Abstract
Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Antibody Complex
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B-Lymphocytes
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CpG Islands
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DNA-Binding Proteins / immunology
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Dendritic Cells / cytology
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Dendritic Cells / metabolism
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HMGB1 Protein / biosynthesis
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HMGB1 Protein / physiology*
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / metabolism
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Lupus Erythematosus, Systemic / pathology
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Mice
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Mice, Inbred C57BL
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Oligodeoxyribonucleotides / immunology*
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Receptor for Advanced Glycation End Products / biosynthesis
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Receptor for Advanced Glycation End Products / physiology*
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Receptors, Cell Surface / metabolism
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Toll-Like Receptor 9 / metabolism*
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Toll-Like Receptor 9 / physiology
Substances
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AGER protein, human
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Antigen-Antibody Complex
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DNA-Binding Proteins
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HMGB1 Protein
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Oligodeoxyribonucleotides
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Receptor for Advanced Glycation End Products
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Receptors, Cell Surface
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Toll-Like Receptor 9