Genetics of systemic autoimmunity and glomerulonephritis in mouse models of lupus

Systemic lupus erythematosus (SLE) is a prototypic antibody-mediated systemic autoimmune disease characterized by a high female predominance (90%), a broad spectrum of autoantibodies that typically includes reactivity to nuclear antigens, and multisystem pathology. There is no single discriminatory test, and clinical manifestations are highly variable among patients. There remains significant morbidity for most patients and increased mortality especially for those with renal or CNS involvement, despite the use of powerful immunosuppressive intervention. Although the cause of SLE is not known, there is substantial evidence pointing to a combination of underlying genetic susceptibility. Definition of the genetic basis for lupus would provide the means to not only identify predisposed individuals, but to develop therapeutics directed at correcting susceptibility gene defects or antagonists to the gene products critical for disease pathogenesis. Research in this area, however, has been hampered by the complex multifactorial inheritance and heterogeneity of SLE. Nonetheless, substantial progress in methods to identify genes responsible for polygenic disorders has been made over the past several years, particularly for animal models. Such models, involving genetically homogeneous animals, are particularly useful in studies of complex inheritance such as lupus because of the ability to control for genetic and environmental variations. Moreover, genetic manipulation can readily be performed to test the function of specific loci and genes. We, and others, are applying these strategies to lupus-prone mouse strains to identify and define the contributions of susceptibility genes, as well as to dissect the function of known genes in the pathogenesis of the disease. Loci predisposing to systemic autoimmunity in lupus-prone mouse strains