Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adjuvants, Immunologic / physiology
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Antigens, Differentiation / physiology
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B-Cell Activating Factor
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B-Lymphocytes / drug effects
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B-Lymphocytes / enzymology
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B-Lymphocytes / immunology
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CD40 Ligand / physiology
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Cell Line
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Chloroquine / pharmacology
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Cytidine Deaminase / biosynthesis
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DNA, Bacterial / pharmacology*
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DNA, Bacterial / physiology
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Gene Rearrangement, B-Lymphocyte* / drug effects
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Humans
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Immunity, Innate / genetics
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Immunoglobulin Class Switching / drug effects
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Immunoglobulin Class Switching / genetics*
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Immunoglobulin Constant Regions / genetics
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Immunoglobulin Constant Regions / metabolism
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Immunoglobulin G / biosynthesis*
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Immunoglobulin G / genetics
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Immunoglobulin G / metabolism
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Immunoglobulin gamma-Chains / genetics
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Immunoglobulin gamma-Chains / metabolism
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Immunoglobulin mu-Chains / genetics
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Immunoglobulin mu-Chains / metabolism
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Interleukin-1 Receptor-Associated Kinases
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Interleukin-10 / pharmacology
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Interleukin-10 / physiology*
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Lymphocyte Activation / genetics*
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / physiology*
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Membrane Proteins / physiology
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Myeloid Differentiation Factor 88
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NF-kappa B / physiology
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NF-kappa B p50 Subunit
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Promoter Regions, Genetic / immunology
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Protein Kinases / physiology
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Proteins / physiology
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Receptors, Antigen, B-Cell / metabolism
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Receptors, Antigen, B-Cell / physiology
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Receptors, Cell Surface / biosynthesis
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic / physiology
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Response Elements / immunology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology*
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 9
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Toll-Like Receptors
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Transcriptional Activation / drug effects
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Transcriptional Activation / immunology
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Tumor Necrosis Factor-alpha / physiology
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Up-Regulation / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Adjuvants, Immunologic
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Antigens, Differentiation
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B-Cell Activating Factor
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CpG-DNA, E coli
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DNA, Bacterial
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Immunoglobulin Constant Regions
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Immunoglobulin G
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Immunoglobulin gamma-Chains
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Immunoglobulin mu-Chains
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MYD88 protein, human
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Membrane Glycoproteins
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Membrane Proteins
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Myeloid Differentiation Factor 88
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NF-kappa B
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NF-kappa B p50 Subunit
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Proteins
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Receptors, Antigen, B-Cell
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Receptors, Cell Surface
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Receptors, Immunologic
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TLR9 protein, human
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TNF Receptor-Associated Factor 6
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TNFSF13B protein, human
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Toll-Like Receptor 9
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Interleukin-10
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CD40 Ligand
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Chloroquine
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Protein Kinases
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Interleukin-1 Receptor-Associated Kinases
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase