Kurzfassung

The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by the occurrence of anti-phospholipid specific antibodies (aPL) and recurrent thrombosis or recurrent fetal losses in female patients. In this context, complement activation plays an important role in the pathophysiology of APS. As suggested by mouse models, this in turn activates neutrophils (PMN) mediating trophoblast injury by the release of reactive oxygen species. PMNs are an essential cell type for the...The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by the occurrence of anti-phospholipid specific antibodies (aPL) and recurrent thrombosis or recurrent fetal losses in female patients. In this context, complement activation plays an important role in the pathophysiology of APS. As suggested by mouse models, this in turn activates neutrophils (PMN) mediating trophoblast injury by the release of reactive oxygen species. PMNs are an essential cell type for the initiation of experimental venous thrombosis. Thus, activation of PMNs by aPL may be a critical molecular event during the development of thrombosis in APS patients. We recently demonstrated that aPL alone are able to directly induce activation of PMN effector functions, while the additional presence of Toll-like receptor (TLR) agonists, such as LPS or Pam3Cys, strongly enhances these effects, indicating a synergistic activation pathway of aPL and microbial products. This is corroborated by additional results demonstrating an influence of aPL on TLR7/8 signalling in plasmacytoid dendritic cells and monocytes further supporting the notion that aPL directly interact with innate inflammatory cells. We plan to further characterize the activation status of PMN under inflammatory conditions in the presence of aPL and the resulting impact on APS symptoms. This will provide novel insights for a better understanding of the pathophysiology of APS.
The aim of this project will be to analyze the receptors and pathways involved in aPL induced PMN activation using monoclonal aPL (clones HL5B/HL7G, provided by the Institute of Clinical Chemistry and Laboratory Medicine). In addition, we will investigate in detail PMN activation induced by aPL and additional inflammatory conditions in the presence or absence of TLR agonists in comparison to monocytic cells. For this, we will use established PMN effector assays and employ Western blot as well as phospho-flow analyses to screen for important PMN signalling molecules. To determine the impact of aPL/TLR ligand-activated PMN on the procoagulant activity, we will cooperate with D. Manukyan (CTH Virchow fellow, Institute of Laboratory Medicine and Clin. Chemistry) and CTH platform 4. For validation we will also include studies with IgG fractions of APS patients as well as PMN from APS patients (in cooperation with I. Scharrer, IIIrd Dept. of Medicine).
This project contributes to an improved understanding of the pathophysiology of APS and integrates basic scientific questions with translational patient related studies creating a direct connection in the scope of the CTH.
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