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.

NZB（新西兰黑色）和NZW（新西兰白色）菌株的F1混合体已被研究为全身性红斑狼疮（SLE）的鼠模型。在杂化小鼠中，B1（CD5+）细胞被证明是自身抗体产生的原因。但是，这些小鼠的SLE表型的表达严格取决于CD4+ T细胞。这些小鼠显示出异常的细胞因子生产反映的外周CD4+ T细胞的年龄自发性激活和子集偏斜，CD4+ T细胞的频率升高，阳性的早期激活标记CD69的阳性，以及CD4+ T细胞的频率降低了CD4+ T细胞的频率CD62L和/OR NTA260。为了研究（NZB X NZW）F1小鼠外周周围CD4^+T细胞异常特征的遗传控制，我们对定量性状基因座（QTL）进行了调节CD69+CD4+CD4+CD4+CD4+和NTA260+CDW4+T的频率的定量性状基因座（QTL）。 NZW背钩老鼠。 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.这些遗传相互作用与参与B1细胞异常功能的遗传相互作用不同。因此，在（NZB X NZW）F1小鼠中，CD4+ T细胞和B1细胞的异常功能基于不同的多遗传易感性，这两者都有助于混合小鼠的SLE表型的表现。

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。

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,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）。

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)。

Saito T, Kumagai Y, Hiramatsu T, Kurosawa M, Sato S, Habu S, Mitsui K, Kodera Y, Hiroto M, Matsushima A, Inada Y, Nishimura H: "Immune tolerance induced by polyethylene glycol-conjugate of protein antigen : clonal deletion of antigen-specific Th cells in

Saito T、Kumagai Y、Hiramatsu T、Kurosawa M、Sato S、Habu S、Mitsui K、Kodera Y、Hiroto M、Matsushima A、Inada Y、Nishimura H：“蛋白质抗原的聚乙二醇缀合物诱导的免疫耐受：克隆