CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10.
TLRs are pattern recognition receptors that initiate innate immune responses. TLR9 detects microbial DNA with hypomethylated CpG motifs and in humans is preferentially expressed by IFN-alpha-producing plasmacytoid dendritic cells and B cells. In addition to favoring IFN-alpha release, TLR9 signals B cell activation, proliferation, and IgM production. Recent findings suggest that CpG DNA-TLR9 interaction plays a key role in systemic lupus erythematosus and rheumatoid arthritis, two autoimmune disorders characterized by dysregulated production of DNA-reactive IgG. We show that CpG DNA initiates germline C(gamma)1, C(gamma)2, and C(gamma)3 gene transcription by activating B cells through a TLR9-mediated NF-kappaB-Rel-dependent innate pathway that cooperates with IL-10 through STAT proteins and IFN-responsive factors. This pathway is inhibited by chloroquine, a drug that attenuates the clinical manifestations of IgG-mediated autoimmune disorders. Germline C(gamma) gene transcription is associated with up-regulation of activation-induced cytidine deaminase, a key element of the B cell class switch-inducing machinery, and is followed by class switch DNA recombination from C(micro) to C(gamma)1, C(gamma)2, and C(gamma)3. Subsequent IgG production requires additional signals from BCR and a B cell-activating factor of the TNF family (BAFF), produced by dendritic cells upon exposure to IFN-alpha. Our findings suggest that CpG DNA-TLR9 interaction may be important to initiate or amplify early T cell-independent IgG responses against pathogens. This implies that CpG DNA released during infections may exacerbate autoimmunity by stimulating autoreactive B cells to switch from an IgM to a more pathogenic IgG isotype.
He
Bing
B
Department of Pathology, Weill Medical College, Cornell University, New York, NY 10021, USA.
Qiao
Xugang
X
Cerutti
Andrea
A
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000502:physiology; D000943:Antigens, Differentiation / Q000502:physiology; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D023201:CD40 Ligand / Q000502:physiology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D003564:Cytidine Deaminase / Q000096:biosynthesis; D004269:DNA, Bacterial / Q000494:pharmacology* / Q000502:physiology; D015322:Gene Rearrangement, B-Lymphocyte / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics*; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007142:Immunoglobulin gamma-Chains / Q000235:genetics / Q000378:metabolism; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000502:physiology; D052002:NF-kappa B p50 Subunit; D011401:Promoter Regions, Genetic / Q000276:immunology; D011494:Protein Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D000943:Antigens, Differentiation; D053264:B-Cell Activating Factor; C472452:CpG-DNA, E coli; D004269:DNA, Bacterial; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007142:Immunoglobulin gamma-Chains; D007148:Immunoglobulin mu-Chains; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495371:TLR9 protein, human; D048029:TNF Receptor-Associated Factor 6; C505719:TNFSF13B protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; D002738:Chloroquine; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase