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.
| Wakui, Masatoshi; Morel, Laurence; Butfiloski, Edward J et al. (2005) Genetic dissection of systemic lupus erythematosus pathogenesis: partial functional complementation between Sle1 and Sle3/5 demonstrates requirement for intracellular coexpression for full phenotypic expression of lupus. J Immunol 175:1337-45 |
| Wakui, Masatoshi; Kim, Jinho; Butfiloski, Edward J et al. (2004) Genetic dissection of lupus pathogenesis: Sle3/5 impacts IgH CDR3 sequences, somatic mutations, and receptor editing. J Immunol 173:7368-76 |
| Sobel, Eric S; Satoh, Minoru; Chen, Yifang et al. (2002) The major murine systemic lupus erythematosus susceptibility locus Sle1 results in abnormal functions of both B and T cells. J Immunol 169:2694-700 |
