U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self...

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Bibliographic Details
Published in:Blood 2006-04, Vol.107 (8), p.3229-3234
Main Authors: Savarese, Emina, Chae, Ohk-wha, Trowitzsch, Simon, Weber, Gert, Kastner, Berthold, Akira, Shizuo, Wagner, Hermann, Schmid, Roland M., Bauer, Stefan, Krug, Anne
Format: Article
Language:English
Subjects:
Animals
Antibodies, Antinuclear - immunology
Antibodies, Antinuclear - pharmacology
Antigen-Antibody Complex - immunology
Antigen-Antibody Complex - pharmacology
Biological and medical sciences
Cells, Cultured
Dendritic Cells - immunology
Dendritic Cells - metabolism
Dendritic Cells - pathology
fms-Like Tyrosine Kinase 3 - immunology
General aspects
Humans
Immunopathology
Interferon-alpha - biosynthesis
Interferon-alpha - immunology
Interleukin-6 - biosynthesis
Interleukin-6 - immunology
Lupus Erythematosus, Systemic - immunology
Lupus Erythematosus, Systemic - metabolism
Lupus Erythematosus, Systemic - pathology
Medical sciences
Membrane Glycoproteins - deficiency
Membrane Glycoproteins - immunology
Mice
Mice, Knockout
Oligoribonucleotides - immunology
Oligoribonucleotides - pharmacology
Plasma Cells - immunology
Plasma Cells - metabolism
Plasma Cells - pathology
Ribonucleoprotein, U1 Small Nuclear - immunology
Ribonucleoprotein, U1 Small Nuclear - pharmacology
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Toll-Like Receptor 7 - deficiency
Toll-Like Receptor 7 - immunology
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Summary:Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-α and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-α and IL-6 by U1snRNPs in murine bone marrow–derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-α and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous “self” ligand for Tlr7 and triggers IFN-α and IL-6 production in PDCs.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2005-07-2650