The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 17 October 2005. doi:10.1084/jem.20050914
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 8, 1131-1139
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 233K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Barrat, F. J.
Right arrow Articles by Coffman, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barrat, F. J.
Right arrow Articles by Coffman, R. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

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.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS