Pathogenesis of SLE: Linkage Analysis of Critical Signaling Pathways

• Project/Area Number: 23591450
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Toin University of Yokohama
• Principal Investigator: NISHIMURA Hiroyuki 桐蔭横浜大学, 医用工学部, 教授 (60189313)
• Co-Investigator(Kenkyū-buntansha): 大辻 希樹 桐蔭横浜大学, 医用工学部, 専任講師 (30398664)
• Co-Investigator(Renkei-kenkyūsha): 広瀬 幸子 順天堂大学, 医学部, 准教授 (00127127)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 全身性エリテマトーデス / SLE / 全身性自己免疫疾患 / 疾患感受性遺伝子 / 遺伝連鎖解析 / QTL解析 / 多因子疾患 / 免疫寛容 / Fcgr2b / FcgRIIB / MHC class II / 自己免疫疾患 / NZB mice / NZW mice / 自己免役疾患

Research Abstract

In contrast to normal mice, autoimmune-prone New Zealand Black (NZB) mice are defective in susceptibility to tolerance induced by deaggregated bovine gamma globulin (DBGG). Susceptibility loci for this defect were examined by genome-wide analysis using F2 intercross of non-autoimmune C57BL/6 (B6) and NZB mice. One NZB locus on the telomeric chromosome 1, designated Dit (Defective immune tolerance)-1, showed a highly significant linkage. This locus overlapped with t a locus coding for polymorphic Fcgr2b and Slam family genes. The similar defective tolerance was observed in Fcgr2b-deficient mice with autoimmune-type Slam family genes, but not in Fcgr2b-deficient mice with normal C57BL/6-type Slam family genes indicating that epistatic interaction of both polymorphic genes is involved. Thus, this epistatic interaction is likely playing a pivotal role in the genetic predisposition to autoimmunity in NZB and related autoimmune-prone strains inclusing SLE model (NZB x NZW) F1 mice.

