DNA‐like prototypic INH‐ODNs selectively inhibit B cell receptor for antigen (BCR) triggered TLR9 activation in autoimmune B cells

Multiple lines of evidence suggest a role for nucleic‐acid sensing receptors in the pathogenesis of SLE. Strategies to preferentially block autoimmune B cells may be preferred over currently advocated non‐selective B cell depletion protocols. We have developed a new generation of small TLR9 inhibitors (Class R INH‐ODNs). These DNA‐like INH‐ODNs have a very low potency for naive resting B cells, but are very potent inhibitors of macrophages and DCs. We wondered what the effects of these agents were on autoimmune B cells. Therefore, we studied the innate activation of autoreactive B cells from MRL‐lpr/lpr lupus mice and AM‐14 RF‐specific transgenic B cells. B cells were stimulated with linear or palindromic CpG ligands; or with immune complexes containing PL2.3 or ID4 antibodies. Both dsDNA‐reactive B cells and AM‐14 B cells were inhibited with low nanomolar concentrations of Class R INH‐ODN when activation required ligand delivery via the BCR. However, when autoreactive B cells were stimulated with linear TLR9 ligands, bypassing the BCR‐mediated entry, similarly to naïve resting B cells the potency of Class R INH‐ODNs was 10–33 fold lower. Similar differences were observed in MRL‐lpr/lpr mice in vivo where the prototypic Class R INH‐ODN appeared to be more effective compared to its linear derivative. In conclusion, refinement of Class R INH‐ODN structure for human use may result in a new line of therapeutics for SLE.