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

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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.