Discrimination of self and non-self DNAs

Cellular recognition of pathogen DNA is used as a means to signal infection. Toll-like receptor 9 (TLR9) recognizes DNA containing unmethylated CpG motifs within the endosomes of B cells, dendritic cells, and mouse macrophages. A number of factors appear to contribute to the generation of TLR9 responses to bacterial and viral DNAs, but not self DNA: (1) the CpG dinucleotide occurs at relatively low frequency in vertebrate genomes; (2) cytosine methylation of CpG motifs, prevalent in vertebrates, greatly reduces cellular responses; (3) saturable DNA uptake determines that only DNA with a certain threshold frequency of active sequences will accumulate to sufficient levels to activate cells; and (4) inhibitory DNA motifs may limit activation by self DNA. Apart from TLR9 responses, recent evidence indicates that cells can respond to double-stranded (ds) DNA within the Cytoplasm as an indication of viral infection. In this case, the definition of the DNA as foreign or dangerous may rely on its abnormal location. Evidence suggests that discrimination of self from non-self DNA is defective in the autoimmune disease known as systemic lupus erythematosus (SLE), and this may involve both TLR9 and TLR-independent pathways.