Systemic lupus erythematosus (SLE) is a complex autoimmune disorder initiated by a loss of immunologictolerance to self-antigens. Our previous studies in mouse demonstrated that members of the SLAM genecluster are responsible for the elevated ANA titers and predisposition to SLE seen in the B6.S/e)bcongenicstrain which carries the NZM-derived lupus susceptibility loci, Slelb. Slelb is the most potent member of theNZM2410-derived Sie1 multi-gene locus and has been shown to play a role in the first step toward thedevelopment of fatal lupus nephritis, causing elevated ANA titers as well as the B cell abnormalities seen inthe NZM2410 mouse strain. In addition, the chromosomal interval in the mouse that contains these genes issyntenic to human chromosome 1q21-q23 and multiple human linkage studies have associated this regionwith susceptibility to lupus. Furthermore, it has been shown that genes in the SLAM family play importantroles in regulating immune responses, encoding adhesion molecules that mediate co-stimulatory and/orinhibitory signaling during cell-cell interactions between T cell, B cell, monocyte and NK cell lineages.Hence, the current proposal will test the hypothesis that allelic variants of the SLAM gene cluster confersusceptibility to lupus in humans. Variants within these genes have been identified using information frompublicly available databases and examined for their frequency in a large cohort consisting of 4320 SLEcases and unrelated controls. Functional analyses of the mutations identified in this screen will be used toprove our hypothesis. The identification of disease-associated sequence polymorphisms represents a majoradvance in understanding lupus pathogenesis. Knowledge gained from these studies is critical to identifyingthose individuals at greatest risk for lupus as well as to the development of new, early-treatment therapeuticstrategies.Relevance to Public Heath: Members of the SLAM gene cluster have been shown to be important inmaintaining proper function of the immune system. Mutations in the SLAM gene cluster shown to beresponsible for proper expression and function of these genes in lupus patients will have far-reachingimplications, perhaps predisposing individuals to a variety of systemic autoimmune diseases. Our long termgoal is to develop a screen for these functional variants in order to identify individuals at greatest risk prior tothe onset of clinical disease and major organ damage and to identify novel therapeutic targets.
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