Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to certain cellular macromolecules, such as the small nuclear ribonucleoprotein particles (snRNPs), which had been considered to be passive targets of the autoimmune response. SLE is also characterized by the increased expression of type I interferon (IFN), which appears to be associated with the development and severity of disease. Here, we show that specific, highly conserved RNA sequences within snRNPs can stimulate Toll-like receptors (TLRs) 7 and 8 as well as activate innate immune cells, such as plasmacytoid dendritic cells (pDCs), which respond by secreting high levels of type I IFN. SLE patient sera containing autoantibodies to snRNPs form immune complexes that are taken up through the Fc receptor γRII and efficiently stimulate pDCs to secrete type I IFNs. These results demonstrate that a prototype autoantigen, the snRNP, can directly stimulate innate immunity and suggest that autoantibodies against snRNP may initiate SLE by stimulating TLR7/8.
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5 December 2005
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December 05 2005
Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8
Jörg Vollmer,
Jörg Vollmer
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
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Sibylle Tluk,
Sibylle Tluk
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
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Claudia Schmitz,
Claudia Schmitz
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
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Svetlana Hamm,
Svetlana Hamm
2Institute for Medical Microbiology, Hygiene and Immunology, D-81675 Munich, Germany
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Marion Jurk,
Marion Jurk
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
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Alexandra Forsbach,
Alexandra Forsbach
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
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Shizuo Akira,
Shizuo Akira
3Department of Host Defense, Research Institute for Microbial Diseases, Suita, Osaka 565-0871, Japan
4ERATO, Japan Science and Technology Corporation, Osaka 565-0047, Japan
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Kindra M. Kelly,
Kindra M. Kelly
5Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610
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Westley H. Reeves,
Westley H. Reeves
5Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610
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Stefan Bauer,
Stefan Bauer
2Institute for Medical Microbiology, Hygiene and Immunology, D-81675 Munich, Germany
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Arthur M. Krieg
Arthur M. Krieg
6Coley Pharmaceutical Group, Inc., Wellesley, MA 02481
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Jörg Vollmer
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
Sibylle Tluk
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
Claudia Schmitz
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
Svetlana Hamm
2Institute for Medical Microbiology, Hygiene and Immunology, D-81675 Munich, Germany
Marion Jurk
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
Alexandra Forsbach
1Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
Shizuo Akira
3Department of Host Defense, Research Institute for Microbial Diseases, Suita, Osaka 565-0871, Japan
4ERATO, Japan Science and Technology Corporation, Osaka 565-0047, Japan
Kindra M. Kelly
5Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610
Westley H. Reeves
5Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610
Stefan Bauer
2Institute for Medical Microbiology, Hygiene and Immunology, D-81675 Munich, Germany
Arthur M. Krieg
6Coley Pharmaceutical Group, Inc., Wellesley, MA 02481
CORRESPONDENCE Arthur M. Krieg: [email protected]
Abbreviations used: Flt3L, Fms-like tyrosine kinase 3 ligand; mDC, myeloid DC; ODN, oligodeoxynucleotide; ON, oligonucleotide; ORN, oligoribonucleotide; pDC, plasmacytoid DC; SLE, systemic lupus erythematosus; snRNP, small nuclear ribonucleoprotein particle; TLR, Toll-like receptor.
Received:
August 22 2005
Accepted:
November 01 2005
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 202 (11): 1575–1585.
Article history
Received:
August 22 2005
Accepted:
November 01 2005
Citation
Jörg Vollmer, Sibylle Tluk, Claudia Schmitz, Svetlana Hamm, Marion Jurk, Alexandra Forsbach, Shizuo Akira, Kindra M. Kelly, Westley H. Reeves, Stefan Bauer, Arthur M. Krieg; Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8 . J Exp Med 5 December 2005; 202 (11): 1575–1585. doi: https://doi.org/10.1084/jem.20051696
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