Research ArticleAutoimmune Disease

Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA–Peptide Complexes in Systemic Lupus Erythematosus

Science Translational Medicine  09 Mar 2011:
Vol. 3, Issue 73, pp. 73ra19
DOI: 10.1126/scitranslmed.3001180

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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.

Footnotes

  • * Present address: Department of Dermatology, University Hospital Lausanne CHUV, 1011 Lausanne, Switzerland.

  • These authors contributed equally to this work.

  • Citation: R. Lande, D. Ganguly, V. Facchinetti, L. Frasca, C. Conrad, J. Gregorio, S. Meller, G. Chamilos, R. Sebasigari, V. Riccieri, R. Bassett, H. Amuro, S. Fukuhara, T. Ito, Y.-J. Liu, M. Gilliet, Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA–Peptide Complexes in Systemic Lupus Erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).

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