The New England Journal of Medicine Review Articles Advances in Immunology TABLE 1. THE THREE MAIN PHYSIOLOGIC ACTIVITIES OF THE COMPLEMENT SYSTEM. I AN R. MACKAY, M.D., AND FRED S. ROSEN, M.D., Editors ACTIVITY COMPLEMENT PROTEIN RESPONSIBLE FOR ACTIVITY Host defense against infection COMPLEMENT Opsonization Covalently bound fragments of C3 and C4 Chemotaxis and activation Anaphylatoxins (C5a, C3a, and C4a); ana- of leukocytes phylatoxin receptors on leukocytes First of Two Parts Lysis of bacteria and cells Membrane-attack complex (C5b–C9) Interface between innate MARK J. WALPORT, PH.D., F.R.C.P. and adaptive immunity Augmentation of antibody C3b and C4b bound to immune complexes responses and to antigen; C3 receptors on B cells and antigen-presenting cells OMPLEMENT is part of the innate immune Enhancement of immuno- C3b and C4b bound to immune complexes system and underlies one of the main effec- logic memory and to antigen; C3 receptors on follicular dendritic cells tor mechanisms of antibody-mediated immu- C Disposal of waste nity. It has three overarching physiologic activities Clearance of immune com- C1q; covalently bound fragments of C3 (Table 1): defending against pyogenic bacterial infec- plexes from tissues and C4 tion, bridging innate and adaptive immunity, and Clearance of apoptotic cells C1q; covalently bound fragments of C3 disposing of immune complexes and the products of and C4 inflammatory injury. In this review, each of these ac- tivities will be placed in a clinical context. Complement was first identified as a heat-labile principle in serum that “complemented” antibodies in the killing of bacteria. We now know that complement is a system of more than 30 proteins in plasma and on multiple names. Several complement proteins are cell surfaces. Complement proteins in plasma amount cleaved during activation of the system, and the frag- to more than 3 g per liter and constitute approxi- ments are designated with lowercase suffixes — for mately 15 percent of the globulin fraction. The no- example, C3 is cleaved into two fragments, C3a and menclature of complement follows the historical or- C3b. Normally, the large fragment is designated “b,” der of discovery of the proteins and is one of the less and the small fragment “a.” Anarchy reigns with re- friendly aspects of the complement system. spect to the fragments of C2: the large fragment is The first complement pathway that was discovered, designated C2a, and the small, C2b, for historical the classical pathway, begins when antibody binds to reasons. a cell surface and ends with lysis of the cell. The pro- The pathways leading to the cleavage of C3 are teins of this pathway are designated C1 through C9 triggered enzyme cascades, analogous to the coagu- (Fig. 1). It was subsequently discovered that the num- lation, fibrinolysis, and kinin pathways. The terminal bering of the proteins did not quite correspond with complement pathway, leading to the formation of the the order of the reaction, since C1 is followed in suc- membrane-attack complex, is a unique system that cession by C4, C2, C3, and C5, with numerical sanity builds up a lipophilic complex in cell membranes from restored from C6 through C9. Proteins of the sec- several plasma proteins. There are three pathways of ac- ond pathway to be discovered, the alternative path- tivation of the complement system: the classical, man- way, are called factors, followed by a letter, such as nose-binding lectin, and alternative pathways (Fig. 1 factor B. Complement proteins on cell membranes can and Table 2). be receptors for activated complement proteins or The regulatory mechanisms of complement are proteins that regulate complement. They often have finely balanced so that, on the one hand, the activa- tion of complement is focused on the surface of in- vading microorganisms and, on the other hand, the From the Rheumatology Section, Division of Medicine, Imperial Col- deposition of complement on normal cells and tis- lege of Science, Technology and Medicine, Hammersmith Campus, Lon- sues is limited. When the mechanisms that regulate don. Address reprint requests to Dr. Walport at the Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane this delicate balance go awry, the complement sys- Rd., London W12 0NN, United Kingdom, or at [email protected]. tem may cause injury, and some of the resulting dis- 1058 · N Engl J Med, Vol. 344, No. 14 · April 5, 2001 · www.nejm.org ADVANCES IN IMMUNOLOGY eases will be discussed at the end of this review. Par- plex and infection is with neisserial disease, particular- ticular attention will be paid to illustrating the ways ly Neisseria meningitidis.1-3 This complex is necessary in which the meticulous study of patients with ab- for the complement system to form a lytic channel normalities of the complement system has illuminated in neisseriae. Extracellular lysis is a major mechanism our understanding of the immunobiology of com- of killing these