Abstract
Autoimmune disease is a complex multigenic disease. Variable combinations of susceptibility genes at multiple loci determine the diverse autoimmune disease phenotypes. Major genes predisposing to autoimmune diseases are no doubt related to key events in the pathogenesis, and may involve a variety of genes in the immune system. Recently, the application of the polymerase chain reaction and the availability of maps of microsatellites and single nucleotide polymorphisms (SNPs) have facilitated a genome-wide scan to define the number and locations of genes for complex traits. However, the large number of susceptibility loci and the extensive complexity of multi-factorial inheritance have delayed the completion of a genome-wide analysis of loci for human autoimmune diseases. Genetic studies of murine models of autoimmune disease have shed light on these obstacles evident in studies of human diseases. Major genetic loci and several potent candidate polymorphic genes have been identified, particularly in SLE-prone mouse strains. These candidate genes frequently show epistatic interaction in the expression of autoimmune phenotypes, and thus can explain the complexity of their inheritance patterns. Nevertheless, the final identification of the nature and function of the susceptibility genes and their roles in the pathogenesis of SLE need further investigation. The ultimate goal for the identification of susceptibility genes will largely depend on the generation of genetically manipulated mutant mice with homologous recombination of the potential target gene. Such knowledge will lead to elucidation of the genetic and cellular mechanisms involved in the dysregulation of self-reactive lymphocytes in the pathogenesis of autoimmune disease. Prophylactic and therapeutic clinical approaches can then be better designed.
