Molecular analysis of complement activation via the classical pathway

人类免疫系统使用两种主要武器来对抗入侵的病原体：适应性免疫，包括随着时间的推移产生针对入侵细菌的抗体;先天免疫，它一直存在并识别细菌的保守部分，例如它们的细胞壁。补体级联提供了先天免疫和适应性免疫之间的桥梁：它通过先天过程直接破坏细菌，并有助于指导和刺激有效的适应性反应。由于其核心作用，补体功能障碍与一系列人类疾病有关，包括严重的细菌感染、肾脏疾病和自身免疫性疾病，如狼疮和类风湿性关节炎。补体激活的主要途径之一被称为经典途径，其中补体蛋白与细菌结合并引发一系列旨在杀死细菌的反应。在这项资助提案中，我们的目标是通过研究组分相互作用以启动反应级联的方式来深入了解这一途径。我们已经建立了使用重组DNA技术生产关键元件的方法，以便系统地研究它们的作用模式。除了提供新的信息，帮助我们了解补体是如何工作的，该项目还将促进可用于改变补体活性的新试剂的开发。例如，补体抑制剂可用于防止补体在错误的时间或地点激活的情况下的组织损伤。类似地，经修饰的组分可用于结合和中和特定靶标，例如抗生素抗性细菌或患病细胞。

The human immune system uses two main weapons to counter invading pathogens: adaptive immunity, which includes the production of antibodies that develop over time to target invading bacteria; and innate immunity, which is ever present and recognizes conserved parts of bacteria, such as their cell walls. The complement cascade provides a bridge between innate and adaptive immunity: it destroys bacteria directly via innate processes and helps to direct and stimulate an effective adaptive response. Because of its central role, complement dysfunction is associated with a range of human diseases, including severe bacterial infections, kidney disease and autoimmune diseases such as lupus and rheumatoid arthritis. One of the main pathways of complement activation is known as the classical pathway, in which complement proteins bind to bacteria and set off a chain of reactions directed at killing them. In this grant proposal, we aim to develop a thorough understanding this pathway by studying the way in which the components interact with each other to initiate the reaction cascade. We have already established methods for producing key elements using recombinant DNA technology so that their mode of action can be investigated in a systematic way. As well as providing novel information that will help us to understand how complement works, this project will also foster the development of novel reagents which can be used to change complement activity. For example, inhibitors of complement could be used to prevent tissue damage in conditions where complement activates at the wrong time or place. Similarly, modified components can be used to bind and neutralize specific targets such as antibiotic resistant bacteria or diseased cells.