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.
Azulay-Debby
Hilla
H
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Edry
Efrat
E
Melamed
Doron
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007075:Immunoglobulin M / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D011951:Receptors, Complement / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D016271:Proto-Oncogene Proteins c-myc; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011951:Receptors, Complement; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C032402:complement 1q receptor; D017493:Leukocyte Common Antigens