Toll-like receptors in systemic lupus erythematosus; prospects for therapeutic intervention

Abstract

Recent experimental and clinical studies have placed new emphasis on the role of the innate immune system in SLE. Nucleic acid-containing immune complexes activate the innate response by engaging specific Toll-like receptors (TLRs) and promote the generation of autoantibodies. Pharmacologic modulation of TLR-directed pathways may offer new therapeutic approaches for the treatment of SLE.

Figure 1. Scheme for the perpetuation of autoimmune responses to nucleic acid self-antigens in SLE by TLR-7 and TLR-9

In the presence of autoantibodies and a pre-existing defect in self tolerance, nucleic acids released from apoptotic bodies form anti-nucleic acid immune complexes. These complexes bind to FcγRIIa on dendritic cells and are transported into the endosomal compartments where DNA interacts with TLR-9 and RNA with TLR-7. In response to immune complexes, plasmacytoid dendritic cells secrete IFN-α. Under the influence of IFN-α, dendritic cells upregulate MHC and co-stimulatory molecules, and efficiently present autoantigens to autoreactive T cells. IFN-α also promotes self-reactive B cell activation and expansion, immunoglobulin isotype switching, and antibody production. Anti-nucleic acid immune complex may directly activate autoreactive B cells via BCR/TLR co-engagement. Stimulation of TLR-7 and TLR-9 in B cells then leads to B cell proliferation, differentiation, and immunoglobulin class switching independent of T cell-help. The resulting auto-antibodies perpetuate immune complex formation and sustain a feed-forward cycle of autoimmunity in SLE.