title: Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus.
abstract: 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.
authors.affiliation: Dynavax Technologies Corporation, Berkeley, CA 94710, USA. fbarrat@dvax.com
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: Thea
authors.initials: T
authors.lastname: Meeker
authors.forename: Josh
authors.initials: J
authors.lastname: Gregorio
authors.forename: Jean H
authors.initials: JH
authors.lastname: Chan
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Bonnie
authors.initials: B
authors.lastname: Chang
authors.forename: Omar
authors.initials: O
authors.lastname: Duramad
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009841:Oligonucleotides / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014780:Viruses / Q000276:immunology
chemical_list: D016898:Interferon-alpha; D009841:Oligonucleotides; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9