page 1333). Thus, it may be possible to block an autoimmune response to self-DNA without compromising the beneficial response to pathogenic DNA.
Microbial DNA is mopped up by macrophages and dendritic cells, which get activated via Toll-like receptors (TLRs), resulting in the production of interferon-β (IFNβ). Recent studies have shown that mammalian DNA complexed to antibodies can also trigger IFNα production via a TLR (specifically TLR9).
The immune system can also be activated by naked self-DNA, leading to some autoimmune diseases. One such state occurs in mice lacking DNaseII. These mice accumulate undigested self-DNA from dead cells in their macrophages, and act as a model for systemic lupus erythematosus (SLE), a disease characterized by autoantibodies to circulating self-DNA.
The up-regulation of IFNβ in these mice kills precursor red blood cells, induces severe anemia, and causes the observed embryonic lethality. A DNaseII-IFN receptor double knock-out rescued these effects. In the current study, however, the DNaseII− phenotype, including the IFNβ up-regulation, is not rescued by knock-out of TLR9, TLR3, or their adaptor molecules MyD88 and TRIF.
The results imply that a TLR-independent pathway of IFN activation exists. Therefore, it may be possible to block that autoimmune response pathway while leaving the TLR-dependent response to pathogens intact.