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

Persistent Link:
http://hdl.handle.net/10150/610359
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
Author:
Lenert, Petar; Yasuda, Kei; Busconi, Liliana; Nelson, Patrice; Fleenor, Courtney; Ratnabalasuriar, Radhika; Nagy, Peter; Ashman, Robert; Rifkin, Ian; Marshak-Rothstein, Ann
Affiliation:
Departments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USA; Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA
Issue Date:
2009
Publisher:
BioMed Central
Citation:
Arthritis Research & Therapy 2009, 11:R79 (doi:10.1186/ar2710)
Journal:
Arthritis Research & Therapy
Rights:
© 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)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
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.
EISSN:
1478-6362
DOI:
10.1186/ar2710
Version:
Final published version
Additional Links:
http://arthritis-research.com/content/11/3/R79

Full metadata record

DC FieldValue Language
dc.contributor.authorLenert, Petaren
dc.contributor.authorYasuda, Keien
dc.contributor.authorBusconi, Lilianaen
dc.contributor.authorNelson, Patriceen
dc.contributor.authorFleenor, Courtneyen
dc.contributor.authorRatnabalasuriar, Radhikaen
dc.contributor.authorNagy, Peteren
dc.contributor.authorAshman, Roberten
dc.contributor.authorRifkin, Ianen
dc.contributor.authorMarshak-Rothstein, Annen
dc.date.accessioned2016-05-20T09:05:05Z-
dc.date.available2016-05-20T09:05:05Z-
dc.date.issued2009en
dc.identifier.citationArthritis Research & Therapy 2009, 11:R79 (doi:10.1186/ar2710)en
dc.identifier.doi10.1186/ar2710en
dc.identifier.urihttp://hdl.handle.net/10150/610359-
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
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://arthritis-research.com/content/11/3/R79en
dc.rights© 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)en
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
dc.typeArticleen
dc.identifier.eissn1478-6362en
dc.contributor.departmentDepartments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USAen
dc.contributor.departmentDepartments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USAen
dc.identifier.journalArthritis Research & Therapyen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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