Role of the allelic polymorphism of osteopontin gene on the pathogenesis and development of autoimmune glomerulonephritis

骨桥蛋白基因等位多态性在自身免疫性肾小球肾炎发病、发展中的作用

• 批准号: 11670217
• 负责人: MIYAZAKI Tatsuhiko
• 金额: $ 2.3万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670217/
• 关键词: Osteopontin; Allelic Polymorphism; Glomerulonephritis; MRL; lpr mice; Synthetic functional protein; Functional analysis; IgG3; TNFα; lprマウス; TNFα; IL-1β; 合成多型蛋白; サイトカイン

An MRL/Mp・lpr/lpr strain of mice(MRL/lpr)with deficit in Fas is a well-known model of autoimmune diseases including lupus nephritis, while C3H/HeJ-lpr/lpr(C3H/lpr)mice do not develop the diseases. We performed genome wide screening of susceptibility loci to the development of glomerulonephritis, defined in pathological manifestations, using 179 MRL/lpr ×(MRL/lpr × C3H/lpr)F1 backcross mice and 266(MRL/lpa × C3H/lpr)F2 intercross mice, followed by precise mapping on chromosome 5 using 526 F2 intercross mice. As a result, the highest significant linkage of glomerulonephritis was mapped at the position of D5Mit115 on chromosome 5 in the same alias of osteopontin(OPN)gene, manifesting a dominant mode of susceptible inheritance of the MRL allele. To clarify the functional difference between the OPN allele of MRL and C3H strains in the developmental mechanisms of glomerulonephritis, we carried out a functional analysis of the polymorphic OPN derived from both strains, which were synthetically prepared in a Cell-Free System, using the short term co-culture system with splenocytes of MRL or C3H mice. MRL-OPN induced higher mRNA expression and production of IgG3 as well as cytokines including TNF-α and IL-1β than C3H-OPN.These findings suggest that an allelic polymorphism of OPN may play a critical role for the development of glomerulonephritis in MRL/lpr mice.

Fas缺陷的MRL/Mp·lpr/lpr品系小鼠(MRL/lpr)是众所周知的狼疮性肾炎等自身免疫性疾病模型，而C3H/HeJ-lpr/lpr(C3H/lpr)小鼠则不会患上这些疾病。我们使用 179 只 MRL/lpr ×(MRL/lpr × C3H/lpr)F1 回交小鼠和 266 只(MRL/lpa × C3H/lpr)F2 交叉小鼠，对病理表现中定义的肾小球肾炎发生的易感位点进行全基因组筛查，然后使用 526 只 F2 交叉小鼠在 5 号染色体上进行精确定位。 老鼠。结果，肾小球肾炎的最高显着连锁定位于与骨桥蛋白（OPN）基因同名的第5号染色体上的D5Mit115位置，体现了MRL等位基因易感遗传的显性模式。为了阐明MRL和C3H菌株的OPN等位基因在肾小球肾炎发生机制中的功能差异，我们使用与MRL或C3H小鼠脾细胞的短期共培养系统，在无细胞系统中合成制备了源自这两种菌株的多态性OPN，进行了功能分析。与 C3H-OPN 相比，MRL-OPN 诱导更高的 mRNA 表达和 IgG3 以及细胞因子（包括 TNF-α 和 IL-1β）的产生。这些发现表明 OPN 的等位基因多态性可能在 MRL/lpr 小鼠肾小球肾炎的发生中发挥关键作用。

项目成果

Ito, M.R.et al: "Experimental lupus nephritis in severe combined immunodeficient(SCID)mice : remodelling of the glomerular lesions by bystander IgM antibodies."Clinical and Experimental Immunology. 119・2. 340-345 (2000)

Ito, M.R. 等人：“严重联合免疫缺陷 (SCID) 小鼠的实验性狼疮肾炎：旁观者 IgM 抗体重塑肾小球病变”。《临床和实验免疫学》119·2 (2000)。

Nose,M., et al.: "Genome analysis of collagen disease in MRL/lpr mice : polygenic inheritance resulting in the complex pathological manifestations."Inaternational Journal of Cardiology. 75・Suppl.1. S53-61 (2000)

Nose, M., et al.：“MRL/lpr 小鼠胶原病的基因组分析：导致复杂病理表现的多基因遗传。”国际心脏病学杂志 75·Suppl.1 (2000)。

Nose M,Nishihara M,Kamogawa J,Terada M,Nakatsuru S.: "Genetic basis of autoimmune disease in MRL/lpr mice:Dissection of the complex pathological manifestations and their susceptibility loci.."Rev Immunogenet. (in press).

Nose M、Nishihara M、Kamokawa J、Terada M、Nakatsuru S.：“MRL/lpr 小鼠自身免疫性疾病的遗传基础：复杂病理表现及其易感位点的解剖。”Rev 免疫基因。

Qu, WM.et al: "Genetic dissection of vasculitis in MRL/lpr lupus mice : a novel susceptibility locus involving the CD72c allele."European Journal of Immunology. 30・7. 2027-2037 (2000)

Qu, WM.等人：“MRL/lpr 狼疮小鼠血管炎的基因解剖：涉及 CD72c 等位基因的新型易感基因座。”欧洲免疫学杂志 30・7 (2000)。

Qu, W, M.et al.: "Genetic dissection of vasculitis in MRL/lpr lupus mice : a novel susceptibility locus involving the CD72c allele."Eur.J.Immunol.. 30(7). 2027-2037 (2000)

Qu, W, M.等人：“MRL/lpr 狼疮小鼠血管炎的基因解剖：涉及 CD72c 等位基因的新易感基因座。”Eur.J.Immunol.. 30(7)。