Through the analysis of SLE serum and patient-derived monoclonal antibodies, we found that a subset of anti-DNase1L3 antibodies is also reactive with dsDNA, providing a rational explanation that SLE disease activity is associated with a single autoantibody with dual reactivity to DNase1L3 and dsDNA. The gene discussed is DNASE1L3; the disease is systemic lupus erythematosus.