Immunostimulatory CpG motifs and DNA vaccines

Bacterial DNA, but not vertebrate DNA, causes direct stimulation of several components of the vertebrate immune system. This activation is due to the presence of unmethylated CpG dinucleotides (1), which are present at the expected frequency in bacterial DNA, but are underrepresented ("CpG suppression") and methylated in vertebrate DNA (2). The immunostimulatory effects include direct induction of B cell proliferation and immunoglobulin (Ig) secretion (1), as well as activation of monocytes, macrophages, and dendritic cells to upregulate their expression of costimulatory molecules, which drive immune responses, and secreting a variety of cytokines, including high levels of IL-12 (3,4). These cytokines then, in turn, stimulate natural killer (NK) cells to secrete IFN-γ and to have increased lytic activity (5). Overall, CpG DNA induces a Th1 like pattern of cytokine production dominated by IL-12 and IFN-γ, with little secretion of Th2 cytokines (4,5). These effects can also be obtained with synthetic oligonucleotides (ODN) (6,7) or plasmid DNA vectors (8) containing CpG immunostimulatory motifs. From a teleological view, it appears likely that the rapid immune activation in response to CpG DNA may have evolved as one component of the innate immune defense mechanisms that recognize structural patterns specific to microbial molecules.