Fc gamma RIIB on liver sinusoidal endothelial cells is essential for antibody-induced GPVI ectodomain shedding in mice
Authors: Stegner, David; Popp, Michael; Lorenz, Viola; Wax, Jacqueline K.; Gessner, J. Engelbert; Nieswandt, Bernhard
The activating platelet collagen receptor glycoprotein VI (GPVI) is a promising antithrombotic target because of its central role in arterial thrombosis and its minor relevance for normal hemostasis. The receptor can be specifically targeted by antibodies and irreversibly downregulated in circulating platelets in vivo, resulting in long-term antithrombotic protection in mice. This GPVI immunodepletion predominantly occurs through ectodomain shedding, which is accompanied by a transient drop in peripheral platelet counts. Mechanistic studies on this targeted GPVI loss have been hampered because it cannot be reproduced in isolated platelets in vitro. Here we show that both the transient thrombocytopenia and GPVI ectodomain shedding depend on the Fc portion of the anti-GPVI antibody and its interaction with the inhibitory Fc gamma receptor (Fc gamma R)IIB. In wild-type, but not Fcgr2b(-/-) mice, anti-GPVI-opsonized platelets became transiently trapped in the liver followed by the appearance of the soluble GPVI ectodomain in the plasma. Depletion of Kupffer cells neither affected anti-GPVI-induced platelet accumulation nor GPVI shedding, demonstrating that the other major Fc gamma RIIB-expressing cell type, liver sinusoidal endothelial cells, is required for both processes to occur. These results reveal a novel and unexpected function of hepatic Fc gamma RIIB in the targeted downregulation of GPVI in vivo. (Blood. 2016;128(6):862-865)
Endothelial expression of Fc gamma receptor IIb in the full-term human placenta
Authors: Mishima, T.; Kurasawa, G.; Ishikawa, G.; Mori, M.; Kawahigashi, Y.; Ishikawa, T.; Luo, S. -S.; Takizawa, T.; Goto, T.; Matsubara, S.; Takeshita, T.; Robinson, J. M.; Takizawa, T.
In the third trimester, human placental endothelial cells express Fc gamma receptor IIb (Fc gamma RIIb). This expression is unique because Fc gamma RIIb is generally expressed on immune cells and is typically undetectable in adult endothelial cells. Recently, we found a novel Fc gamma RIIb-defined, IgG-containing organelle in placental endothelial cells; this organelle may be a key structure for the transcytosis of IgG across the endothelial layer. In this study, we verify the expression of Fc gamma RIIb in endothelial placenta cells and use reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing analyses to define the expressed FCGR2B mRNA transcript variant. We also investigated the distribution of FCGR2B mRNA and protein within the vascular tree of the full-term human placenta by RT-PCR and quantitative microscopy. The mRNA sequence of FCGR2B expressed specifically in placental endothelial cells is that of transcript variant 2. Fc gamma IIb expression and synthesis occur throughout the placental vascular tree but do not extend into the umbilical cord. This study provides additional information on Fc gamma RIIb expression in the human placenta. (c) 2006 Elsevier Ltd. All rights reserved.