8 - Genes and genetics of murine lupus

Abstract

Advances in transgenic, gene knockout, and quantitative trait mapping have greatly aided in the identification of the genes and genetically related changes operative in murine models of spontaneous lupus. Genome-wide quantitative trait loci scans of several lupus strains have resulted not only in the identification of multiple predisposing loci, but have advanced our understanding of the nature and complexity of genetic susceptibility. Studies in genetically manipulated normal background mice with an altered expression of specific immune-related genes have revealed a diversity of perturbations that can lead to tolerance defects and manifestations of systemic autoimmunity. Importantly, these findings suggest that spontaneous systemic autoimmunity can be induced by independent genetic abnormalities affecting the various checkpoints that normally control immune responses. Gene alterations affecting B- and T-cell activation, apoptosis, complement, clearance of self-antigens, certain cytokines, and the cell cycle have thus far been implicated. Similar studies assessing germline alterations in lupus-predisposing mice have also identified a variety of genes that are primarily inhibitory, although a few can enhance the disease severity. Combined mapping and genetic manipulation studies have made it apparent that murine lupus susceptibility involves considerable genetic heterogeneity, which will complicate identification of the predisposing genes. Once accomplished, however, specific therapeutic interventions can be based on the individual genotypes and their associated traits.