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

Petar Lenert; Kei Yasuda; Liliana Busconi; Patrice Nelson; Courtney Fleenor; Radhika S Ratnabalasuriar; Peter L Nagy; Robert F Ashman; Ian R Rifkin; Ann Marshak-Rothstein

doi:10.1186/ar2710

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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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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

Petar Lenert, Kei Yasuda, Liliana Busconi, Patrice Nelson, Courtney Fleenor, Radhika S Ratnabalasuriar, Peter L Nagy, Robert F Ashman, Ian R Rifkin and Ann Marshak-Rothstein

Arthritis research & therapy, Vol.11(3), pp.R79-R79

2009

DOI: 10.1186/ar2710

PMCID: PMC2714127

PMID: 19476613

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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.

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Title: Subtitle: 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
Creators: Petar Lenert - Departments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USA
Kei Yasuda - Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA
Liliana Busconi - Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA
Patrice Nelson - Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA
Courtney Fleenor - Departments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USA
Radhika S Ratnabalasuriar - Departments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USA
Peter L Nagy - Departments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USA
Robert F Ashman - Departments of Internal Medicine and Pathology, Carver College of Medicine, The University of Iowa, Iowa City, C312GH, 200 Hawkins Drive, IA 52242, USA
Ian R Rifkin - Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA
Ann Marshak-Rothstein - Departments of Microbiology and Medicine, Boston University School of Medicine, Boston, 715 Albany Street, MA 02118, USA
Resource Type: Journal article
Publication Details: Arthritis research & therapy, Vol.11(3), pp.R79-R79
DOI: 10.1186/ar2710
PMID: 19476613
PMCID: PMC2714127
NLM abbreviation: Arthritis Res Ther
ISSN: 1478-6354
eISSN: 1478-6362
Publisher: BioMed Central
Language: English
Date published: 2009
Academic Unit: Immunology; Internal Medicine
Record Identifier: 9984094605902771

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