ArticleArthritis research & therapy2009
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-Fas(lpr/lpr) mice in vivo.
Article in Arthritis research & therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed.
- Host-pathogen protein-nucleic acid interactions: A comprehensive review.Computational and structural biotechnology journal · 2022Review
- A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza.The Journal of experimental medicine · 2021Article
- Role of nucleic acid sensing in the pathogenesis of type 1 diabetes.World journal of diabetes · 2021Review
- Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles.Nature reviews. Drug discovery · 2019Review
- Cross-Reactive Antigen Expressed by B6 Splenocytes Drives Receptor Editing and Marginal Zone Differentiation of IgG2a-Reactive AM14 Vκ8 B Cells.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- DNA-Based Biomaterials for Immunoengineering.Advanced healthcare materials · 2019Review
- Lupus-Associated Immune Complexes Activate Human Neutrophils in an FcγRIIA-Dependent but TLR-Independent Response.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides.Pharmacological research · 2016Review
- Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells.Journal of immunology research · 2016Review
- Immunomodulatory spherical nucleic acids.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- Guanine-modified inhibitory oligonucleotides efficiently impair TLR7- and TLR9-mediated immune responses of human immune cells.PloS one · 2015Article
- Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation.Journal of immunology (Baltimore, Md. : 1950) · 2013Article
- Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9.Nucleic acids research · 2013Article
- B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice.Journal of immunology (Baltimore, Md. : 1950) · 2012Article
- Myeloid dendritic cells from B6.NZM Sle1/Sle2/Sle3 lupus-prone mice express an IFN signature that precedes disease onset.Journal of immunology (Baltimore, Md. : 1950) · 2012Article
- Modulating toll-like receptor 7 and 9 responses as therapy for allergy and autoimmunity.Current allergy and asthma reports · 2012Review
- A novel pathogenetic concept-antiviral immunity in lupus nephritis.Nature reviews. Nephrology · 2012Review
- Mdm2 promotes systemic lupus erythematosus and lupus nephritis.Journal of the American Society of Nephrology : JASN · 2011Article
- Nucleic acid-binding polymers as anti-inflammatory agents.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
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Abstract
introductionB 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.
methodsWe 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.
resultsClass 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.
conclusionsThe 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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