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I143 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 1144 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. < Pro1eo1ysls 01 Ag antibody formation NO Anfig*n Release 01 auIMnliwnr Cylokirvlr (DNA- inhlbllor Aclin) ~ Fig. 1 . ScliettiriJi)rrhe huridliti~c ~ / ' i m r t i i r r i ci~orrrp1iixes < (hmplemetir us at1 itiflumttiurory mediuror The role o f complement in enhancing inflammation is a function o f the early steps of the complement system culminating in the cleavage of CS. The molecular mechanisms appear t o be two-fold: the actions o f the so-called anaphylatoxins CSa, C3a and, t o a much lesser extent, C4a; and the reaction o f the covalently-bound complement fragments C3b, C4b and their breakdown products with the complement receptors CRI, CR2, CR3 and CR4. The anaphylatoxins arc discussed by Dr Hugli (p. 1 154). CSa is the most strikingly active and is a chemotactic factor as well as directly activating a variety of cells and causing the degranulation of mast cells and having a direct effect on their microvasculature. It remains a puzzle that in spite of the dramatic biological activities of C5a iti v i m , it is difficult to ascribe clinical effects to CS deficiency that are different from those seen in C6 o r C7 deficiency. The interactions o f membrane bound C3b and C4b with complement receptors have been studied extensively in recent years. Two groups of molecules have such receptor activity. CR I and CR2 are 'necklaces' of the 'short consensus repeat' and it is interesting that their ligand-binding properties are somewhat different. CRI is essentially a C3b and C4b receptor with weaker binding of iC3b. CR2 binds primarily C3d,g and, more weakly, iC3b. CR2 is confined essentially to cells o f the B lymphocyte series and its role lies in the regulation of the immune response. CR1 is a widespread receptor and is of interest in being the only complement receptor on primate erythrocytes. CR 1 has cofactor activity for factor I, the enzyme that splits C3b first to iC3b and subsequently to C3d,g. For this important second split, CRI is thc only physiological cofactor. Although C R l is a good adherence receptor its role in phagocytosis is limited. The other family of complement rcccptors (of which CR3 is the best studied). bclongs to the 8 2 intcgrins. a group of molecules containing, besides CR3 and CR4, the lymphocyte marker LFA- 1. These molecules share a common B-chain, and a group of closely linked a-chains. The importance of these receptors is demonstrated by the conscquenccs of their genetic absence - the leukocyte adhesion deficiency syndrome. Children with this deficiency suffer from delayed separation o f the umbilical cord, hypertrophied gums. a tendency t o have indolent staphylococcal skin infections which heal with 'paper thin' scars and they often succumb to staphylococcal septicacmias. The prognosis is more sinister than was originally thought s o that affected children arc now regarded as suitable subjects for bone-marrow transplantation. The major reason for the lack o f inflammatory response is that polymorph or monocyte emigration into inflammatory sites fails to occur. This may be related t o the lack o f binding, not to the complement ligand, but rather t o ligands o n endothelial cells. The ligand for LFA-I (I-CAMI) is now well known and there may be yet other ligands for CR3. There is now great intcrest in the usc of antibodies t o these molecules, both to CR3 and to LFA-I and t o the ligand I-CAM I , in preventing inflammatory injury in non-infective situations, for example transplantation and reperfusion injury. CR3 as a complement receptor is highly specific f o r iC3b. Part of this binding is associated with a carbohydratebinding site o n CR3 which also binds @-glucan.Thc binding site is complex and P-glucan does not inhibit iC3b rosctting, although iC3b does inhibit the binding o f the glucan o r o f zymosan. Both bindings can also be inhibited by adequate concentrations o f N-acetyl D-glucosamine. It has bccn claimed that there is an 'RGD'-binding site in CR3 but this has not been widely accepted. The combination o f zymosan with CR3 ;IS a powerful stimulant of the respiratory burst and CR3 is believed t o bc an important inflammatory receptor. C'omplemetir arid rhe proper hatidlirig of immirtir cwnplcJxcJs A major paradox in complement function derives from the parallel observations that, o n the one hand, complement is necessary for the production o f immune complex inflammation at all extra-renal sites while, o n the other hand, genetic deficiencies o f the early components o f the classical pathway have, as their major clinical association. autoimmune immune complex disease. This association has concentrated attelltion on the role that an intact complemeiit system has in the handling o f immune complexes. Two major functions have been identified. One is that complemcnt has an important influence on immune complex size and causes C O M P L E M E N T SYSTEM immune complexes to be formed that arc much smaller and more soluble than those formed in its absence. Very small complcxes are not able to generate immune complex disease and the production of more small complexes in itself probably reduces their pathogenicity. Complexes that are potentially phlogistic are those of intermediate size and it appears to be of considerable importance that these are transported to the liver where they are removed by the Kuppfer cells which d o not function as antigen-presenting cells since there is n o lymphatic tissue in the liver. It seems that transport to the liver occurs optimally for immune complexes bound to erythrocyte C R 1 presumably because such erythrocyte-bound complexes d o not come into contact with the endothelium o f blood vessels and therefore are less likely to contact vascular endothelium where they can give rise t o inflammation and feedback antibody formation. This scheme is shown in Fig. 1 and has been discussed in greater detail elsewhere by Lachmann [ 101. I t does appear to be one of the major activities of the complement system in vivo t o prevent the generation of immunc complex disease and it is noteworthy that to bc dcficient in C1 and C4 is a more or less sufficient predispossession to get these diseases. While the great majority o f patients with autoimmune immune complex disease arc not homozygous for complcmcnt deficiency it has been shown that over half of them carry a null allele at the C 4 A locus. C 4 A is the isotype of C4 which binds to immune complexes. 