Genetics of systemic autoimmunity

Despite enormous efforts, the pathogenesis of lupus and other autoimmune diseases remains unresolved, but recent studies in lupus mice have contributed several major advances that provide new impetus to this research. Among these is the identification of the Fas/FasL apoptosis gene defects in the lymphoaccumulation-manifesting lpr and gld mutant lupus mice. Although the specific Fas/FasL defects are confined to lpr/gld phenotypes and to some rare cases of human systemic autoimmunity, this and other findings suggest that abnormal apoptotic mechanisms may have broad underlying importance in lupus aetiology. Another important development has been the identification of predisposing loci in New Zealand lupus mice through genome-wide searches with microsatellite-based maps. The findings suggest that the genetics of murine lupus follow a multiplicative epistatic model of inheritance wherein specific combinations of genes additively contribute to phenotype expression. Further studies in these directions will eventually lead to identification of the specific predisposing genes that lead to broad T- and B-cell tolerance defects in this disease.