Production of autoantibodies to RNA and DNA self-antigens in systemic lupus erythematosus has recently been shown to be dependent on signals through TLR7 and TLR9. Knockout studies unexpectedly demonstrated that TLR9 has an overall protective effect despite its contribution to anti-DNA antibody production, while TLR7 signals contribute to disease and anti-RNA antibody production. These findings were surprising, as the two receptors are thought to have similar expression patterns and downstream signaling pathways. The studies proposed here will dissect the contributions of these two innate immune signaling molecules to the complex lupus disease phenotype. We will examine the genetic interaction between the two signals by simultaneous knockout of both receptors in a mouse model of lupus. We will determine the cell-specific roles of the two receptors in B cells and myeloid cells through mixed bone marrow chimeras and cell-type specific ablation of the receptors. Finally, we will examine possible mechanisms by which TLR9 and TLR7 can exert their differential effects on lupus pathogenesis. These studies will increase our understanding of the mechanisms of lupus pathogenesis and may therefore lead to identification of new treatment targets for rational drug design. Lay description: Systemic lupus erythematosus is an autoimmune disease affecting as many as 40 in 100,000 Americans. Recent work has identified two genes of the immune system normally involved in detecting infection which are critically important in the initiation and progression of lupus. The experiments described here will expand and enhance our understanding of the effects of these genes on autoimmune disease and may thereby lead to improved treatment strategies for lupus and other related diseases. [unreadable] [unreadable] [unreadable]