Epistatic interaction of FcgammaRIIB and Sle16 polymorphism in rheumatoid arthritis

• Project/Area Number: 24590491
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Juntendo University
• Principal Investigator: HIROSE Sachiko 順天堂大学, 医学部, 准教授 (00127127)
• Co-Investigator(Renkei-kenkyūsha): AMANO Hirofumi 順天堂大学大学, 医学部, 准教授 (50318474)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 疾患モデル / 関節リウマチ / ループス腎炎 / 疾患感受性 / 疾患感受性遺伝子 / FcγRIIB / 素因遺伝子 / サイトカイン / 全身性エリテマトーデス

Outline of Final Research Achievements

FcγRIIB is expressed on B cells and a wide variety of immune cells, and negatively controls function of these cells. In the present studies, we examined whether the lack of FcγRIIB expression leads an aberrant activation of immune cells and the development of autoimmune diseases, by establishing FcγRIIB-deficient B6 congenic strains. The result suggested that the epistatic interaction between Fcgr2b null-mutation and autoimmune-type 129-derived polymorphic gene(s) in Sle16 region located in the distal of Fcgr2b gene contributes to the RA susceptibility. Identification of the susceptibility gene(s) for RA is of paramount importance to shed light on the genetic mechanisms that control RA in humans.

Research Products

• [Journal Article] IL-6 signal blockade ameliorates the enhanced osteoclastogenesis and the associated joint destruction in a novel FcγRIIB-deficient rheumatoid arthritis mouse model. (2015)
  • Author(s): Ohtsuji M, Lin Q, Nishikawa K, Ohtsuji N, Okazaki H, Tsurui H, Amano H, Shirai T, Nishimoto N, Nishimura H, and Hirose S.
  • Journal Title: Mod. Rheumatol. Volume: 25 Issue: 2 Pages: 270-277
  • DOI: 10.3109/14397595.2014.950035
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TNFα but not IL-17 is critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcγRIIB-deficient mouse model. (2014)
  • Author(s): Okazaki H, Lin Q, Nishikawa K, Ohtsuji N, Tsurui H, Ohtsuji M, Amano H, Tada N, Sudo K, Nishimura H, Shirai T, and Hirose S.
  • Journal Title: Mod. Rheumatol. Volume: 24 Issue: 6 Pages: 931-938
  • DOI: 10.3109/14397595.2014.886351
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dichotomy in the FcγRIIB deficiency and autoimmune-prone SLAM haplotype clarifies the roles of the Fc receptor in development of autoantibodies and glomerulonephritis. (2014)
  • Author(s): Kanari Y, Sugahara–Tobinai A, Takahashi H, Inui M, Nakamura A, Hirose S, Takai T.
  • Journal Title: BMC Immunol Volume: 15 Issue: 1 Pages: 47-47
  • DOI: 10.1186/s12865-014-0047-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD72c is a modifier gene that regulates Faslpr-induced autoimmune disease. (2013)
  • Author(s): Xu, M., Hou, R., Sato-Hayashizaki, A., Man, R., Zhu, C., Wakabayashi, C, Hirose, S., Adachi, T. and Tsubata, T.
  • Journal Title: J. Immunol. Volume: 190 Issue: 11 Pages: 5436-5445
  • DOI: 10.4049/jimmunol.1203576
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcgRIIB-deficient C57BL/6 (2013)
  • Author(s): Kawano S, Lin Q, Amano H, Kaneko T, Nishikawa K, Tsurui H, Tada N, Nishimura H,Takai T, Shirai T, Takasaki Y and Hirose S
  • Journal Title: mice. Volume: 43 Issue: 3 Pages: 770-778
  • DOI: 10.1002/eji.201243057
  • Peer Reviewed
• [Journal Article] Development of a model of early-onset IgA nephropathy. (2012)
  • Author(s): Okazaki K, Suzuki Y, Otsuji M, Suzuki H, Kihara M, Kajiyama T, Hashimoto A, Nishimura H, Brown R, Hall S, Novak J, Izui S, Hirose S, Tomino Y.
