Haplotype-Specific Effects of the Slam/Cd2 Family on the Immune Response
The Sle1b susceptibility interval mediates a breach in tolerance to nuclear antigens in the NZM2410 model of systemic lupus erythematosus (SLE). Congenic B6 mice carrying the Sle1b locus produce anti-nuclear autoantibodies (ANAs) but do not develop lupus nephritis as seen in the parental NZM2410 strain. Fine mapping of the Sle1b locus placed it within a 900kb interval between 171.3 and 172.2Mb on chromosome 1. A Bacterial Artificial Chromosome (BACs) contig that spanned the interval was constructed, and a tiling pathway comprised of six BACs was sequenced. Sequence analysis revealed a dense region of 24 expressed genes. Expression studies determined numerous polymorphisms between B6 and the B6.Sle1b congenic and identified a cluster of genes known as the Slam/CD2 family as the primary candidates for Sle1b. These immunoregulatory receptors play a role in intercellular interactions and regulate function in several immune cell lineages. Of the seven family members within the locus, Ly108 appears to be the strongest candidate as B6.Sle1b shows a differential expression in isoforms. Ly108-1 is highly expressed, while Ly108-2 is expressed at much lower level in the congenic when compared to B6. When lymphocytes are stimulated, Ly108-2 is strongly up-regulated in B6, but not B6.Sle1b. Sequence analysis of the extra-cellular immunoglobulin domains of the Slam/CD2 family revealed two stable haplotypes in a panel of 33 common inbred strains of mice. The first haplotype is only found in B6 and other C57- related strains. The more common second haplotype is found in Sle1b and other autoimmune strains such as MRL, NOD, and NZB, as well as non-autoimmune strains such as 129Sv and Balb/c. The presence of this haplotype on B6 mediates autoimmunity as B6 congenics carrying the Sle1b locus from 129Sv also produce ANAs. Signaling studies on both B6.Sle1b and B6.129 reveal an altered pattern of calcium mobilization upon stimulation in T cells. In addition, CD4 T cells from B6.Sle1b demonstrate a reduction in IL-4 expression and secretion upon activation, suggesting that haplotype 2 of the Slam/CD2 family alters the immune response in T cells. Studies to understand the mechanisms by which this haplotype mediates autoimmunity are in progress.