The genes of systemic autoimmunity

Autoimmune diseases include a wide spectrum of disorders, which have been d ivided into systemic and organ-specific disorders. Lupus, the prototypic sy stemic autoimmune disease, is characterized by female predominance, multior gan pathology, and autoantibodies, primarily directed against nuclear antig ens. The disease is heterogeneous, with variable organ involvement, serolog y, and clinical course. Susceptibility to lupus is inherited as a polygenic trait with added contributions from environmental and stochastic variance. Concerted efforts have recently been made by several laboratories to defin e the genetic basis of this disease in predisposed mice and humans. The ide ntification of the Fas/FasL defects in lpr and gld lupus mice was the first example of spontaneous mutations of apoptosis-promoting genes being associ ated with systemic autoimmunity. This research was instrumental in clarifyi ng the roles of these genes in tolerance and immunoregulation, and in extra polating these results to other autoimmune diseases, as well as cancer and transplantation. To these findings have been added those from transgenic an d gene knockout mouse studies that have helped to define the systemic autoi mmunity-inducing or -modifying effects of specific genes in normal backgrou nd and lupus-congenic mice. In addition, the findings from genome-wide sear ches have begun to identify predisposing loci (and ultimately genes) for th e spontaneous lupus-like diseases in various mouse strains and in humans. T he emerging picture is that multiple genetic contributions can independentl y lead to systemic autoimmunity in mice, which reinforces the view that hum an lupus may be similarly composed of diverse genotypes. This complexity un derscores the importance of defining the predisposing alleles and mechanism s of action, an undertaking that is certainly feasible given current techno logies and future advances in the definition of mammalian genomes.