We previously produced three congenic strains carrying lupus susceptibility genes (Sle1-Sle3) from the lupus-prone NZM2410 mouse on the C57BL͞6 background and characterized their component phenotypes. Sle1 mediates the loss of tolerance to nuclear antigens; Sle2 lowers the activation threshold of B cells; and Sle3 mediates a dysregulation of CD4 ؉ T cells. We have now created a collection of bi-and tricongenic strains with these intervals and assessed the autoimmune phenotypes they elicit in various combinations. Our results indicate that Sle1 is key for the development of fatal lupus. The combination of Sle1 with Sle2, Sle3, or the BXSB-derived autoimmune accelerating gene yaa results in the development of systemic autoimmunity with variably penetrant severe glomerulonephritis culminating in kidney failure. In contrast, two locus combinations of Sle2, Sle3, and yaa failed to mediate fatal disease. These results indicate that the loss of tolerance to chromatin mediated by Sle1 is essential for disease pathogenesis and identify the pathway occupied by Sle1 as a strategic target for therapeutic intervention in systemic lupus erythematosus. The coexpression of Sle1, Sle2, and Sle3 as a B6-triple congenic results in severe systemic autoimmunity and fully penetrant, fatal glomerulonephritis. These results demonstrate the fulfillment of the genetic equivalent of Koch's postulate, where susceptibility loci in a lupus-prone strain have been identified by a genome scan, isolated and functionally characterized by congenic dissection, and finally shown to mediate full disease expression when recombined in a normal genome.

The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that Sle1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the location of Sle1 has determined that three loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin. Each displays a distinctive profile of serological and cellular characteristics, with T and B cell functions being more affected by Sle1a and Sle1b, respectively. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted, however, by these three loci alone, suggesting the existence of an additional locus, termed Sle1d. These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes. This level of genetic complexity, combined with similar findings in other systems, supports the possibility that many complex trait loci reflect the impact of polymorphisms in linked clusters of genes with related functions. S ystemic lupus erythematosus (SLE) susceptibility is inherited as a multifactorial genetic disease (1). Thus far, linkage analyses in multiple murine models have detected 31 susceptibility loci distributed among 21 nonoverlapping genomic intervals, clearly illustrating the complexity of the genetic basis for susceptibility to systemic autoimmunity (2). In SLE patients, association and case-control studies have analyzed the contribution of numerous candidate genes, and several linkage analyses have been performed (3). Remarkably, one region of the genome, telomeric chromosome (chr) 1 in the mouse and its syntenic equivalent 1q21-44 in humans, has shown strong linkage in all human studies and in all genome scans conducted in the (NZB ϫ NZW)F 1 model and its derivative, the NZM2410 strain. In the mouse, three loci have been identified in that region: NZW-derived Sle1 in NZM2410 (4), and NZB-derived Lbw7 (5) and Nba2 (6) in (NZB ϫ NZW)F 1 . In addition to linkage studies, association͞case-control or gene disruption studies have shown that genes located in this region, such as those encoding for Fc␥RIIA, and Fc␥RIIIA (7, 8), ADPRP (9), FcR␥ (10), and SAP (11), play a role in SLE susceptibility.The characterization of the phenotypes of B6.Sle1, a congenic strain that carries the NZM susceptibility interval on a C57BL͞6 (B6) background, has shown that Sle1 is associated with a selective loss of tolerance to chromatin and with a preferential targeting of H2A͞H2B͞DNA subnucleosomes (12, 13). Sle1 is expressed in B and T cells (ref. 13 and E. S. Sobel, unpublished data), and Sle1-expressing lymphocytes have a spontaneously activated phenotype, as indicated by an increased expression of B7-2 and CD69 on B and T cells, re...