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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AR008633-01
Application #
6209937
Study Section
Special Emphasis Panel (ZRG1-IMB (01))
Program Officer
Gretz, Elizabeth
Project Start
2000-09-01
Project End
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$37,516
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390