Mechanismus des niedrigen Geburtsgewichts bei fetal-neonataler Alloimmunthrombozytopenie (FNAIT): Antikörper-abhängige Beeinträchtigung der Trophoblastenfunktion
Yannick Waxmann (Gießen / DE), Stefanie Jehle (Gießen / DE), Mareen Althoff (Gießen / DE), Darvin Preuss (Gießen / DE), Carolin Natge (Gießen / DE), Anja-Petra Spies-Naumann (Gießen / DE), Behnaz Bayat (Gießen / DE), Ulrich Sachs (Gießen / DE)
In addition to thrombocytopenia, a reduction in birth weight has been reported as a clinical feature of fetal-neonatal alloimmune thrombocytopenia (FNAIT), potentially indicating an impaired placental function. Previous analyses have shown that the most common antibodies in FNAIT, anti-HPA-1a, react not only with aIIbb3 on platelets but also with avb3, which is expressed on the trophoblast. Using a human first-trimester trophoblast cell line (HTR-8), we investigated the effects of antibodies on trophoblast cell function.
Trophoblast network formation and remodeling were investigated in HTR-8 cells using time-lapse video microscopy. VEGF pre-stimulated cells were cultured on Matrigel and the effects of antibodies against b3, av, or avb3 on network formation were studied. In addition, using a silicone insert, a standardized wound area was generated, and the migratory capacity of HTR-8 cells was evaluated. Cellular effects of antibody binding were investigated using a flow-cytometry-based assay for the detection of reactive oxygen species (ROS).
A significant inhibition of the trophoblast network formation was observed following incubation with complex-specific antibodies, but not with anti-b3 or anti-av. Similarly, in contrast to single-chain specific antibodies, the presence of complex-specific antibodies significantly slowed down the migration of HTR-8 cells into the wound area and induced a delayed wound closure. Finally, a 1.5-fold increase in cellular ROS production was observed following incubation with complex-specific antibodies.
Our results suggest that upon binding of complex-specific antibodies recognizing avb3, a signaling pathway is initiated, which promotes the release of ROS. In vitro, this signal impairs the migratory capacity of trophoblast cells. We consider this mechanism to be one potential cause of impaired placental growth, which affects the birth weight of FNAIT babies.
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