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

致病性 IgG 自身抗体的产生是系统性红斑狼疮 (SLE) 的标志。对易患 SLE (NZB x NZW) Fl 小鼠的免疫球蛋白可变区 (IgV) 基因序列和 IgM 和 IgG 抗 DNA 单克隆抗体的 DNA 结合活性的研究表明，在 IgM 至 IgG 同型转换的过程中，IgG 抗 DNA 抗体经过克隆选择、体细胞突变并具有高亲和力。相比之下，IgM 对应抗体具有多反应性和低亲和力性质，其 IgV 基因几乎没有体细胞突变。这些 IgM 抗 DNA 抗体甚至在正常个体中也能观察到，并且源自在自然免疫中正常发挥作用的 B 1 细胞。高度突变的致病性 IgG 抗 DNA 抗体仅在 SLE 患者中观察到。为了了解这些致病性自身抗体的产生机制，我们尝试建立氯霉素乙酰转移酶（CAT）基因转基因易患系统性红斑狼疮的小鼠品系。 CAT基因被插入到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转基因与IgV同时发生突变，因此CAT转基因突变将是IgV突变的良好标记。基因组中有多种 IgV，许多情况下无法获得种系序列。我们的小鼠将有助于了解 SLE 专利中致病性突变 IgG 自身抗体产生的机制。

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.