Netting Neutrophils Activate Autoreactive B Cells in Lupus

Lupus erythematosus (LE) patients develop autoantibodies that form circulating immune complexes (ICs) with extracellular self-nucleic acids. These ICs are deposited into peripheral tissues, where they trigger detrimental organ inflammation. Recent evidence suggests that ICs contain LL37-DNA complexes derived from neutrophil extracellular traps (NETs) and that LE patients develop pathogenic autoantibodies against these structures, including Abs to LL37. However, the mechanism that leads to the generation of these Abs is unknown. In this study, we show that NETs directly trigger Ab production by human memory B cells. This occurs via LL37-DNA complexes present in NETs, which have the unique ability to gain access to endosomal compartments of B cells and to trigger TLR9 activation. In LE patients, NET-derived LL37-DNA complexes trigger polyclonal B cell activation via TLR9, but also specifically expand self-reactive memory B cells producing anti-LL37 Abs in an Ag-dependent manner. These findings suggest a unique link between neutrophils and B cells in which NETs trigger a concerted activation of TLR9 and BCR leading to anti-NET autoantibody production in lupus.