Biological functions of the complement system.

T h e phenomenology of the complement system was quite extensively worked out by the early IY4Os when the four classical complement components. C'l, C'4. C'3 and C'2, had been described as had the 'anlage' of the observations that there were multiple pathways of activation. In the lY6Os, the complement components were purified as proteins and as antigens. T h e biochemistry of their interactions began to be worked o u t and it became recognized that a number of components were proteases. T h e first great surprise that this wave of work produced was the high concentration at which complement components occur in the serum. T h e one *hit' theory o f complement lysis, put forward by Manfred Mayer and his group [ I ] , had until that time been interpreted in molecular terms as if the functional 'hits' represented individual protein molecules. This had given rise t o the idea that the concentration of complement in the blood was trivial and had discouraged attempts at purification. It now became clear that this interpretation was wrong and that complement forms a significant part o f the plasma protein pool probably making up in total about S mg per 100 ml. T h e second surprise was that there werc far more complement components than had been previously known about. Fractionation showed that C I was made up of three sub-components and that the component that had been called 'C3' was made u p of six separate components: C3 itself and the five components of what is now known as the membrane attack complex (MAC): CS, C6. C7, CX and CY. Then it was discovered that the alternative pathway of complement activation had several components unique to itself notably the C2-like component. factor €3; and the C I like component, factor D; as well as properdin. the original molecule discovered by Pillemer and his colleagues [ 2, 3 I. I t was also established that the complement system is quite distinct from other plasma triggered enzyme cascades. Thus deficiencies of complement components d o not give rise to major disturbances o f the kinin-generating fibrinolytic o r coagulation systems and tice t'ersu. T h e major exception t o this generalization is C 1 inhibitor, an essential control molecule for complement but also an inhibitor of kallikrein, plasmin and certain clotting enzymes. The seminal discovery in I YO2 by Landerman et (11.141 and in 1963 by Donaldson & Evans [ S ] that deficiency o f this inhibitor gave rise t o the disease known as hereditary angioedema. gave rise to a new field o f investigation which will be discussed later in thc colloquium.