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

Sci Transl Med. 2011 Mar 9;3(73):73ra19. doi: 10.1126/scitranslmed.3001180.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Antinuclear / blood
  • Antigen-Antibody Complex / blood
  • Autoantigens / blood
  • B-Lymphocytes / immunology
  • Case-Control Studies
  • Cathelicidins / immunology
  • DNA / blood
  • DNA / immunology
  • Dendritic Cells / immunology*
  • Humans
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation
  • Neutrophils / immunology*
  • Peptides / blood
  • Peptides / immunology
  • Toll-Like Receptor 9 / metabolism

Substances

  • Antibodies, Antinuclear
  • Antigen-Antibody Complex
  • Autoantigens
  • Cathelicidins
  • Peptides
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • antimicrobial peptide LL-37
  • DNA