Systemic lupus erythematosus (SLE) is a chronic autoimmune disease leading to inflammatory tissue damage in multiple organs (e.g., lupus nephritis). Current treatments including steroids, antimalarials, and immunosuppressive drugs have significant side effects. There is an unmet medical need for new drugs with less side effects. We evaluated the role of two proteases, namely activated protein C (aPC) and cathepsin S (Cat S), in the pathogenesis of SLE in MRL-Fas(lpr) mice.