Complement as a therapeutic target

Published on December 31, 2017   43 min

Other Talks in the Series: The Complement System

Other Talks in the Series: Macular Degeneration

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Hello, my name is Claire Harris and I'm a professor at Newcastle University in the UK. Today, I'll be talking about "Complements as a Therapeutic Target".
I'll start with an introduction to complements. It is best known for its role in innate immunity. That is the first line of defense against the invading pathogen. However, recent years also demonstrate emerging and critical roles in adaptive immunity, and I'll mention those in brief here. So the complement system comprises around 30 proteins, both activated and controlled, and these exist alone or in specific complexes. The majority are made by the liver as well as by cells and tissues. Although a few proteins such as C7 and properdin are made only at extrahepatic sites. Complement proteins make up to five percent of total protein and plasma. That's an enormous amount, when considering complements as a therapeutic target. Drugs which target cytokine for example bind targets with a concentration of just picograms per ml. Complement is always active through a mechanism known as ticks-over. The central component C3 activates a very low level in plasma, and this triggers the alternative pathway of activation. In health, this is rapidly and effectively controlled, but it does provide the body with a means to react rapidly in the face of infection. There is no need to wait for a period of priming. The complement system is a cascade. Protein circulates in an inactive form in plasma. But once the system is activated, one active protein or protein complex, activates the next in the pathway. The system is also amplifying. One active complex activates more than one protein on the cascade. An active C3 cleaving enzyme for example, can rapidly cleave hundreds of molecules of C3. As each protein is activated, in many cases, they change shape. This is true for the proteins generating the cleaving enzyme that's C3 and factor B, for example, and also for the proteins generating a lytic pore also known as a membrane attacker complex or MAC. The cascade activates very rapidly and efficiently when there is an activating surface such as a bacterium or an antibody coated surface, and it can do a lot of damage unless it's properly controlled. Of course, this is fine if the surface is foreign. But if the activating surfaces are our own cells, this can cause a lot of damage and potentially, disease. This might be the case if an individual lacks the right complement control proteins for example. For this reason, there are as many proteins in our body which control the system as there are which activate it.