Inhibitory short synthetic oligodeoxynucleotides and lupus

Abstract

B cells and antigen-presenting cells express a group of intracellular Toll-like receptors (TLRs) that recognize nucleic acids and can be accessed only when apoptotic debris or immune complexes are internalized by B-cell receptors or Fc receptors. This results in rapid cell activation and release of inflammatory mediators that perpetuate the autoantibody response. TLR-7 and TLR-9 are required to generate autoantibodies to RNA and DNA, respectively. Synthetic oligodeoxynucleotides that inhibit the activity of these intracellular TLRs attenuate systemic lupus erythematosus in mouse models and may be of therapeutic benefit in human systemic lupus erythematosus.

Figure 1

T-independent autoantibody production may be propagated by an amplification loop involving TLRs, IFNα, and BAFF/APRIL. BAFF, B-cell activating factor; BCR, B-cell receptor; DC, dendritic cell; FcR, Fc receptor; IFN, interferon; IL, interleukin; mDC, monocyte-derived dendritic cell; ODN, short synthetic oligodeoxynucleotide; pDC, plasmacytoid dendritic cell; SLE, systemic lupus erythematosus; TLR, Toll-like receptor.