title: Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells.
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.
authors: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Mainz, Germany.
authors: Nadine
authors: N
authors: Prinz
authors: Natascha
authors: N
authors: Clemens
authors: Dennis
authors: D
authors: Strand
authors: Inge
authors: I
authors: Pütz
authors: Mareike
authors: M
authors: Lorenz
authors: Andreas
authors: A
authors: Daiber
authors: Pamela
authors: P
authors: Stein
authors: Adriana
authors: A
authors: Degreif
authors: Markus
authors: M
authors: Radsak
authors: Hansjörg
authors: H
authors: Schild
authors: Stefan
authors: S
authors: Bauer
authors: Philipp
authors: P
authors: von Landenberg
authors: Karl J
authors: KJ
authors: Lackner
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016736:Antiphospholipid Syndrome / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000235:genetics; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D016898:Interferon-alpha; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides