International Immunology Advance Access originally published online on March 30, 2009
International Immunology 2009 21(5):607-619; doi:10.1093/intimm/dxp030
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Sequences derived from self-RNA containing certain natural modifications act as suppressors of RNA-mediated inflammatory immune responses
1 Coley Pharmaceutical GmbH—A Pfizer Company, Merowingerplatz 1a, 40225 Düsseldorf, Germany
2 Pfizer Vaccine Ottawa, 340 Terry Fox Drive, Suite 200, Kanata (Ottawa), Ontario K2K 3A2, Canada
3 Pfizer Research Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA
4 Institute for Immunology, Biomedizinisches Forschwngszentrum, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany
Correspondence to: J. Vollmer; E-mail: joerg.vollmer{at}pfizer.com
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.
Keywords: methylation, oligoribonucleotide, RNA, siRNA, TLR7, TLR8
Transmitting editor: R. A. Flavell
Received 18 April 2008, accepted 3 March 2009.
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