Research Products

• [Journal Article] Genome-wide genetic study in autoimmune disease-prone mice. (2014)
  • Author(s): Obata M, Ohtsuji M, Iida Y, Shirai T, Hirose S, Nishimura H
  • Journal Title: Methods Mol Biol Volume: 1142 Pages: 111-41
  • DOI: 10.1007/978-1-4939-0404-4_13
  • ISBN: 9781493904037, 9781493904044
  • Peer Reviewed
• [Journal Article] TNFalpha but not IL-17 is critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcgammaRIIB-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, Hirose S
  • Journal Title: Mol Rheumatol Volume: Mar 4 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Peripheral tolerance of antigen-specific Th cells induced with polyethylene glycol-conjugate of protein antigen (2013)
  • Author(s): Obata M, Fujii T, Ohtsuji M, Kodera Y, Nishimura H
  • Journal Title: Open J Immunol Volume: 3 Pages: 62-70
• [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] Peripheral tolerance of antigen-specific Th cells induced with polyethylene glycol-conjugate of protein antigen. (2013)
  • Author(s): Obata M, Fujii T, Ohtsuji M, Kodera Y. Nishimura H.
  • Journal Title: Open Journal of Immunology Volume: 3 Pages: 1-8
  • 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] Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcy receptor type Iib-deficient C57BL/6 genetic background. (2011)
  • Author(s): Sato-Hayashizaki A, Ohtsuji M, Lin Q, Hou R, Ohtsuji N, Nishikawa K, Tsurui H, Sudo K, Ono M, Izui S, Shirai T, Takai T, Nishimura H, Hirose S
  • Journal Title: Arthritis & Rheumatism Volume: 63 Issue: 10 Pages: 2930-2938
  • DOI: 10.1002/art.30485
  • Peer Reviewed
• [Journal Article] Susceptibility loci for the defective foreign protein-induced tolerance in New Zealand Black mice : implication of epistatic effects of Fcgr2b and Slam family genes (2011)
  • Author(s): Fujii T, Hou R, Sato-Hayashizaki A, Obata M, Ohtsuji M, Ikeda K, Mitsui K, Kodera Y, Shirai T, Hirose S, Nishimura H
  • Journal Title: Eur J Immunol Volume: 41 Issue: 8 Pages: 2333-40
  • DOI: 10.1002/eji.201141552
• [Journal Article] Susceptibility loci for the defective foreign protein-induced tolerance in New Zealand Black mice: Implication of epistatic effects of Fcgr2b and Slam family genes. (2011)
  • Author(s): Fujii T, Hou R, Sato-Hayashibara A, Obata M, Ohtsuji M, Ikeda K, Mitsui K, Kodera Y, Shirai T, Hirose S, Nishimura H
  • Journal Title: Eur. J. Immunol. Volume: 41 Pages: 2333-2340
  • Peer Reviewed
• [Journal Article] Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγ receptor type IIb-deficient C57BL/6 genetic background. (2011)
  • Author(s): Sato-Hayashizaki A, Ohtsuji M, Lin Q, Hou R, Ohtsuji N, Nishikawa K, Tsurui H, Sudo K, Ono M, Izui S, Shirai T, Takai T, Nishimura H, Hirose S
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 2930-2938
  • Peer Reviewed
• [Journal Article] ポリエチレングリコール修飾抗原による免疫寛容の誘導 (2011)
  • Author(s): 尾畑賢臣 藤原 龍 西村裕之 小寺 洋
  • Journal Title: 臨床免疫・アレルギー科 Volume: 56 Pages: 429-433
  • NAID: 40019053111
• [Presentation] Peripheral tolerance of antigen-specific Th cell induced with polyethylene glycol-conjugate of protein antigen. (2013)
  • Author(s): Obata M, Ohtsuji M, Shirai T, Hirose S, Nishimura H.
  • Organizer: 第42回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ、千葉市
• [Presentation] Mechanism of Th-cell tolerance induced with the tolerogenic protein antigen conjugated with polyethylene glycol (2012)
  • Author(s): Obata M, Kodera Y, Ohtsuji M, Shirai T, Hirose S, Nishimura H.
  • Organizer: Toin International Symposium on Biomedical Engineering 2012,
  • Place of Presentation: Toin University of Yokohama, Aoba-ku Yokohama, Japan
• [Presentation] Mechanism of Th cell tolerance induced with tolerogenic polyethylene glycol(PEG)-conjugate of protein antigen (2012)
  • Author(s): Obata M, Ohtsuji M, Shirai T, Hirose S, Nishimura H.
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場、神戸
• [Presentation] Phenotype conversion from RA to SLE in FcgRIIB-deficient B6 mice by Yaa mutation. (2012)
  • Author(s): Kawano S, Amano H, Lin Q, Kaneko T, Nishikawa K, Okazaki H, Tsurui H, Nishimura H, Shirai T, Takasaki Y, Hirose S
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場、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 T, Amano H, Ohtsuji M, Nishikawa K, Shinya K, Ohtsuji M, Lin Q, Okazaki H, Tsurui H, Nishimura H, Shirai T, Takasaki Y, Hirose S.
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場、神戸
• [Presentation] The role of SLAM-signal in SLE. (2012)
  • Author(s): Lin Q, Tsurui H, Nishikawa K, Okazaki H, Ohtsuji M, Nishimura H, Ono M, Shirai T, Hirose S.
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場、神戸
• [Presentation] SLEにおけるSLAMシグナルの役割・The role of SLAM signal in SLE (2011)
  • Author(s): 林青順、大辻希樹、佐藤綾、大辻奈穂美、西川桂子、鶴井博理、須藤カツ子、西村裕之、小野栄夫、白井俊一、広瀬幸子
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ、千葉市
• [Presentation] ポリエチレングリコール修飾抗原によって誘導されるTh細胞免疫寛容の機序・Mechanism of Th-cell tolerance induced with tolerogenic protein antigen conjugated with polyethylene glycol. (2011)
  • Author(s): 藤原龍、尾畑賢臣、藤井琢磨、大辻希樹、小寺洋、広瀬幸子、西村裕之
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ、千葉市
• [Presentation] Presumptive role of 129 strain-derived Sle16 locus for rheumatoid arthritis in a new mouse model with FcgRIIB-deficient C57BL/6 genetic background. (2011)
  • Author(s): Sato A, Ohtsuji M, Lin Q, Ohtsuji N, Nishikawa K, Tsurui H, Ono M, Shirai T, Takai T, Nishimura H, Hirose S.
  • Organizer: 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ、千葉市