Kölm Robert, Schaller Monica, Roumenina Lubka T, Niemiec Iga, Kremer Hovinga Johanna A, Khanicheh Elham, Kaufmann Beat A, Hopfer Helmut, Trendelenburg Marten
Department of Biomedicine, University Hospital, 4031 Basel, Switzerland;
University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, 3010 Bern, Switzerland.
J Immunol. 2016 Nov 1;197(9):3669-3679. doi: 10.4049/jimmunol.1501876. Epub 2016 Oct 3.
Premature atherosclerosis and thrombotic complications are major causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). However, the high incidence of these complications cannot be explained by traditional risk factors alone, suggesting direct effects of an activated immune system on hemostasis. The unexpected nucleotide sequence homology between SLE patient-derived autoantibodies against complement C1q (Fab anti-C1q) and von Willebrand factor (VWF) led us to investigate a potential interaction between the complement and hemostatic systems on the level of initiating molecules. VWF was found to bind to surface-bound C1q under static conditions. The binding could specifically be inhibited by Fab anti-C1q and C1q-derived peptides. Under shear stress the C1q-VWF interaction was enhanced, resembling the binding of VWF to collagen I. Additionally, we could show that C1q-VWF complexes induced platelet rolling and firm adhesion. Furthermore, we observed VWF binding to C1q-positive apoptotic microparticles and cholesterol crystals, as well as increased VWF deposition in C1q-positive glomeruli of SLE patients compared with control nephropathy. We show, to our knowledge for the first time, binding of VWF to C1q and thus a direct interaction between starter molecules of hemostasis and the classical pathway of complement. This direct interaction might contribute to the pathogenic mechanisms in complement-mediated, inflammatory diseases.
动脉粥样硬化过早和血栓形成并发症是系统性红斑狼疮（SLE）患者发病和死亡的主要原因。然而，这些并发症的高发病率不能仅用传统危险因素来解释，这表明激活的免疫系统对止血有直接影响。SLE患者来源的抗补体C1q自身抗体（Fab抗C1q）与血管性血友病因子（VWF）之间意外的核苷酸序列同源性，促使我们研究补体系统和止血系统在起始分子水平上的潜在相互作用。我们发现，在静态条件下，VWF可与表面结合的C1q结合。这种结合可被Fab抗C1q和C1q衍生肽特异性抑制。在剪切应力作用下，C1q-VWF相互作用增强，类似于VWF与I型胶原的结合。此外，我们还发现C1q-VWF复合物可诱导血小板滚动和牢固黏附。此外，我们观察到VWF与C1q阳性凋亡微粒和胆固醇晶体结合，并且与对照肾病相比，SLE患者C1q阳性肾小球中VWF沉积增加。据我们所知，我们首次证明了VWF与C1q的结合，从而证明了止血起始分子与补体经典途径之间存在直接相互作用。这种直接相互作用可能有助于补体介导的炎症性疾病的致病机制。
