Biological functions of the complement system - Semantic Scholar

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C O M P L E M E N T SYSTEM

Proteins of the Complement System Society/Host/Peptide and Protein Group Joint Colloquium Organized and Edited by J. E. Fothergill (University of Aberdeen) and K. B. M. Reid (University of Oxford)

Biological functions of the complement system PETER J. LACHMANN Molecirlur Immirrioputhology Unit, Medical Keseurch C'oirticil ('etitrc, Iiills R o d , C'urnhridge C'R2 2QII. U.K.

The biological firnctiori.~o f complement

T h e functions o f the complement system can be separated into those of the MAC and those of the earlier steps of the complement system. T h e functions of the MAC are unique among the effector systems o f blood plasma. T h e conI t I trodirctiorI sequence of the assembly of the MAC o n a membrane is to T h e phenomenology of the complement system was quite make the membrane leak. This is associated with channel extensively worked out by the early IY4Os when the four formation although the extent to which the membrane leak is ' classical complement components. C'l, C'4. C'3 and C'2, had due to the formation of a 'leaky patch' or of a true proteinbeen described as had the 'anlage' of the observations that lined transmembrane channel has never been fully resolved there were multiple pathways of activation. In the lY6Os, the in spite o f many years of increasingly sophisticated investigacomplement components were purified as proteins and as tion. antigens. T h e biochemistry of their interactions began to be In erythrocytes the consequence of 'membrane attack' is worked o u t and it became recognized that a number of t o lyse the cell. Lysis is largely, though not wholly, dependent components were proteases. upon the incorporation o f C9 and its subsequent unfolding T h e first great surprise that this wave of work produced and insertion followed frequently by its circular polymerizawas the high concentration at which complement compo- tion to form the characteristic torus of poly-C9 which gives nents occur in the serum. T h e one *hit' theory o f complement rise to the characteristic electron microscopic appearance of lysis, put forward by Manfred Mayer and his group [ I ] , had complement lysis. A n entirely analogous lytic process is until that time been interpreted in molecular terms as if the brought about by the MAC o n viruses that have lipoprotein functional 'hits' represented individual protein molecules. membranes, although the lysis of viruses is accompanied by a This had given rise t o the idea that the concentration of marked 'disassembly' o f the membrane. This presumably complement in the blood was trivial and had discouraged reflects the lack o f cytoskeleton in the virus to maintain the attempts at purification. It now became clear that this morphological integrity after lysis. Insertion of the MAC into interpretation was wrong and that complement forms a bacteria will kill a range o f bacteria. T h e situation here is significant part o f the plasma protein pool probably making substantially more complicated than on red cells since up in total about S mg per 100 ml. T h e second surprise was bacteria have a cell wall as well as a plasma membrane that there werc far more complement components than had (which is the essential layer damaged by complement) and been previously known about. Fractionation showed that C I complement requires both to have access to the plasma was made u p of three sub-components and that the compo- membrane and t o be able t o get inserted into it. nent that had been called 'C3' was made u p of six separate O n nucleated cells the actions o f the MAC arc also more components: C3 itself and the five components of what is complex than on red blood cells. It has become apparent that now known as the membrane attack complex (MAC): CS, whereas an adequately rapid and intense complement attack C6. C7, CX and CY. does indeed produce lysis, less rapid formation of the Then it was discovered that the alternative pathway of channels can be repaired by the cell and the effects of subcomplement activation had several components unique to lethal complement damage may activate the cell. It has been itself notably the C2-like component. factor €3; and the C I - shown for polymorphonuclear leukocytes by Morgan er (11. like component, factor D; as well as properdin. the original [ 61 that these temporary channels are, to some extent, selecmolecule discovered by Pillemer and his colleagues [ 2, 3 I. tive for calcium and activate the cells by allowing calcium It was also established that the complement system is quite entry into the cell. Similarly, it is possible that the activation distinct from other plasma triggered enzyme cascades. Thus of calcium dependent enzymes may produce slow damage of deficiencies of complement components d o not give rise to the cell. I t has further bccn demonstrated that MAC activamajor disturbances o f the kinin-generating fibrinolytic o r tion of nucleated cells gives rise t o liberation o f fatty acids coagulation systems and tice t'ersu. T h e major exception t o from phospholipids and stimulates arachidonic acid metathis generalization is C 1 inhibitor, an essential control bolism. molecule for complement but also an inhibitor of kallikrein, One characteristic and unusual feature of complement plasmin and certain clotting enzymes. T h e seminal discovery lysis is that it is subject to 'homologous restriction': complcin I YO2 by Landerman et (11.141and in 1963 by Donaldson ment from one species being inefficient in lysing cells o f the & Evans [ S ]that deficiency o f this inhibitor gave rise t o the same species. Although this phenomenon has long been disease known as hereditary angioedema. gave rise to a new known. it is only in recent years that it has been discovered field o f investigation - which will be discussed later in thc that it is d u e to the presence o f specific membrane proteins colloquium. that interact with the terminal components. I will be discussAhhrcviations used: MAC. membrane attack complex; EBV, ing this phenomenon further at the end o f the colloquium Epstein-Ihrr Virus. (p. I I S Y ) . Vol. I x

BIOCHEMICAL SOCIETY TRANSACTIONS

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It seems likely that the physiological action of the MAC is largely that exerted on invading micro-organisms; and that the effects o n mammalian cells and in particular in homologous mammalian cells are largely pathological. Deficiency of the components of the MAC in man gives rise to an increased susceptibility to infection with just one family of micro-organisms, the Neisseria. Recurrent attacks of mcningococcal meningitis allows deficiencies of the terminal components to be ascertained. In the United States and in Europe these deficiencies are all strikingly rare in contrast with some third world countries where they are much commoner. Thus, C6 deficiency is relatively common among the coloured population in Cape Town [7] and C7 deficiency among North African and Scphardic Jews in Israel 181.It would appear that there must be some selective advantage maintaining the deficiency genes in such populations and this is borne out in the South African studv bv the, observations that the homozygotes in individual sibships occur at a frequency much closer to 0 . 5 than the expected 0.25. Although the nature of this selective advantage has not been demonstrated convincingly it seems likely to be due to the protection that deficiency of the MAC affords against endotoxin shock produced by Gram-negative organisms. Such protection was demonstrated many years ago in C6deficient rabbits 191. Although the contribution that the complement system makes to endotoxin shock varies from species t o species, it seems likely that in human populations where deaths from shock following infantile gastroenteritis are common, deficiency in the terminal components may contribute t o survival. The pathological role of the MAC in endotoxin shock appears to be related t o its capacity to damage platelets and possibly t o generate cytokine production in cells that have been activated by non-lethal complement attack.