  • Journal Title: J Am Soc Nephrol Volume: 23 Issue: 8 Pages: 2930-2938
  • DOI: 10.1681/asn.2011121160
  • Peer Reviewed
• [Journal Article] Transgenic overexpression of G5PR that is normally augmented in centrocytes impairsthe enrichment of high-affinity antigen-specific B cells, increases peritoneal B-1a cells, and induces autoimmunity in aged female mice (2012)
  • Author(s): hi H, Ohtsuji M, Tsurui H, Hirose S, and Sakaguchi N
  • Journal Title: J. Immunol Volume: 189 Issue: 3 Pages: 1193-1201
  • DOI: 10.4049/jimmunol.1102774
  • Peer Reviewed
• [Journal Article] Nephrotoxic effect of subchronic exposure to <i>S</i>-(1,2-dichlorovinyl)-<i>L</i>-cysteine in mice (2012)
  • Author(s): Shirai N, Ohtsuji M, Hagiwara K, Tomisawa H, Ohtsuji N, Hirose S, Hagiwara H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 37 Issue: 5 Pages: 871-878
  • DOI: 10.2131/jts.37.871
  • NAID: 130004447001
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed
• [Presentation] B cell specific FcγRIIb deficiency is enough for autoantibody production, but not for the progression of Yaa-related lupus nephritis. (2014)
  • Author(s): LIN Qingshun, TSURUI Hiromichi, NISHIKAWA Keiko, AMANO Hirofumi, OHTSUJI Mareki, NISHIMURA Hiroyuki, SHIRAI Toshikazu, VERBEEK Sjef, HIROSE Sachiko.
  • Organizer: 第43回 日本免疫学会総会・学術集会
  • Place of Presentation: 京都、京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Gene expression profile in spleen cells of (NZB x NZW) F1 mice with overt SLE activity. (2014)
  • Author(s): HIRONO Fusako, OBATA Masaomi, KODERA Yo, OHTSUJI Mareki, SHIRAI Toshikazu, HIROSE Sachiko, NISHIMURA Hiroyuki.
  • Organizer: 第43回 日本免疫学会総会・学術集会
  • Place of Presentation: 京都、京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] TNFα and IL-6 but not IL-17 are critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcγRIIB-deficient mouse model. (2014)
  • Author(s): OHTSUJI Mareki, OKAZAKI Hideki, LIN Qingshun, NISHIKAWA Keiko, NISHIMURA Hiroyuki, AMANO Hirofumi, NISHIMOTO Norihiro, SHIRAI Toshikazu, HIROSE Sachiko.
  • Organizer: 第43回 日本免疫学会総会・学術集会
  • Place of Presentation: 京都、京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Genetic dissection of FcγRIIb deficiency and autoimmune-type SLAM haplotype reveals the important role of FcγRIIb in Yaa-related lupus nephritis. (2014)
  • Author(s): NISHIKAWA Keiko, LIN Qingshun, TSURUI Hiromichi, AMANO Hirofumi, NISHIMURA Hiroyuki, SHIRAI Toshikazu, TAKAI Tosjiyuki, HIROSE Sachiko.
  • Organizer: 第43回 日本免疫学会総会・学術集会
  • Place of Presentation: 京都、京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Phenotype conversion from rheumatoid arthritis to systetmic lupus erythematosus by introduction of Yaa mutation into FcγRIIB-deficient C57BL/6 mice. (2014)
  • Author(s): Shinya Kawano, Qingshun Lin, Hirofumi Amano, Toshiyuki Kaneko, Keiko Nishikawa, Hiromichi Tsurui, Norihiro Tada, Hiroyuki Nishimura, Toshiyuki Takai, Toshikazu Shirai, Sachiko Hirose, Yoshinari Takasaki.
  • Organizer: 第58回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京、グランドプリンスホテル新高輪
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] IL-6 signal blockade ameriolates spontaneous occurring rheumatoid arthritis in an FcγRIIB-deficient mouse model through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance. (2014)
  • Author(s): Mareki Ohtsuji, Qingshun Lin, Keiko Nishikawa, Hideki Okazaki, Hiroyuki Nishimura, Norihiro Nishimoto, Sachiko Hirose.
