Molecular Pathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by the formation of a variety of autoantibodies and subsequent development of lupus nephritis. The analyses of autoimmune phenotypes in various mutant mice and in mice congenic for different susceptibility intervals have made it possible to identify lupus susceptibility genes. One interesting example is the Fcgr2b gene encoding an inhibitory IgG Fc receptor, FcγRIIB, since the defective Fcgr2b allele of lupus-prone mice contributes to the development of SLE by promoting the autoantibody production and the immune complex-mediated inflammation. More recently, the role of the innate immune receptors TLR7 and TLR9 in the development of autoimmune responses has emerged. Notably, a duplication of the TLR7 gene has been proposed as the cause of the Yaa (Y-linked autoimmune acceleration) mutation, which markedly accelerates the progression of murine SLE. Finally, using two different monoclonal autoantibodies, the molecular basis for the pathogenic potential of autoantibodies in relation to the Ig isotype and the extent of the terminal sialylation will be discussed.