| Research Abstract |
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.
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