Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus

R Lande, D Ganguly, V Facchinetti, L Frasca… - Science translational …, 2011 - science.org
R Lande, D Ganguly, V Facchinetti, L Frasca, C Conrad, J Gregorio, S Meller, G Chamilos…
Science translational medicine, 2011science.org
Systemic lupus erythematosus (SLE) is a severe and incurable autoimmune disease
characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of
autoantibodies against nuclear self-antigens by hyperreactive B cells. Neutrophils are also
implicated in disease pathogenesis; however, the mechanisms involved are unknown. Here,
we identified in the sera of SLE patients immunogenic complexes composed of neutrophil-
derived antimicrobial peptides and self-DNA. These complexes were produced by activated …
Systemic lupus erythematosus (SLE) is a severe and incurable autoimmune disease characterized by chronic activation of plasmacytoid dendritic cells (pDCs) and production of autoantibodies against nuclear self-antigens by hyperreactive B cells. Neutrophils are also implicated in disease pathogenesis; however, the mechanisms involved are unknown. Here, we identified in the sera of SLE patients immunogenic complexes composed of neutrophil-derived antimicrobial peptides and self-DNA. These complexes were produced by activated neutrophils in the form of web-like structures known as neutrophil extracellular traps (NETs) and efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9). SLE patients were found to develop autoantibodies to both the self-DNA and antimicrobial peptides in NETs, indicating that these complexes could also serve as autoantigens to trigger B cell activation. Circulating neutrophils from SLE patients released more NETs than those from healthy donors; this was further stimulated by the antimicrobial autoantibodies, suggesting a mechanism for the chronic release of immunogenic complexes in SLE. Our data establish a link between neutrophils, pDC activation, and autoimmunity in SLE, providing new potential targets for the treatment of this devastating disease.
AAAS