Pathogenesis of SLE: Linkage Analysis of Critical Signaling Pathways

2013 Fiscal Year Final Research Report

• 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
• 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

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 (2013)
  • Author(s): Obata M, Ohtsuji M, Iida Y, Shirai T, Hirose S and Nishimura H
  • Journal Title: Methods in Molec Biol Volume: 142(PMID:24706281) Pages: 111-41
  • DOI: 10.1007/978-1-4939-0404-4_13
• [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 FcγRIIB-deficient C57BL/6 mice (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, Hirose S
  • Journal Title: Eur J Immunol Volume: 43 Pages: 770-8
  • DOI: 10.1002/eji.201243057
• [Journal Article] Presumptive role of 129 strain- derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγreceptor 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: 2930-8
  • DOI: 10.1002/art.30485
• [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 Pages: 2333-40
  • DOI: 10.1002/eji.201141552