title: Sequences derived from self-RNA containing certain natural modifications act as suppressors of RNA-mediated inflammatory immune responses.
abstract: The ability of the host to distinguish between self and foreign nucleic acids is one of the critical factors contributing to the recognition of pathogens by Toll-like receptors (TLRs). Under certain circumstances, eukaryotic self-RNA may reach TLR-containing compartments allowing for self-recognition. Specific modifications were previously demonstrated to suppress immune activation when placed at several positions in an immune stimulatory RNA or silencing RNA (siRNA). However, we show that even a simple natural modification such as a single 2'-O-methylation at different nucleotide positions throughout a sequence derived from a self-RNA strongly interferes with TLR-mediated effects. Such a single modification can even have an inhibitory effect in vitro and in vivo when placed in a different than the immune stimulatory RNA strand acting as suppressive RNA. Several safeguard mechanisms appear to have evolved to avoid cellular TLR-mediated activation by self-RNAs that may under other circumstances result in inflammatory or autoimmune responses. This knowledge can be used to include as few as a single 2'-O-methyl modification at a specific position in a siRNA sense or anti-sense strand to avoid TLR immune effects.
authors.affiliation: Coley Pharmaceutical GmbH-A Pfizer Company, Merowingerplatz 1a, 40225 Düsseldorf, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Tluk
authors.forename: Marion
authors.initials: M
authors.lastname: Jurk
authors.forename: Alexandra
authors.initials: A
authors.lastname: Forsbach
authors.forename: Risini
authors.initials: R
authors.lastname: Weeratna
authors.forename: Ulrike
authors.initials: U
authors.lastname: Samulowitz
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Jörg
authors.initials: J
authors.lastname: Vollmer