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


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dc.contributor.author Lenert, Petar en_US
dc.contributor.author Yasuda, Kei en_US
dc.contributor.author Busconi, Liliana en_US
dc.contributor.author Nelson, Patrice en_US
dc.contributor.author Fleenor, Courtney en_US
dc.contributor.author Ratnabalasuriar, Radhika S en_US
dc.contributor.author Nagy, Peter L en_US
dc.contributor.author Ashman, Robert F en_US
dc.contributor.author Rifkin, Ian R en_US
dc.contributor.author Marshak-Rothstein, Ann en_US
dc.date.accessioned 2012-01-09T20:51:28Z
dc.date.available 2012-01-09T20:51:28Z
dc.date.copyright 2009 en_US
dc.date.issued 2009-5-28 en_US
dc.identifier.citation Lenert, 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) en_US
dc.identifier.issn 1478-6362 en_US
dc.identifier.uri http://hdl.handle.net/2144/2869
dc.description.abstract INTRODUCTION. 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.sponsorship National Institutes of Health (AI047374, AI064736); Alliance for Lupus Research en_US
dc.language.iso en en_US
dc.publisher BioMed Central en_US
dc.rights 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. en_US
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_US
dc.title 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 en_US
dc.type article en_US
dc.identifier.doi 10.1186/ar2710 en_US
dc.identifier.pubmedid 19476613 en_US
dc.identifier.pmcid 2714127 en_US

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