Clonal evolution and antigen recognition of anti-nuclear antibodies in acute systemic lupus erythematosus

The evolutional process of disease-associated autoantibodies in systemic lupus erythematosus (SLE) remains to be established. Here we show intraclonal diversification and affinity maturationof anti-nuclear antibody( ANA)-producing B cells in SLE. We identified a panel of monoclonal ANAsrecognizing nuclear antigens, such as double-stranded DNA (dsDNA) and ribonucleoproteins(RNPs) from acute SLE subjects. These ANAshad relatively few, but nonetheless critical mutations. High-throughput immunoglobulin sequencing of blood lymphocytes disclosed the existence of sizable ANAlineages shearing critical mutations intraclonally. We further focused on anti-DNA antibodies, which are capable to bind to both single-stranded (ss) and dsDNA at high affinity. Crystal structure and biochemical analysis confirmed a direct role of the mutations in the acquisition of DNA reactivity and also revealed that these anti-DNA antibodies recognized an unpaired region within DNA duplex. Our study unveils the unique properties of high-affinity anti-DNA antibodies that are generated through antigen-driven affinity maturationin acute phase of SLE.