Abstract
Systemic lupus erythematosus severity correlates with elevated serum levels of type I IFNs, cytokines produced in large quantities by plasmacytoid dendritic cells (pDC) in response to engagement of TLR7 and TLR9 with endocytosed nucleic acids. B cell adaptor for PI3K (BCAP) promoted many aspects of TLR7-driven lupus-like disease, including Isg15 and Ifit1 expression in blood and an immature pDC phenotype associated with higher IFN production. BCAP-/- mice produced significantly less serum IFN-α than wild-type mice after injection of TLR9 agonist, and BCAP promoted TLR7 and TLR9-induced IFN-α production specifically in pDC. TLR-induced IFN-α production in pDC requires DOCK2-mediated activation of Rac1 leading to activation of IKKα, a mechanism we show was dependent on BCAP. BCAP-/- pDC had decreased actin polymerization and Rac1 activation and reduced IKKα phosphorylation upon TLR9 stimulation. We show a novel role for BCAP in promoting TLR-induced IFN-α production in pDC and in systemic lupus erythematosus pathogenesis.
Copyright © 2019 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Animals
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Cytokines / genetics
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Cytokines / immunology
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Dendritic Cells / immunology*
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Dendritic Cells / pathology
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Female
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GTPase-Activating Proteins / genetics
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GTPase-Activating Proteins / immunology
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / immunology
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Interferon-alpha / genetics
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Interferon-alpha / immunology*
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / pathology
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Mice
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Mice, Knockout
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Neuropeptides / genetics
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Neuropeptides / immunology
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Plasma Cells / immunology*
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Plasma Cells / pathology
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / immunology
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Toll-Like Receptor 7 / genetics
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Toll-Like Receptor 7 / immunology*
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Toll-Like Receptor 9 / genetics
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Toll-Like Receptor 9 / immunology*
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Ubiquitins / genetics
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Ubiquitins / immunology
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Cytokines
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DOCK2 protein, mouse
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G1p2 protein, mouse
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GTPase-Activating Proteins
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Guanine Nucleotide Exchange Factors
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Ifit1 protein, mouse
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Interferon-alpha
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Membrane Glycoproteins
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Neuropeptides
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Pik3ap1 protein, mouse
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RNA-Binding Proteins
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Rac1 protein, mouse
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Tlr7 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Ubiquitins
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rac1 GTP-Binding Protein