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.
Highlights
B cells have many different roles in systemic lupus erythematosus (SLE), ranging from autoantigen recognition and processing to effector functions
Class R INH-ODNs have 10- to 30-fold higher inhibitory potency when autoreactive B cells are synergistically activated through the B-cell receptor (BCR) and associated TLR7 or 9 than when stimulation occurs via non-BCR-engaged TLR7/9
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
Summary
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). BCR: B-cell receptor; DC: dendritic cell; dsDNA: double-stranded DNA; ELISA: enzyme-linked immunosorbent assay; HRP: horseradish peroxidase; IFN: interferon; Ig: immunoglobulin; IL: interleukin; INH-ODN: inhibitory oligonucleotide; LPS: lipopolysaccharide; mAb: monoclonal antibody; MACS: magnetic-activated cell sorting; MyD88: myeloid differentiation primary response gene 88; ODN: oligonucleotide; PBS: phosphate-buffered saline; PO: phosphodiester; PS: phosphorothioate; SLE: systemic lupus erythematosus; TLR: Toll-like receptor; TNF: tumor necrosis factor. Stimulation with complex TLR9 ligands is more restricted in terms of responding cell types and, in DCs, proceeds through early endosomes instead. The uptake of these complex ligands may be facilitated by CXCL16, which may influence this differential compartmentalization [9]. Type I interferonalpha (IFN-α) secretion is induced by complex class A(D) CpG-oligonucleotides (CpG-ODNs) via early endosomal signaling, whereas interleukin-6/tumor necrosis factor-alpha (IL6/TNF-α) secretion requires late endosomal signaling and is induced primarily by linear TLR9 ligands [8]
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