This study investigates the role of neutrophils in the pathogenesis of systemic lupus erythematosus (SLE) by identifying immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes, formed by activated neutrophils in the form of neutrophil extracellular traps (NETs), efficiently trigger innate plasmacytoid dendritic cell (pDC) activation via Toll-like receptor 9 (TLR9). SLE patients develop autoantibodies to both self-DNA and antimicrobial peptides in NETs, suggesting that these complexes serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients release more NETs than those from healthy donors, further stimulated by antimicrobial autoantibodies, indicating a mechanism for chronic release of immunogenic complexes in SLE. The findings establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for treatment.This study investigates the role of neutrophils in the pathogenesis of systemic lupus erythematosus (SLE) by identifying immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes, formed by activated neutrophils in the form of neutrophil extracellular traps (NETs), efficiently trigger innate plasmacytoid dendritic cell (pDC) activation via Toll-like receptor 9 (TLR9). SLE patients develop autoantibodies to both self-DNA and antimicrobial peptides in NETs, suggesting that these complexes serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients release more NETs than those from healthy donors, further stimulated by antimicrobial autoantibodies, indicating a mechanism for chronic release of immunogenic complexes in SLE. The findings establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for treatment.