CpG DNA stimulates autoreactive immature B cells in the bone marrow

Polyclonal activation of developing B cells is an injurious process, because most of these cells are nontolerant and express autoreactive receptors. CpG DNA is a polyclonal activator of mature B cells, but its effect on developing B cells is unclear. We tested whether developing, nontolerant B cells are responsive to mitogenic stimulation by CpG DNA and whether such a stimulus can interfere with the establishment of central tolerance. We found that developing B cells express Toll-like receptor 9 and undergo a polyclonal response to CpG DNA stimulation, as revealed by proliferation and differentiation to antibody-producing cells. In vitro and ex vivo experiments revealed that stimulation with CpG DNA protects immature B cells from negative selection imposed by apoptosis and receptor editing and results in the production of autoantibodies. Finally, we found that in vivo administration of CpG DNA activates immature B cells in the bone marrow and suppresses the expression of recombination-activating genes in a mouse model of central tolerance and receptor editing. These results suggest that mitogenic signals provided by CpG DNA stimulate nontolerant immature B cells in the bone marrow and have the potential to interfere with central tolerance.