The interaction of C-reactive protein (CRP) with the complement system in the pathogenesis, diagnosis and therapy of the post traumatic inflammatory response

C反应蛋白（CRP）是一种高度保守的五聚体蛋白。它不仅是炎症的标志物，也是炎症的介质。作为先天免疫系统的一部分，它调理细菌并可以调节补体系统的激活。在创伤和败血症中，补体系统不受控制的激活可能导致炎症免疫反应加剧，通过激活补体 C5 导致器官损伤。这种不受控制的免疫反应激活可能发生在所谓的二次打击期间，二次打击是指在最初的创伤性组织损伤后的继发事件中组织损伤增加。控制这种炎症反应是防止其有害后果的关键。我们之前已经证明，五聚体 CRP 与其单个单体亚基的局部解离代表了 CRP 调节炎症区域炎症反应的普遍机制。用一种新化合物阻断这个解离步骤可以显着减少炎症。我们的数据表明，创伤性组织损伤后 CRP 的初始增加可能是后续事件的启动过程，导致继发性损伤时局部 CRP 解离增加。因此，我们认为 CRP 是二次打击反应的关键因素。然而，仍不清楚 CRP 的构象变化如何改变 CRP 对补体系统的调节特性。在这里，我们的目的是研究从五聚体到单体 CRP 的构象变化对其对补体因子（有关现有炎症事件的调节和加重）的影响的影响。我们将研究从补体激活到白细胞亚群差异激活的病理机制后遗症，重点关注 CRP 解离、补体激活和单核细胞亚群激活的相互作用，以便针对二次打击反应制定泰勒特异性治疗方法。我们将把我们的发现转移到已建立的二次打击反应动物模型中，以证实CRP解离在二次打击病理学中的因果作用，并证明靶向CRP解离是调节和控制二次打击中加剧的炎症反应的合适治疗方法。在一项临床试点研究中，我们将研究 CRP 解离产物及其与补体系统因子的相互作用，作为对多发伤具有预测价值的生物标志物。

C-reactive protein (CRP) is a highly conserved pentameric protein. It is not only a marker, but also a mediator of inflammation. As part of the innate immune system it opsonizes bacteria and can regulate activation of the complement system. In trauma, as well as in septicaemia, uncontrolled activation of the complement system can lead to exacerbation of the inflammatory immune response leading to organ damage via activation of complement C5. This uncontrolled activation of the immune response can occur during the so called second-hit, that refers to increased tissue injury in secondary events after initial traumatic tissue injury. Controlling this inflammatory response is key to preventing its detrimental consequences.We have shown previously that localized dissociation of pentameric CRP to its single monomeric subunits represents a ubiquitious mechanism by which CRP regulates the inflammatory response in areas of inflammation. Blocking this dissociation step by a novel compound leads to markedly reduced inflammation. Our data suggest that initial increase of CRP after traumatic tissue injury might be a priming process for following events leading to increased localized CRP dissociation in the event of a following secondary injury. We therefore believe that CRP is a crucial causal factor in the second- hit response. However it remians unclear how the conformational change of CRP alters the modulating properties of CRP on the complement system. Here we aim to investigate the effects of the confomational change from pentameric to monomeric CRP on its effect on complement factors regarding the modulation and aggravation of an existing inflammatory event. We will investigate the pathomechanistic sequelae from complement activation to the differential activation of leukocyte subsets with emphasis on the interaction of CRP dissociation, complement activation and activation of monocyte subsets in order to taylor specific therapeutic approaches targeting the second-hit response. We will transfer our findings to an established animal model of the second-hit response in order to confirm the causal role of CRP dissociation in the pathology of the second-hit and to prove that targeting CRP dissociation is a suitable therapeutic approach to modulate and control the exacerbated inflammatory response in second-hit. In a clinical pilot study we will investigate CRP-dissociation products and their interaction with factors of the complement system as biomarkers with predictive value in polytrauma.