Abstract
The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thromboembolic events and/or fetal loss in the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the pathogenicity of aPLs are still poorly understood. Here we show that 3 human monoclonal aPLs as well as IgG fractions from patients with the APS increase mRNA expression of the intracellular toll-like receptor (TLR) 7 in plasmacytoid dendritic cells and TLR8 in monocytes. Simultaneously they induce the translocation of TLR7 or TLR8 from the endoplasmic reticulum to the endosome. These effects depend on the uptake of aPLs into the endosome, subsequent activation of endosomal NADPH oxidase, and generation of superoxide. As a consequence cells are dramatically sensitized to ligands for TLR7 and TLR8. This observation delineates a novel signal transduction pathway in innate immunity originating from the endosome. Because the overexpression of TLR7 can also be detected in plasmacytoid dendritic cells from patients with the APS ex vivo, our results provide an explanation for proinflammatory and procoagulant effects of aPLs. Because inappropriate expression of TLR7 has been implicated in the development of systemic autoimmunity, these findings may also be relevant for the understanding of autoimmunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Antiphospholipid / administration & dosage*
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Antibodies, Monoclonal / administration & dosage
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Antiphospholipid Syndrome / etiology
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Antiphospholipid Syndrome / immunology
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Antiphospholipid Syndrome / metabolism
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Endosomes / immunology
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Endosomes / metabolism
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Female
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Humans
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Immunity, Innate
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In Vitro Techniques
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Interferon-alpha / genetics
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Ligands
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Male
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / immunology*
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Monocytes / metabolism*
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Protein Transport
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction
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Superoxides / metabolism
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Toll-Like Receptor 7 / antagonists & inhibitors
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Toll-Like Receptor 7 / deficiency
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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 7 / metabolism*
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Toll-Like Receptor 8 / immunology*
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Toll-Like Receptor 8 / metabolism*
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Tumor Necrosis Factor-alpha / genetics
Substances
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Antibodies, Antiphospholipid
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Antibodies, Monoclonal
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Interferon-alpha
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Ligands
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Membrane Glycoproteins
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RNA, Messenger
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TLR7 protein, human
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TLR8 protein, human
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Tlr7 protein, mouse
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Toll-Like Receptor 7
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Toll-Like Receptor 8
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Tumor Necrosis Factor-alpha
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Superoxides