Common Alleles of the SLAM/CD2 Family are Associated with Murine Lupus

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Title: Common Alleles of the SLAM/CD2 Family are Associated with Murine Lupus
Author: Limaye, Nisha
Abstract: The Sle1b locus on telomeric mouse chromosome 1 mediates a break in tolerance to chromatin in the NZM2410 model of the autoimmune disease Systemic Lupus Erythematosus (SLE ) . B6 .Sle1b congenic mice produce anti -nuclear autoantibodies (ANAs ) , and have elevated activated B and CD4+ T cells , and mild splenomegaly . Fine mapping of Sle1b positioned it within a ~900 kb region between 171 .3 and 172 .2 Mb . A contig of 100 B6 -derived Bacterial Artificial Chromosomes (BACs ) was constructed across Sle1b , and sequencing of six BACs that form an overlapping tiling path across it revealed that the interval contains 24 genes , 19 of which are expressed in the spleen , and 14 of which are in B and CD4+ T cells . We carried out extensive candidate gene analyses on the spleen -expressed genes , including sequencing of all the exons and flanking introns in the lupus -resistant B6 and susceptible B6 .Sle1b parental strains , as well as Quantitative Real -time PCR on B and CD4+ T cell cDNA to detect any potentially functional polymorphisms between them . These analyses showed that the SLAM /CD2 family of seven immunoregulatory receptors , clustered within the locus , are by far the best candidates to be the Sle1b gene (s ) . The members of this family play important roles in intercellular interactions , activation , and function , by engaging in homophilic interactions with themselves or with each other , on a wide variety of immune cell types . Sequence analyses of their extracellular ligand -binding immunoglobulin (Ig ) domains revealed that the cluster forms two stable , linked haplotypes of alleles in 33 common inbred laboratory strains of mice . The B6 -like haplotype is found only in a small set of C57 -strains , while the B6 .Sle1b -like haplotype is found in all of the remaining , including the autoimmune -prone MRL , NOD , and NZB , as well as non -autoimmune strains like 129 , Balb /c , and C3H . Introgression of this common haplotype from 129 onto B6 also potentiates autoimmunity , causing phenotypes similar to those of B6 .Sle1b mice , which derive this interval from the NZW parent of NZM2410 . Autoimmunity is mediated , not by a rare mutation peculiar to the region from NZW , but instead by common polymorphic variants of this family , in combination with the downstream signaling and effector molecules and pathways present in the B6 genetic background , underlining the importance of epistasis in such complex , multigenic autoimmune phenotypes . An examination of the SLAM /CD2 Ig domains in a large group of wild -outbred and wild -derived inbred strains belonging to different species of Mus , and sub -species of Mus musculus , has shown that the "disease" alleles of this family are also very common in these populations , demonstrating that their prevalence in the lab strains is not simply an artifact of their inbreeding . The genes also show the presence of ancestral or trans -species polymorphisms , indicative of maintenance of these alleles by balancing selection , although we do not yet know what precisely drives it . The small size of the Sle1b susceptibility interval , and the presence of this linked cluster of attractive candidate genes within it , makes it hard to identify which gene or combination of genes within this family is actually responsible for the autoimmunity by any further recombinational analysis . We have instead turned to a BAC -transgenic rescue strategy by which to localize the gene to a single B6 -derived BAC , by its ability to complement the ANA -production phenotype and rescue autoimmunity in B6 .Sle1b mice . We believe the strategy is feasible because Sle1b has a strong allele dose effect , so that the presence of a B6 allele of the Sle1b gene causes a large drop in penetrance of ANA -production , from about 90 % in nine month old B6 .Sle1b females , to about 33 % in (B6 X B6 .Sle1b ) F1s . Our data show that none of the non -SLAM /CD2 candidates within the region is able to rescue B6 .Sle1b mice , despite being demonstrably expressed from their BAC -transgenes . BACs carrying certain SL
URI: http : / /hdl .handle .net /2152 .5 /468
Date: 2005-04-25


Common Alleles of the SLAM/CD2 Family are Associated with Murine Lupus. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /468 .

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