Systemic lupus erythematosus (SLE) is a heterogenous systemic autoimmune disease with a complicated genetics. Using genome-wide scanning techniques, our group identified a number of genetic loci in the autoimmune NZM2410 strain [derived originally from an (NZB x NZW)F1 intercross] contributing to SLE and have backcrossed these intervals onto the non-autoimmune C57BL/6 (B6) background to produce susceptibility-loci congenic strains. In all cases thus far, a partial phenotype consistent with some features of SLE have been identified. However, while the phenotypes have been immunologically relevant, the direct link to pathologic consequences has been lacking. For example, the B6.NZMc1 congenic strain, bearing an NZW-derived locus on chromosome 1 (Sle1), develops IgG anti-H2A/H2B/dsDNA autoantibodies but no other clinical manifestations of SLE, while the B6.NZMc7 congenic strain, bearing an NZW-derived locus on chromosome 7 (Sle3/5) develops limited humoral autoimmunity but an increased peripheral CD4:CD8 ratio. Interestingly, when these strains are crossed to produce the B6.NZMc1/c7 bicongenic strain, broad-spectrum humoral autoimmunity with highly penetrant glomerulonephritis results. Additional genome-wide scanning studies by Drs. Morel and Wakeland studies have also identified a recessive locus on chromosome 9 (Suppresser of lupus 1, Sol1) that suppresses the development of proliferative GN, apparently by affecting phenotypic expression of Sle1. These results create a unique opportunity to functionally dissect the epistatic relationships governing development or suppression of autoimmune renal disease and not just humoral autoimmunity and is thus a crucial step in the identification and characterization of the genes causing SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI043454-01A1
Application #
6043160
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Kirshner, Susan
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$257,564
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611