Netting Neutrophils Activate Autoreactive B Cells in Lupus

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• Lupus erythematosus (LE) is characterized by autoantibodies forming immune complexes (ICs) with self-nucleic acids, leading to organ inflammation.
• Evidence suggests ICs contain LL37-DNA complexes from neutrophil extracellular traps (NETs), with LE patients developing autoantibodies (Abs) against these structures.
• The precise mechanism driving the generation of anti-LL37 Abs in LE remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which neutrophil extracellular traps (NETs) induce autoantibody production in lupus erythematosus (LE).
• To investigate the role of LL37-DNA complexes in NETs in activating B cells and driving autoantibody generation in LE.

Main Methods:

• Investigated the direct effect of NETs on human memory B cell activation and autoantibody production.
• Utilized LL37-DNA complexes to assess their ability to access B cell endosomal compartments and activate Toll-like receptor 9 (TLR9).
• Analyzed the impact of NET-derived LL37-DNA complexes on polyclonal B cell activation and the expansion of self-reactive memory B cells in LE patients.

Main Results:

• NETs directly trigger autoantibody production by human memory B cells.
• LL37-DNA complexes within NETs access B cell endosomes, activating TLR9.
• In LE patients, NETs induce polyclonal B cell activation via TLR9 and specifically expand self-reactive memory B cells producing anti-LL37 Abs.

Conclusions:

• NETs establish a direct link between neutrophils and B cells in lupus pathogenesis.
• Concerted activation of TLR9 and B cell receptor (BCR) signaling by NETs drives anti-NET autoantibody production in LE.
• This mechanism highlights a novel pathway contributing to the autoimmune response in lupus erythematosus.