  • Organizer: 第58回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京、グランドプリンスホテル新高輪
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] B cell specific deficiency of FcγRIIB is required for autoantibody production, but not enough for early onset of lupus nephritis in B6.Yaa mice. (2014)
  • Author(s): Qingshun Lin, Keiko Nishikawa, Mareki Ohtsuji, Hiroyuki Nishimura, Hirofumi Amano, Sachiko Hirose.
  • Organizer: 第58回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京、グランドプリンスホテル新高輪
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Blockade of TNFa, but not IL-17, ameliorates spontaneously occurring autoimmune arthritis in FcgRIIB-deficient mice. (2013)
  • Author(s): OKAZAKI Hideki, LIN Qingshun, NISHIKAWA Keiko, TSURUI Hiromichi, OHTSUJI Mareki, NISHIMURA Hiroyuki, SHIRAI Toshikazu, HIROSE Sachiko.
  • Organizer: 第42回 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Thorough characterization of TCR-pMHC binding free energy estimated by string model and Miyazawa-Jernigan matrix (III). (2013)
  • Author(s): TSURUI Hiromichi, HIROSE Sachiko.
  • Organizer: 第42回 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Cd72c is a modifier gene that regulates FASlpr-induced autoimmune disease. (2013)
  • Author(s): (口頭) XU Miduo, HIROSE Sachiko, ADACHI Takahiro, TSUBATA Takeshi.
  • Organizer: 第42回 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] B cell specific deficiency of FcgRIIB results in high levels of autoantibodies without severe lupus nephritis in C57BL/6.Yaa mice. (2013)
  • Author(s): (口頭) LIN Qingshun, NISHIKAWA Keiko, TSURUI Hiromichi, OKAZAKI Hideki, OHTSUJI Mareki, NISHIMURA Hiroyuki, AMANO Hirofumi, SHIRAI Toshikazu, HIROSE Sachiko.
  • Organizer: 第42回 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Peripheral tolerance of antigen-specific Th cells induced with polyethylene glycol-conjugate of protein antigen. (2013)
  • Author(s): (口頭) OBATA Masaomi, OHTSUJI Mareki, SHIRAI Toshikazu, HIROSE Sachiko, NISHIMURA Hiroyuki.
  • Organizer: 第42回 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcgRIIB-deficient C57BL/6 mice. (2013)
  • Author(s): (Oral) Sachiko Hirose, Shinya Kawano, Qingshun Lin, Hirofumi Amano, Toshiyuki Kaneko, Keiko Nishikawa, Hiromichi Tsurui, Hiroyuki Nishimura, Toshikazu Shirai.
  • Organizer: 15th International Congress of Immunology,
  • Place of Presentation: Milan, Italy
• [Presentation] Characterization of TCR-pMHC interaction based on string model and Miyazawa-Jernigan matrIX (2013)
  • Author(s): Hiromichi Tsurui, Sachiko Hirose
  • Organizer: 15th International Congress of Immunology,
  • Place of Presentation: Milan, Italy
• [Presentation] A novel locus of B6 mice on chromosome 12 plays a role in common process shared by SLE, RA, and Sjögren syndrome. (2013)
  • Author(s): Toshiyuki Kaneko, Hirofumi Amano, Mareki Ohtsuji, Keiko Nishikawa, Shinya Kawano, Naomi Ohtsuji, Qingshun Lin, Hideki Okazaki, Hiromichi Tsurui, Hiroyuki Nishimura, Toshikazu Shirai, Yoshinori Takasaki, and Sachiko Hirose.
  • Organizer: 5th East Asian Group of Rheumatology
  • Place of Presentation: ソウル,韓国
• [Presentation] Clarification of the role of FcgRIIB for autoimmune disease using the cellspecific FcgRIIB conditionalkanockout mice (2013)
  • Author(s): Qingshun Lin, Hirofumi Amano, Hiroyuki Nishimura, Keiko Nishikawa, Sachiko Hirose
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcγRIIB-deficient C57BL/6 mice. (2013)
  • Author(s): Shinya Kawano, Toshiyuki Kaneko, Aya Sato- Hayashizaki, Lin Qingshun, Hirofumi Amano. Sachiko Hirose, Yoshinari Takasaki.
