Genetic control of the spontaneous activation of CD4+ Th cells in systemic lupus erythematosus (SLE)-prone (NZB x NZW) F1 mice

系统性红斑狼疮 (SLE) 倾向 (NZB x NZW) F1 小鼠 CD4 Th 细胞自发激活的遗传控制

• 批准号: 12670444
• 负责人: NISHIMURA Hiroyuki
• 金额: $ 2.24万
• 依托单位: Toin University of Yokohama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670444/
• 关键词: systemic autoimmune diseases; SLE; New Zealand mice; (NZB x NZW) F1; NZB mice; NZW mice; CD4+Th cells; CD69; CD4陽性T細胞; 自発的活性化; CD4陽性T細胞サブセット; マイクロサテライトDNA; Quantitative Trait Loci(QTL); 主要組織適合遺伝子複合体; リンパ球の活性化; 連鎖解析; Quantitative Trait Loci

The F1 hybrid of NZB (New Zealand Black) and NZW (New Zealand White) strains of mice has been studied as a murine model of systemic lupus erythematosus (SLE). In the hybrid mice, B1 (CD5+) cells were shown to be responsible for the autoantibody production. However, expression of SLE phenotypes of these mice is strictly dependent on CD4+ T cells. These mice show an age-dependent spontaneous activation and subset skewing of peripheral CD4+ T cells as reflected by the abnormal cytokine productions, elevated frequency of CD4+ T cells positive for an early activation marker CD69, and decreased frequencies of CD4+ T cells positive for the differentiation markers CD62L and/or NTA260. To study the genetic control of abnormal features of peripheral CD4^+ T cells in the ( NZB x NZW) F1 mice, we conducted genome-wide mapping of the quantitative trait loci (QTL) regulating the frequencies of CD69+CD4+, CD62L+CD4+ and NTA260+CD4+ T cells in the spleens of (NZB x .NZW) F1 x NZW backcross mice. Elevated frequency of CD69+CD4+ T cells, and decreased frequencies of CD62L+CD4+ and NTA260+CD4+ T cells were under the common multigenic control, in which interaction of the heterozygosity of the MHC class II loci and a hitherto unknown locus designated as Sta-1 ( spontaneous T-cell activation ) on chromosome 12 plays a major role. These genetic interactions were distinct from those involved in the abnormal functions of B1 cells. Therefore, in (NZB x NZW) F1 mice, abnormal functions of CD4+ T cells and B1 cells are based on distinct multi-genetic predisposition, both of which contribute to the manifestation of SLE phenotypes of the hybrid mice.

用新西兰黑(NZB)和新西兰白(NZW)品系的小鼠杂交F1作为系统性红斑狼疮(SLE)的小鼠模型。在杂交小鼠中，B1(CD5+)细胞被证明负责产生自身抗体。然而，这些小鼠的SLE表型的表达严格依赖于CD4+T细胞。这些小鼠表现出依赖年龄的外周CD4+T细胞的自发激活和亚群倾斜，表现为细胞因子产生异常，早期激活标记CD69阳性的CD4+T细胞频率增加，分化标记CD62L和/或NTA260阳性的CD4+T细胞频率下降。为了研究(NZB X NZW)F1小鼠外周血中CD4+T细胞异常特征的遗传控制，我们对(NZB X NZW)F1×NZW回交小鼠脾中CD69+CD4+、CD62L+CD4+和NTA260+CD4+T细胞的频率进行了全基因组定位。CD69+CD4+T细胞频率升高，CD62L+CD4+和NTA260+CD4+T细胞频率降低是共同的多基因控制，其中MHC II类基因的杂合性与12号染色体上一个迄今未知的基因STA-1(T细胞自发激活)的相互作用起主要作用。这些遗传交互作用不同于参与B1细胞功能异常的遗传交互作用。因此，在(NZB×NZW)F1小鼠中，CD4+T细胞和B1细胞的功能异常是基于不同的多基因易感性，这两者都是导致杂交小鼠SLE表型的原因。

项目成果

Shirai T, Nishimura H, Jiang Y, Hirose S.: "Genome screening for susceptibility Loci in Systemic Lupus Enythematosus"Am J Phamacogenomics. 2. 1-12 (2002)

Shirai T、Nishimura H、Jiang Y、Hirose S.：“系统性红斑狼疮易感基因座的基因组筛选”Am J Phamacogenomics。

赤堀正宜,関根詮明: "問題解決能力育成のための理解実験システムの開発と教育効果"教育メディア研究. 6巻2号. 27-32 (2000)

Masanori Akahori、Noriaki Sekine：“培养问题解决能力的理解实验系统的开发和教育效果”教育媒体研究，第 6 卷，第 27-32 期（2000 年）。

広瀬幸子, 西村裕之: "全身性エリテマトーデス感受性遺伝子のモデル動物による解析"BIO Clinica. 16(9). 34-39 (2001)

Sachiko Hirose、Hiroyuki Nishimura：“使用模型动物分析系统性红斑狼疮易感性基因”BIO Clinica 16(9) (2001)。

赤堀正宜: "教育放送の国際展開とその成果 第1章第2節展開期(1970年代)"放送教育の国際展開とその効果〜総括と展望〜. 44-49 (2001)

Masanori Akahori：“教育广播的国际扩张及其结果第 1 章第 2 节发展时期（1970 年代）”广播教育的国际扩张及其影响 - 总结和展望 44-49 (2001)。

Ochiai K, Ozaki S, Tanino A, Watanabe S, Ueno T, Mitsui K, et al.: "Genetic regulation of anti-erythrocyte autoantibodies and splenomegaly in autoimmune hemolytic anemia-probe New Zealand Black mice"Int. Immunol.. 12. 1-8 (2000)

Ochiai K、Ozaki S、Tanino A、Watanabe S、Ueno T、Mitsui K 等人：“自身免疫性溶血性贫血探针新西兰黑小鼠中抗红细胞自身抗体和脾肿大的遗传调节”Int。