Investigating the role of complement component 5a in ANCA-associated vasculitis

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The immune system is the body's powerful response system that acts to defend us against infections. It has two main protective methods - mediated by immune cells and soluble components like 'antibodies' and 'complement' proteins which can punch holes in microbes. Unfortunately, the immune system sometimes gets wrongly activated and responds to our own tissues and organs. This causes a group of diseases called 'autoimmune' diseases. One subtype is a disease called 'vasculitis', literally meaning 'inflammation of blood vessels', which occurs as a result of immune attack by antibodies and complement. Blood vessel inflammation causes patients to get organ damage in the lungs and kidneys. Sadly, this kidney damage can be severe enough to cause kidney failure, requiring blood cleaning therapy (dialysis). The treatments that we have used for the past 20 years are variably effective, and have lots of side effects, but recently, a new drug that blocks the complement system was used in patients with vasculitis in a clinical trial. This complement blocker drug seemed to reduce kidney damage, but we don't know exactly how it does this.This project will investigate blood, kidney tissue, and tissue taken from the back of the nose that contains immune cell collections (called the adenoids). We will take these tissue samples from patients with vasculitis who come to our clinic before and after they receive the complement blocker drug. We will use new technologies to analyse antibodies and tissue cells to produce a clearer picture of the effect of blocking complement on the human immune system and kidney. One of these technologies uses information about how the genetic code of cells is translated into action, by measuring genetic messenger molecules called 'RNA'. The Clatworthy lab are international experts in studying RNA, down to the level of individual immune or tissue cells. We can also match up this information with changes in blood immune cells and kidney function and can determine the location of immune cells in tissues affected by the complement blocking drug using a special microscope technique that can measure where RNA molecules are in tissue. The information that our project will generate is important because it will tell us more about how complement affects the immune system in humans and how the complement-blocking drug works, both in inflamed kidneys and in immune tissues, potentially opening it up to be used to treat other autoimmune and kidney diseases.