  • Organizer: 5th East Asian Group of Rheumatology.
  • Place of Presentation: ソウル、韓国
• [Presentation] Clarification of the role of FcgRIIB for autoimmune disease using the cell-specific FcgRIIB conditional knockout mice. (2013)
  • Author(s): Qingshun Lin, Hirofumi Amano, Hiroyuki Nishimura, Keiko Nishikawa, Sachiko Hirose.
  • Organizer: 第57回日本リウマチ学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] 重篤な関節リウマチを自然発症するFcγレセプターIIB欠損マウスの樹立 (2012)
  • Author(s): 広瀬幸子、佐藤綾、林青順、天野浩文、大辻希樹、西村裕之
  • Organizer: 第56回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] FcγレセプターIIB欠損マウスにおけるYaa遺伝子の与える影響 (2012)
  • Author(s): 河野晋也、天野浩文、金子俊之、佐藤綾、林青順、広瀬幸子、高崎芳成
  • Organizer: 第56回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Effect of SAP-deficiency on B cell-mediated autoimmune disease (2012)
  • Author(s): Qingshun Lin, Mareki Ohtsuji, Aya Hayashizaki, Hiroyuki Nishimura, Masao Ono, Sachiko Hirose
  • Organizer: 第56回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Mechanism of Th cell tolerance induced with tolerogenic polyethylene glycol(PEG)-conjugate of protein antigen. (2012)
  • Author(s): OBATA Masaomi, OHTSUJI Mareki, SHIRAI Toshikazu, HIROSE Sachiko, NISHIMURA Hiroyuki.
  • Organizer: 第41回 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸
• [Presentation] Thorough characterization of TCR-pMHC binding free energy estimated by string model and Miyazawa-Jernigan matrix. (2012)
  • Author(s): TSURUI Hiromichi, HIROSE Sachiko.
  • Organizer: 第41回 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸
• [Presentation] Phenotype conversion from RA to SLE in FcγRIIB-deficient B6 mice by Yaa mutation. (2012)
  • Author(s): KAWANO Shinya, AMANO Hirofumi, LIN Qingshun, KANEKO Toshiyuki, NISHIKAWA Keiko, OKAZAKI Hideki, TSURUI Hiromichi, NISHIMURA Hiroyuki, SHIRAI Toshikazu, TAKASAKI Yoshinari, HIROSE Sachiko
  • Organizer: 第41回 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸
• [Presentation] The role of SAP-signal in SLE. (2012)
  • Author(s): LIN Qingshun, TSURUI Hiromichi, NISHIKAWA Keiko, OKAZAKI Hideki, OHTSUJI Mareki, NISHIMURA Hiroyuki, ONO Masao, SHIRAI Toshikazu, HIROSE Sachiko.
  • Organizer: 第41回 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸
• [Presentation] Servival of antigen-derived germinal center B-cell is controlled by centrocyte-associated expression of apoptosis-regulator G5PR. (2012)
  • Author(s): KITABATAKE Masahiro, TODA Teppei, KUWAHARA Kazuhiro, IGARASHI Hideya, OHTSUJI Mareki, HIROSE Sachiko, SAKAGUCHI Nobuo
  • Organizer: 第41回 日本免疫学会総会・学術集会.
  • Place of Presentation: 神戸
• [Presentation] A novel locus of B6 mice on chromosome 12 plays a role in common process shared by SLE, RA, and Sjogren syndrome. (2012)
  • Author(s): KANEKO Toshiyuki, AMANO Hirofumi, KAWANO Shinya, Lin Qingshun, OKAZAKI Hideki, TSURUI Hiromichi, NISHIMURA Hiroyuki, SHIRAI Toshikazu, TAKASAKI Yoshinari, HIROSE Sachiko.
  • Organizer: 第41回 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸
• [Book] Arthritis Research, Methods and Protocols, Second Edition. (2014)
  • Author(s): Masaomi Obata, Mareki Ohtsuji, Yukiyasu Iida, Toshikazu Shirai, Sachiko Hirose, and Hiroyuki Nishimura
  • Total Pages: 204
  • Publisher: Human Press