Back to basics; the role of complement C3 and its degradation fragments in immuno-inflammatory disease

我们将汇集来自英国各地的补体介导疾病专家，将我们的注意力集中在肾脏、眼睛和大脑的疾病上。补体是先天免疫系统的一部分，当传染病或病原体进入人体时，它会立即做出反应，杀死它们。已知补体在许多疾病中攻击这些器官，包括多发性硬化症、C3肾小球疾病、常见的老年性疾病黄斑变性等。针对这些疾病正在开发的抗补体药物通过直接关闭补体来发挥作用，这可能会使患者容易受到感染。我们研究了一种新的假设，即补体与免疫系统细胞的相互作用实际上可能是导致其中一些疾病的原因。如果这是真的，那么其他类型的治疗可能会更有效。补体非常迅速地激活，并将病原体包裹在蛋白质中，标志着它们被白血球吞噬，导致死亡和清除。为了实现这种快速反应，补体在体内总是处于低水平的活跃状态，因此我们自己的细胞可能会意外地被补体蛋白覆盖。在健康中，这种涂层是最小的，不会造成伤害；然而，在某些情况下，这些沉积物会在组织中积累并导致疾病。这可能是因为我们的基因突变，阻碍了“安全守卫”机制的正常运作，或者是异常的触发因素，比如结合细胞的自身抗体，诱骗免疫系统认为细胞是外来的或具有传染性的。我们对导致不同补体介导性疾病的机制有很多了解。到目前为止，我们一直专注于不适当地推动补体在我们自己的细胞上沉积的“激活”机制。然而，最近来自动物模型的数据，以及在人类中发现的一些有趣的基因联系，导致人们意识到下游的灭活或清除过程实际上可能导致疾病。我们将产生并分享新的研究工具，称为抗体，这将使我们能够近距离观察人类组织中的补体。我们将共同努力产生初步但关键的数据，以验证我们的假设，并为实质性的后续计划奠定基础。我们将使用这些新的研究工具：-开发高度特异性的分析方法，以测量来自健康人和患者的血液样本中的补体激活片段，即所谓的“生物标记物”。在许多疾病中，补体系统会在血液中留下诊断性的“标记”，这是一种容易接触到的组织。新的抗体将提供更详细的信息，并对疾病的机制和驱动因素提供新的见解。这部分研究的结果将是数字和定量的。-提供补体确切地如何以及在哪里攻击不同器官的准确图景。我们将使用一种名为免疫组织化学的技术来检测组织中存在的碎片类型，并确定免疫系统的哪些部分，包括细胞，正在被招募到造成损害的组织部位。这部分研究的输出将是科学图像或组织图像。-在实验室建立模型并了解疾病情况(‘体外’研究)。我们将使用修改后的血液样本，使其与补体介导性疾病患者的血液相似。我们将使用在第一个目标中验证的分析方法来了解疾病机制和补体生物标记物之间的联系，并为我们的后续建议播下种子，该建议将相关的体外功能分析与血液生物标记物和组织成像的更广泛研究联系起来。这种对补体介导的炎症性疾病背后机制的详细研究将指导我们寻找适合于治疗罕见和常见疾病的药物，并可能为大量患者带来好处。

We will bring together experts in complement-mediated disease from around the UK and focus our attention on diseases of kidney, eye and brain. Complement is part of the innate immune system which reacts immediately to kill infectious agents, or pathogens, when they enter the body. Complement is known to attack these organs in a large number of diseases, including multiple sclerosis, C3 glomerulopathy, the common ageing disease macular degeneration, and many others. Anti-complement drugs being developed for these diseases work by directly turning complement off, this can leave patients vulnerable to infection. We investigate a new hypothesis that cross-talk of complement with cells of the immune system might actually be responsible for some of these diseases. If this is true, then other kinds of treatments might be more effective for therapy.Complement activates very swiftly and coats pathogens in proteins that marks them for 'engulfment' by white blood cells, resulting in death and 'clearance'. To enable this quick reaction, complement is always active at a low level in the body, thus our own cells can accidentally become coated with complement proteins. In health, this coating is minimal and causes no harm; however, in some circumstances these deposits accumulate in tissues and lead to disease. This can be due to mutations in our genes that prevent correct functioning of 'safe-guarding' mechanisms, or abnormal triggers, such as auto-antibodies which bind cells, tricking the immune system into thinking the cells are foreign or infectious. We have a lot of knowledge around mechanisms leading to different complement-mediated diseases. To date we have focussed on the 'activating' mechanisms that inappropriately drive complement deposition on our own cells. However, recent data from animal models, and some interesting genetic linkages discovered in humans, have led to the realisation that the downstream inactivation or clearance processes might actually be causing disease. We will generate and share new research tools, called antibodies, which will enable us to take a close look at complement in human tissues. We will work together to produce preliminary, yet critical, data to validate our hypothesis and build the groundwork for a substantial follow-up proposal.We will use these new research tools:-To develop highly specific assays to measure the complement activation fragments, known as 'biomarkers', in samples of blood from healthy people and from patients. In many diseases, the complement system leaves a diagnostic 'signature' in blood, a readily accessible tissue. The novel antibodies will provide more detailed information and give new insight into mechanisms and drivers of disease. The output of this part of the study will be numerical and quantitative.-To provide an accurate picture of exactly how and where complement is attacking the different organs. We will use a technique called immunohistochemistry to detect the kind of fragment present in tissues and determine which parts of the immune system, including cells, are being recruited to those tissue sites where they cause damage. The output of this part of the study will be scientific images or pictures of the tissues.-To model and understand the disease situation in the laboratory ('in vitro' studies). We will use samples of blood modified to resemble blood from patients with complement-mediated disease. We will use the assays validated in the first aim to understand the link between disease mechanism and complement biomarkers and sow the seeds for our follow-up proposal which will link together the relevant in vitro functional assays with wider studies of blood biomarkers and tissue imaging. This detailed examination of the mechanisms behind complement-mediated inflammatory diseases will guide our pursuit of drugs suitable to treat both rare and common diseases and will potentially bring benefit to a huge number of patients.