My name is Lucio Luzzatto, I am an Hematologist at Muhimbili University of Health and Applied Sciences in Dar-es-Salaam, Tanzania. I was asked to discuss with you the role of complement in hemolytic anaemias.
I will start with other hemolytic anaemias and then I will continue with Paroxysmal Nocturnal Hemoglubinuria or PNH, a disease on which I've worked on for many years, and in which the role of complement is particularly prominent and also important because it has been the target of a new form of therapy.
I will not discuss in detail the complement system which is illustrated here in this pathway. I would only like to point out a few items. First of all, complement can be activated through different mechanisms which are referred to as the classic pathway, the alternative pathway based on bacterial life of polysaccharide, and the alternative pathway based on spontaneous hydrolysis of C3. Also, please note that, what is in black are the activation pathways, what is in red are the inhibitory elements in the complexity of the system. This is very, very important because complement must be activated very efficiently when needed, but it must be all the time regulated, lest it goes out of hand. So, these three pathways, one, two and three, they all converge on one component called C5, that is hydrolyzed by what is called the C5 convertase, of which there are two types, one produced by the alternative pathways and the other produced by the classic pathway. And once we are there, then C5 is cleaved, and that precipitates what we call, the distal pathway of complement. Eventually, the formation of the membrane attack complex which can lyse bacterial cells and God forbid, can also lyse human cells. And that is the basis of many of the diseases in which complement plays a role. The only other point I'd like to particularly bring to your attention is this, the alternative pathway shown here called spontaneous C3 hydrolysis means that at a low rate, the complement is activated all the time. But when an antigen-antibody reaction takes place here then C1q is recruited, the classic pathway starts. And this can work at about thousand times faster than the spontaneous complement activation. But the spontaneous complement activation means that all the time, the complement must be regulated in order, as I said before, to avoid mischief. The biochemical basis of these, what are being called pathways but also being called cascades, is in general and that there are enzymatic reactions. For instance, it is an enzymatic reaction that produces the convertase, but the convertase in turn is an enzyme which cleaves C5. So, what was a substrate is cleaved and becomes an enzyme and then, what was the substrate is cleaved and does something else.

Complement in PNH and other hemolytic anaemias 1

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