The Journal of Experimental Medicine
Cytokines in immune regulation
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Published 17 October 2005. doi:10.1084/jem.20050914
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 8, 1131-1139
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ARTICLE

 Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus

Franck J. Barrat1, Thea Meeker1, Josh Gregorio1, Jean H. Chan1, Satoshi Uematsu2, Shizuo Akira2, Bonnie Chang1, Omar Duramad1, and Robert L. Coffman1

1 Dynavax Technologies Corporation, Berkeley, CA 94710
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita-ku, Osaka 565-0871, Japan

CORRESPONDENCE Franck J. Barrat: fbarrat{at}dvax.com

Raised serum levels of interferon (IFN)-{alpha} have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN-{alpha} is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN-{alpha}. We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-{alpha} production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN-{alpha} production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN-{alpha} by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.

Abbreviations used: CT, threshold cycle; ds, double-stranded; IC, immune complex; IRS, immunoregulatory DNA sequences; ISS, immunostimulatory sequences; MOI, multiplicity of infection; ODN, oligonucleotide; PDC, plasmacytoid pre-DC; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; TLR, Toll-like receptor.


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