Role of Complement CRP complexes in Inflammation and Organ Dysfunction

创伤会导致炎症和组织--以及细胞损伤。最初的侮辱会导致补体级联的激活，而补体级联会协调炎症和组织破坏。补体在清除创伤损伤的细胞以及凋亡和坏死性颗粒方面起着重要的作用。这种消除被可溶的急性时相蛋白C反应蛋白(CRP)增强。在这个项目中，我们计划研究可溶性补体抑制因子H与C反应蛋白的相互作用以及H因子：C反应蛋白复合体在创伤和炎症中的作用。我们提出了这种复合体在清除受损颗粒中的作用。显然，在受损颗粒表面，补体激活继续进行C3沉积，但进一步的进展受到抑制。后一步被可溶性补体抑制剂因子H和C4BP的结合所阻断，这两种物质结合在受损细胞的表面，与CRP结合。此外，还将研究两种新的CRP配体--因子H相关蛋白FHR-4A和FHR-4B的作用。三种补体调节因子(因子H、FHR-4A和FHR-4B)很可能通过使CRP复合，阻止受损细胞表面补体级联的放大，抑制炎症，并允许吞噬细胞清除。对这些机制的了解将有助于确定合适的补体抑制剂，以调节这些反应。

Trauma induces inflammation and tissue- as well as cell damage. The initial insult causes activation of the complement cascade which orchestrates inflammation and tissue destruction. Complement plays an important role in the clearance of trauma induced damaged cells and of apoptotic and necrotic particles. This elimination is enhanced by the soluble acute phase protein C-reactive protein (CRP). In this project we plan to study the interaction of the soluble complement inhibitor Factor H with CRP and the function of the Factor H:CRP complex during trauma and inflammation. We propose a role of this complex in the clearance of damaged particles. Apparently at the surface of damaged particles complement activation proceeds to C3 deposition, but further progression of the is inhibited. The later step is blocked by binding of the soluble complement inhibitors Factor H and C4BP, which attach to the surface of damaged cells in combination with CRP. In addition the role of two novel CRP ligands, the Factor H related proteins FHR-4A and FHR-4B will be studied. Most likely by complexing CRP all three complement regulators (Factor H, FHR-4A and FHR-4B) block amplification of the complement cascade on the surface of damaged cells, inhibit inflammation and allow removal by phagocytes. The understanding of these mechanisms will help to define appropriate complement inhibitors in order to modulate these reactions.