organisms, which are capable of in- plement. tracellular survival. This review is organized around the three main as- In parts of the world where meningococcal infec- sociations between complement and disease (Table 3): tions are highly endemic,4,5 there appears to be a high complement deficiency and susceptibility to infec- prevalence of deficiencies of proteins of the mem- tion, the consequences of abnormalities in the regu- brane-attack complex. It has been argued that the lation of the complement system, and the role of com- homozygous deficiency of C6 offers a selective ad- plement deficiency in inflammatory diseases. vantage by protecting against the deleterious effects of complement activation by endotoxin in infantile COMPLEMENT AND THE DEFENSE gastroenteritis.5,6 AGAINST INFECTION There are good data from epidemiologic studies Three types of complement deficiency can cause in Japan on the association between a deficiency of increased susceptibility to pyogenic infections: a de- proteins of the membrane attack complex and neis- ficiency of the opsonic activities of the complement serial infection. A survey of nearly 150,000 consec- system, which causes a general susceptibility to pyo- utive blood donors7 revealed 154 with the absence genic organisms; any deficiency that compromises the of one of these proteins (138 had a C9 deficiency, lytic activity of complement, which can increase the and 16 had a deficiency of C5, C6, C7, or C8), none susceptibility to neisserial infections; and deficient of whom had a history of neisserial infection. How- function of the mannose-binding lectin pathway. ever, among 17 patients with meningococcal disease ascertained from a register in Fukuoka, 8 had an in- Pyogenic Infections herited complement deficiency (4 of C7 and 4 of C9), Increased susceptibility to pyogenic bacteria such and a 9th patient had systemic lupus erythematosus as Haemophilus influenzae and Streptococcus pneumo- with acquired complement deficiency.8 From incidence niae occurs in patients with defects of antibody pro- data for meningococcal disease,8 the prevalence of duction, complement proteins of the classical pathway, complement deficiency among patients with sporadic or phagocyte function. Study of these patients shows cases of meningococcal disease, and the frequency of that the normal pathway of defense against pyogenic inherited complement deficiencies among Japanese bacteria is opsonization with antibody, followed by blood donors,7, 8 the risk of meningococcal disease for the activation of complement, phagocytosis, and in- a person with a complement deficiency in Japan can tracellular killing. The most important complement be calculated to be 0.5 percent per year. This is a rel- opsonins in the defense against bacterial infection are ative risk of 5000, as compared with the incidence of C3b and iC3b, the covalently-bound cleavage frag- meningococcal disease among Japanese persons with- ments of C3. out a complement deficiency. Complement Deficiency and Neisserial Infections Mannose-Binding Lectin Deficiency The sole clinical association between inherited de- In 19769 a group of children between the ages of ficiency of components of the membrane-attack com- six months and two years was described who had re- Figure 1 (facing page). The Three Activation Pathways of Complement: the Classical, Mannose-Binding Lectin, and Alternative Pathways. The three pathways converge at the point of cleavage of C3. The classical pathway is initiated by the binding of the C1 complex (which consists of C1q, two molecules of C1r, and two molecules of C1s) to antibodies bound to an antigen on the surface of a bacterial cell. C1s first cleaves C4, which binds covalently to the bacterial surface, and then cleaves C2, leading to the formation of a C4b2a enzyme complex, the C3 convertase of the classical pathway. The mannose-binding lectin pathway is initiated by binding of the complex of mannose-binding lectin and the serine proteases mannose-binding lectin–associated proteases 1 and 2 (MASP1 and MASP2, respectively) to arrays of mannose groups on the surface of a bacterial cell. MASP2 acts in a fashion similar to tha t of C1s to lead to the formation of the C3 convertase enzyme C4b2a. MASP1 may be able to cleave C3 directly. The alternative pathwa y is initiated by the covalent binding of a small amount of C3b to hydroxyl groups on cell-surface carbohydrates and proteins and is activated by low-grade cleavage of C3 in plasma. This C3b binds factor B, a protein homologous to C2, to form a C3bB complex. Factor D cleaves factor B bound to C3b to form the alternative pathway C3 complex C3bBb. The binding of properdin stabilizes this enzyme. The C3 convertase enzymes cleave many molecules of C3 to C3b, which bind covalently around the site of complement activation. Some of this C3b binds to the C4b and C3b in the convertase enzymes of the classical and alternative pathways, respec- tively, forming C5 convertase enzymes.