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dc.contributor.authorLenert, Petaren_US
dc.contributor.authorYasuda, Keien_US
dc.contributor.authorBusconi, Lilianaen_US
dc.contributor.authorNelson, Patriceen_US
dc.contributor.authorFleenor, Courtneyen_US
dc.contributor.authorRatnabalasuriar, Radhika S.en_US
dc.contributor.authorNagy, Peter L.en_US
dc.contributor.authorAshman, Robert F.en_US
dc.contributor.authorRifkin, Ian R.en_US
dc.contributor.authorMarshak-Rothstein, Annen_US
dc.date.accessioned2012-01-09T20:51:28Z
dc.date.available2012-01-09T20:51:28Z
dc.date.copyright2009
dc.date.issued2009-5-28
dc.identifier.citationLenert, Petar, Kei Yasuda, Liliana Busconi, Patrice Nelson, Courtney Fleenor, Radhika S Ratnabalasuriar, Peter L Nagy, Robert F Ashman, Ian R Rifkin, Ann Marshak-Rothstein. "DNA-like class R inhibitory oligonucleotides (INH-ODNs) preferentially block autoantigen-induced B-cell and dendritic cell activation in vitro and autoantibody production in lupus-prone MRL-Faslpr/lpr mice in vivo" Arthritis Research & Therapy 11(3):R79. (2009)
dc.identifier.issn1478-6362
dc.identifier.urihttp://hdl.handle.net/2144/2869
dc.description.abstractINTRODUCTION. B cells have many different roles in systemic lupus erythematosus (SLE), ranging from autoantigen recognition and processing to effector functions (for example, autoantibody and cytokine secretion). Recent studies have shown that intracellular nucleic acid-sensing receptors, Toll-like receptor (TLR) 7 and TLR9, play an important role in the pathogenesis of SLE. Dual engagement of rheumatoid factor-specific AM14 B cells through the B-cell receptor (BCR) and TLR7/9 results in marked proliferation of autoimmune B cells. Thus, strategies to preferentially block innate activation through TLRs in autoimmune B cells may be preferred over non-selective B-cell depletion. METHODS. We have developed a new generation of DNA-like compounds named class R inhibitory oligonucleotides (INH-ODNs). We tested their effectiveness in autoimmune B cells and interferon-alpha-producing dendritic cells in vitro and in lupus-prone MRL-Faslpr/lpr mice in vivo. RESULTS. Class R INH-ODNs have 10- to 30-fold higher inhibitory potency when autoreactive B cells are synergistically activated through the BCR and associated TLR7 or 9 than when stimulation occurs via non-BCR-engaged TLR7/9. Inhibition of TLR9 requires the presence of both CCT and GGG triplets in an INH-ODN, whereas the inhibition of the TLR7 pathway appears to be sequence-independent but dependent on the phosphorothioate backbone. This difference was also observed in the MRL-Faslpr/lpr mice in vivo, where the prototypic class R INH-ODN was more effective in curtailing abnormal autoantibody secretion and prolonging survival. CONCLUSIONS. The increased potency of class R INH-ODNs for autoreactive B cells and dendritic cells may be beneficial for lupus patients by providing pathway-specific inhibition yet allowing them to generate protective immune response when needed.en_US
dc.description.sponsorshipNational Institutes of Health (AI047374, AI064736); Alliance for Lupus Researchen_US
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.rightsCopyright 2009 Lenert et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.0
dc.titleDNA-like Class R Inhibitory Oligonucleotides (INH-ODNs) Preferentially Block Autoantigen-Induced B-Cell and Dendritic Cell Activation in Vitro and Autoantibody Production in Lupus-Prone MRL-Faslpr/lpr Mice in Vivoen_US
dc.typearticleen_US
dc.identifier.doi10.1186/ar2710
dc.identifier.pubmedid19476613
dc.identifier.pmcid2714127


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Copyright 2009 Lenert et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as Copyright 2009 Lenert et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.