The Journal of Experimental Medicine
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Published 5 December 2005. doi:10.1084/jem.20051696
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1575-1585
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ARTICLE

 Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8

Jörg Vollmer1, Sibylle Tluk1, Claudia Schmitz1, Svetlana Hamm2, Marion Jurk1, Alexandra Forsbach1, Shizuo Akira3,4, Kindra M. Kelly5, Westley H. Reeves5, Stefan Bauer2, and Arthur M. Krieg6

1 Coley Pharmaceutical GmbH, 40764 Langenfeld, Germany
2 Institute for Medical Microbiology, Hygiene and Immunology, D-81675 Munich, Germany
3 Department of Host Defense, Research Institute for Microbial Diseases, Suita, Osaka 565-0871, Japan
4 ERATO, Japan Science and Technology Corporation, Osaka 565-0047, Japan
5 Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610
6 Coley Pharmaceutical Group, Inc., Wellesley, MA 02481

CORRESPONDENCE Arthur M. Krieg: akrieg{at}coleypharma.com

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 {gamma}RII 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.

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.


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