: doi:10.1111/j.1365-2443.2011.01550.x
  • Peer Reviewed
• [Journal Article] Rapid cell division contributes to efficient induction of A/T mutations during Ig gene hypermutation (2011)
  • Author(s): Kano, C., Ouchida, R., Kokubo, T. and Wang J.-Y.
  • Journal Title: Mol. Immunol. Volume: 15-16 Pages: 1993-1999
  • DOI: doi:10.1016/j.molimm.2011.06.218
  • Peer Reviewed
• [Journal Article] Defining the immunological phenotype of Fc receptor-like B (FCRLB) deficient mice: confounding role of the inhibitory FcγRIIb(Featured in "In This Issue") (2010)
  • Author(s): Masuda, K., Mori, H., Ohara, O., Nakayama, M., Wang, J.-Y. and Burrows, P.
  • Journal Title: Cell. Immunol. Volume: 266 Pages: 24-31
  • DOI: doi:10.1016/j.cellimm.2010.08.007
  • Peer Reviewed
• [Journal Article] A role for lysosomal-associated protein transmembrane 5 in the negative regulation of surface BCR levels and B cell activation (2010)
  • Author(s): Ouchida, R., Kurosaki, T. and Wang, J.-Y.
  • Journal Title: J. Immunol. Volume: 185 Pages: 294-301
  • DOI: doi:10.4049/jimmunol.1000371
  • Peer Reviewed
• [Journal Article] Identification of TOSO/FAIM3 as an Fc receptor for IgM (2010)
  • Author(s): Shima, H., Takatsu, H., Fukuda, S., Ohmae, M., Hase, K., Kubagawa, H., Wang, J.-Y., and Ohno, H.
  • Journal Title: Int. Immunol. Volume: 22 Pages: 149-156
  • DOI: doi:10.1093/intimm/dxp121
  • Peer Reviewed
• [Presentation] Critical role of the IgM Fc receptor in IgM homeostasis (2012)
  • Author(s): Wang J-Y
  • Organizer: B cell survival and humoral immune responses International Symposium of the Japanese Society of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2012-12-06
• [Presentation] The IgM Fc receptor positively regulates B cell survival and antibody production (2012)
  • Author(s): Wang J-Y
  • Organizer: Innovation Summit Tokyo 2012 - Chronic Inflammation and Autoimmune Diseases
  • Place of Presentation: Tokyo
  • Year and Date: 2012-04-17
• [Presentation] The Fc receptor for IgM (FcμR) positively regulates primary and memory B cell responses (2012)
  • Author(s): Ouchida R, Mori H, Hase K, Kurosaki T, Ohno H, Wang J-Y
  • Organizer: Keystone Symposium on Regulation of Lymphocyte Signaling
  • Place of Presentation: Keystone, USA
  • Year and Date: 2012-03-13
• [Presentation] The Fc receptor for IgM (FcμR) positively regulates B cell survival and activation (2011)
  • Author(s): Wang J-Y
  • Organizer: International Symposium of the Japanese Society of Immunology
  • Place of Presentation: Chiba, Japan
  • Year and Date: 2011-11-27
• [Presentation] A critical role for REV1 in induction of C:G transitions and A:T mutations during immunoglobulin gene hypermutation (2010)
  • Author(s): Masuda K, Li Y, Ouchida R, Mori H, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-26
• [Presentation] Induction of A:T mutations is dependent on cellular environment but independent of mutation frequency and target gene location (2010)
  • Author(s): Kano C, Ouchida R, Moritan T, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-26
• [Presentation] Identification and characterization of the elusive IgM Fc receptor (FcμR) (2010)
  • Author(s): Kubagawa H, Oka S, Kubagawa Y, Torii I, Takayama E, Kang D, Gartland GL, Bertoli L, Mori H, Takatsu H, Kitamura T, Ohno H, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-25
• [Presentation] Identification of TOSO/FAIM3 as an Fc receptor for IgM (2010)
  • Author(s): Shima H, Takatsu H, Fukuda S, Ohmae M, Hase K, Kubagawa H, Wang J, Ohno H
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-25
• [Presentation] The autonomous termination of pre-BCR expression through BLNK-mediated induction of LAPTM5 (2010)
  • Author(s): Kawano Y, Ouchida R, Wang J, Yoshikawa S, Yamamoto M, Kitamura D, Karasuyama H
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-24
• [Presentation] A transcription factor regulates apoptosis of germinal center B cells and the production of high-affinity antibodies (2010)
  • Author(s): Li Y, Ouchida R, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-24
• [Presentation] The lysosomal protein LAPTM5 negatively regulates B cell activation and antibody production by downmodulating cell surface BCR expression (2010)
  • Author(s): Ouchida R, Mori H, Wang J-Y
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-23
• [Presentation] Induction of A:T mutations is dependent on cellular environment but independent of target gene location. (2010)
  • Author(s): Wang J, Kano C
  • Organizer: Experimental Biology
  • Place of Presentation: Anaheim, USA
  • Year and Date: 2010-04-28
• [Presentation] LAPTM5 controls B cell antigen receptor levels and negatively regulates B cell activation (2010)
  • Author(s): Ouchida R, Wang J-Y
  • Organizer: Keystone Symposium on Lymphocyte Activation and Gene Expression
  • Place of Presentation: Breckenridge, USA
  • Year and Date: 2010-03-01