Systemic lupus erythematosus (SLE) is a complex genetic disorder and occurs 8-9 times more frequently in women than men with variable penetrance. In the lupus-prone mouse strain, NZM 2410, four regions have been identified on chromosomes 1, 4, 7, and 17. We are interested in identifying the gene(s) known to be responsible for the autoimmune response seen in SLE. Isolated in congenic mouse strains against a C57BL/6 background, the chromosome 1 region, Sle1, has been associated with either loss of tolerance to chromatin or increased immune response leading to splenomegaly and production of autoantibodies. The region of murine chromosome 1 that Sle1 maps to is syntenic to human chromosome 1 where a locus for lupus susceptibility has been linked (29- 33). Therefore, identification of the mouse gene may also help in identifying the human gene. We have been able to further narrow the Sle1 region using congenic meiotic recombinants and have found that there are three genes in the Sle1 region, Sle1a, Sle1b, and Sle1c that confer autoantibody production. Our studies have revealed that Sle1b is the strongest of the three loci regarding antichromatin IgG production. We have a sequence-ready BAC contig of the region and will use both BAC sequencing and cDNA direct selection to identify candidate genes for Sle1b. Candidate genes will then be analyzed for proper expression and the ability to reproduce the phenotype in a B6 mouse knockout. As Sle1b may be important in focusing the autoimmune response to selected targets, identification of the gene will be important in understanding how the autoimmune cascade is initiated.
