Studies on mechanism of pathogenic autoantibody production using CAT-transgenic autoimmune-prone mice

使用 CAT 转基因自身免疫小鼠研究致病性自身抗体产生机制

• 批准号: 10670310
• 负责人: HIROSE Sachiko
• 金额: $ 2.37万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670310/
• 关键词: SLE; Natural antibody; IgG anti-DNA antibody; autoantibody; somatic mutation; Ig variable region gene; affinity selection; CAT gene; 抗体可変領域遺伝子

The production of pathogenic IgG autoantibodies is a hallmark of systemic lupus erythematosus (SLE). Studies on immuoglobulin variable region (IgV) gene sequences and DNA-binding activities of IgM and IgG anti-DNA monoclonal antibodies from SLE-prone (NZB x NZW) Fl mice showed that, in the process of IgM to IgG isotype switching, IgG anti-DNA antibodies are clonally selected, somatically mutated, and have a high-affinity nature. In contrast, IgM counterpart antibodies have poly-reactive and low-affinity nature and little if any somatic mutation in their IgV genes. These IgM anti-DNA antibodies are observed even in normal individuals and derived from B 1 cells normally functioning in natural immunity. Highly mutated pathogenic IgG anti-DNA antibodies are only observed in patients with SLE. To understand the mechanism of production of these pathogenic autoantibodies, we tried to establish chloramphenicil acetyl transferase (CAT) gene-transgenic SLE-prone mouse strains. CAT gene are inserted between IgH promoter region and intron enhancer, thus, in mice introduced with these CAT gene, transgene are expressed only in B cell lineages. Since CAT transgene is shown to be mutated in parallel with IgV, CAT transgene mutation will be a good marker for IgV mutation. There are many kinds of IgV in genomes and germ-line sequences are not available in many cases. Our mice will be useful to understand the mechanism of pathogenic mutated IgG autoantibody production in patents with SLE.

致病性IgG自身抗体的产生是系统性红斑狼疮（SLE）的标志。对SLE易感（NZB × NZW）F1小鼠免疫球蛋白可变区（IgV）基因序列和IgM、IgG抗DNA单克隆抗体DNA结合活性的研究表明，在IgM向IgG同种型转换的过程中，IgG抗DNA抗体经过克隆选择、体细胞突变，具有高亲和力的性质。相反，IgM对应抗体具有多反应性和低亲和力性质，并且在其IgV基因中几乎没有体细胞突变。这些IgM抗DNA抗体甚至在正常个体中观察到，并且来源于正常发挥天然免疫功能的B 1细胞。高度突变的致病性IgG抗DNA抗体仅见于SLE患者。为了了解这些致病性自身抗体的产生机制，我们试图建立氯霉素乙酰转移酶（CAT）基因转基因SLE易感小鼠品系。CAT基因插入在IgH启动子区和内含子增强子之间，因此，在引入这些CAT基因的小鼠中，转基因仅在B细胞谱系中表达。由于CAT转基因显示与IgV平行突变，CAT转基因突变将是IgV突变的良好标记。基因组中存在多种IgV，在许多情况下无法获得种系序列。我们的小鼠将有助于了解致病性突变IgG自身抗体的产生与SLE患者的机制。

项目成果

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