7'1ic role of cwmplernerit in tlie iridirctiori of tlic iriirnirrie respor i s e This is a topic that has excited much interest since it was dcmonstratcd by Pepys [ 1 I ] that cobra vcnom treatment of mice reduced their antibody formation t o sheep erythrocytes and since it was recognized that C R 2 is identical to the Epstein Barr Virus ( E B V ) rcccptor. EBV is the most potent B cell stimulator in man. Nevertheless it has proved difficult to define the exact role o f complcmcnt in thc induction of immune responscs. It has been demonstrated that in guinca-pigs deficient in C4. C2 and particularly in C3. there is difficulty in making antibodies t o low concentrations o f antigen in the absence of efficient adjuvants but that the difficulty can gcncrally be overcome by increasing antigen dose o r using powerful adjuvants. In complement deficient humans there is generally 1145 no clinically significant antibody deficiency and overall immunoglobin levels are normal. It has however more recently been shown that lgG4 levels are low in patients with total deficiencies of C1, C 4 , C2 and C3. Since IgG4 is the last IgG isotype t o be made in an immune response, this may reflect a difficulty in generating efficient B cell memory. Of the various explanations advanced for how complement influences antibody formation, two are now considered to be important. T h e first is the observation made originally by Klaus & Humphrey [ 121, that it requires both antibody and complement to allow the localization o f antigen on the follicular dendritic cells in the germinal centres of lymphoid follicles and that this antigen localization seems to be necessary for the development of efficient B cell memory. T h c other mechanism is the activation of B cells via CR2. This can be demonstrated with aggregated C3d,g as the ligand (as well as with E B V ) and some antibodies to CR2 also have a stimulating effect in vitro. However, patients deficient in Factor I, who cannot generate C3d.g, have no defect in antibody formation. Also those patients with nephritic factor who have high circulating levels of (monomeric) C 3 d g present continuously also make normal antibodies. 1 . Mayer. M. M. ( I96 1 ) in Immrinoc~hernicciIA p p r o d i e s t o l'rohlcws in Microbiology (Heidelherger, M. & Plescia. O., eds.), pp. 268-279. Kutgers University Press, New 13runswick 2. Pillemer, L.. Blum, L., Lepow, 1. H., Ross, 0.A,, Todd, E. W. & Wardlaw, A. C. ( 1954) Science 120.279-285 3. Pillemer, L.. Schoenherg, M. D., Wum, L. 6i Wurz. L. (lY54) Scicvice 122. 545-549 4. Landerman. N. S.. Wehster. M. E.. Becker. E. L. & Katcliffe, H. E. (1962)J . Allergj 33,330-341 5. 1)onaldson. V. H. & Evans, R. R. ( 1963)Am. J. Mcd. 35. 37-44 6 . Morgan, B. P.. Luzio. J. P. & Campbell, A. K. ( I Y X h ) ('c,ll ('ctlcirtm I . 399-41 I 7. Orren, A,, Potter, P. C., Cooper, K. C. & du l o i t , E. ( 1987) Immitnologj~62.249-253 8. Schlesinger. M.. Nave. Z.. Levy, Y.. Slater. P. E. 6i Fishelson. Z. (1990) <'/in. Lvp. Immtrnol. 81. 423-427 9. Brown. D. L. & Lachmann. P. J. ( I Y73) I t i t . Arch. ~ l l ~ ~ ~ ~ ~ ~ l p p l , Immrtnol. 45. 193-205 10. Lachmann, P. J. ( 1990) ('liem. I m m r i r i o l . 49, 245-263 I 1. Pepys. M. B. ( 1972) Ntrtiirc, (Loticloti) New Niol. 231. 157- I59 12. Klaus, G. G. B. & Humphrey. J. H. (1977) I m m i i n o l o ~33, ~ 3 1-30 Received 1 August I990 Interaction of Clq, and other proteins containing collagen-like domains, with the C l q receptor RAJNEZESH MALHOTRA, R O B E R T B. SIM and KENNETH B. M. REID* M. K.C'. Itiir~iirriochemistr?,Unit, Ileppcrrtmerit of Hiochcrnistn~. Osfbrd Uni\ier.sity. South Parks Road. Oxford 0x1 3QU, U .K. Human C l q (460 kDa) is composed of 18 polypeptide chains ( 6 A . 6 B and 6C) cach o f which is approx. 225 amino acid residues long and is composed of a short N-terminal non-collagen-like region ( 3 t o 9 residues) followed by a collogcn-like region of approx. 8 1 residues and a C-tcrminal Ahhrcviations uzed: MHP. monnan hinding protein: SP-A. xurfnctant protein A; SP-I). surfactant protein I>. *l'o whom correspondence should he addreszed. VOl. 1 8 non-collagen-like region o f approx. 136 residues I I ] . T h e 18 chains form a molecule which is seen in the electron microscope t o have six globular heads linked through six collagen-like stalks to a fibril-like region 12, 31. This hexameric structure results from the formation of six triple-helical regions. from thc 8 1-residue-long collagen-like scquenccs present in the 6A-. 6B- and 6C-chains which are seen as the central-fibril like region and stalks, while cach o f the six globular heads is formed by association o f the ('-terminal regions o f one A-, one B- and one C-chain 14. 51. T h c complcte amino acid sequences o f A-, B- and C-chains o f C I q have been established by: protein sequencing (the complete A- and B-chains and collagen-like region of the C-chain 16-81; sequencing o f c D N A (the complete B-chain and part o f the A-chain 19, 101, G. C. Scllnr, D. J. Blake XL K. B. M. Reid. unpublished work); sequencing o f genomic D N A (the com-