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

致病性自身抗体的产生是系统性红斑狼疮(SLE)的一个标志。对系统性红斑狼疮(NZB X NZW)F1小鼠免疫球蛋白可变区(IGV)基因序列和免疫球蛋白抗DNA单抗的DNA结合活性的研究表明，在IgM向Ig G亚型转换的过程中，Ig G抗DNA抗体是克隆选择、体细胞突变的，具有高亲和力。相比之下，IgM对应抗体具有多反应和低亲和力的性质，其IGV基因几乎没有体细胞突变。这些IgM抗DNA抗体即使在正常人中也能观察到，它们来自于正常发挥自然免疫功能的B1细胞。高度突变的致病免疫球蛋白抗DNA抗体仅在SLE患者中观察到。为了了解这些致病自身抗体的产生机制，我们试图建立转氯霉素乙酰转移酶(CAT)基因的SLE易感小鼠株系。CAT基因被插入到IgH启动子区域和内含子增强子之间，因此，在导入这些CAT基因的小鼠中，转基因只在B细胞系中表达。由于CAT转基因的突变与IGV的突变是平行的，因此CAT转基因突变将是IGV突变的良好标志。IGV在基因组中的种类很多，在许多情况下无法获得生殖系序列。我们的小鼠将有助于了解SLE患者致病突变的免疫球蛋白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.