RT Journal Article
SR Electronic
T1 Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 73ra20
OP 73ra20
DO 10.1126/scitranslmed.3001201
VO 3
IS 73
A1 Garcia-Romo, Gina S.
A1 Caielli, Simone
A1 Vega, Barbara
A1 Connolly, John
A1 Allantaz, Florence
A1 Xu, Zhaohui
A1 Punaro, Marilynn
A1 Baisch, Jeanine
A1 Guiducci, Cristiana
A1 Coffman, Robert L.
A1 Barrat, Franck J.
A1 Banchereau, Jacques
A1 Pascual, Virginia
YR 2011
UL http://stm.sciencemag.org/content/3/73/73ra20.abstract
AB Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)–induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)–dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid–recognizing antibodies and type I IFN production in this disease.