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

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.

SUBMITTER: Lande R

PROVIDER: S-EPMC3399524 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Lande Roberto R Ganguly Dipyaman D Facchinetti Valeria V Frasca Loredana L Conrad Curdin C Gregorio Josh J Meller Stephan S Chamilos Georgios G Sebasigari Rosalie R Riccieri Valeria V Bassett Roland R Amuro Hideki H Fukuhara Shirou S Ito Tomoki T Liu Yong-Jun YJ Gilliet Michel M

Science translational medicine 20110301 73

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 ...[more]

PMID: 21389263

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Project description:BackgroundIt is well known that interferon (IFN)-alpha is important to the pathogenesis of systemic lupus erythematosus (SLE). However, several reports have indicated that the number of IFN-alpha producing cells are decreased or that their function is defective in patients with SLE. We studied the function of plasmacytoid dendritic cells (pDCs) under persistent stimulation of Toll-like receptor (TLR)9 via a TLR9 ligand (CpG ODN2216) or SLE serum.MethodsThe concentrations of IFN-alpha were determined in serum and culture supernatant of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls after stimulation with CpG ODN2216 or SLE serum. The numbers of circulating pDCs were analyzed by fluoresence-activated cell sorting analysis. pDCs were treated with CpG ODN2216 and SLE serum repeatedly, and levels of produced IFN-alpha were measured. The expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling were examined in PBMCs from SLE patients and healthy control individuals.ResultsAlthough there was no significant difference in serum concentration of IFN-alpha and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-alpha producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-alpha production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-alpha in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-alpha production, continuous TLR9 stimulation may lead to decreased production of IFN-alpha in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-alpha stimulation and had become desensitized to TLR signaling.ConclusionWe suggest that the persistent presence of endogenous IFN-alpha inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-alpha.

Dataset Information

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

Publications

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

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