Targeting the extracellular scavenger DNASE1L3 on SLE

Systemic lupus erythematosus (SLE) is characterized by breakdown of immune tolerance to self-antigens, production of large amount of anti-nuclear antibodies (ANA) and immune-mediated injury in multiple organs. Anti-dsDNA antibody is one of the major components of ANA and has been proven to play major pathogenic role in the tissue damage of SLE. The production of anti-DNA antibodies in SLE has long been associated with defective clearance of apoptotic nuclear debris, which when entering the circulation, may form microparticles (MP) containing DNA and other nuclear components (1). The investigation of the underlying mechanism for impaired clearance of apoptotic cells has been focused on an endonuclease, DNASE1, which can degrade chromatin into low molecular weight fragments, and is associated with disposal of apoptotic nuclear debris. The role of DNASE1 has been implicated in the pathogenesis of SLE for several decades (2). For example, an earlier study in a murine model for DNASE1-deficiency demonstrated that the presence of ANA, and deposition of immune complex in glomeruli developed full-blown glomerulonephritis. Reduced serum DNASE1 activity was found to be linked to the development of autoantibodies and active SLE disease in patients and lupus-prone mice (3). However, the reasons for such an association, as well as the basis for increased concentration of DNA in the serum were not well understood.