The Complement System:An Overview

  • B. Paul Morgan
Part of the Methods in Molecular Biology book series (MIMB, volume 150)


The complement (C) system consists of a group of 12 soluble plasma proteins that interact with one another in two distinct enzymatic activation cascades (the classical and alternative pathways) and in the nonenzymatic assembly of a cytolytic complex (the membrane attack pathway) (Fig. 1; Table 1). A third activation pathway, termed the lectin pathway, has recently been described (1,2). Control of these enzymatic cascades, essential to prevent rapid consumption of C in vivo, is provided by 10 or more plasma and membrane -bound inhibitory proteins acting at multiple stages of the system. C plays a central role in innate immune defense, which provides a system for the rapid destruction of a wide range of invading microorganisms.
Fig. 1.

The complement system and its control. The constituent pathways of the C system and the component proteins are shown. Enzymatic cleavages are represented by thick arrows. The lectin pathway differs from the CP only in that the MBP-MASP complex replaces the Cl complex. Regulators act to inhibit either the enzymes of the activation pathways (activated Cl, C3 convertases, C5 convertases) or assembly of the MAC.

Table 1

The Component Proteins of the Complement System



Plasma conc (mg/L)

Classical Pathway



Complicated molecule, composed of 3 subunits, C1q (460 kDa), C1r (80 kDa), C1s (80 kDa) in a complex (C1qr2s2)



3 chains (α, 97 kDa; β, 75 kDa, γ, 33 kDa); from a single precursor



single chain, 102 kDa


Alternative Pathway



single chain, 93 kDa



single chain, 24 kDa


Properdin Common:

oligomers of identical 53 kDa chains



2 chains: α, 110 kDa, β, 75 kDa


Terminal Pathway



2 chains: 115 kDa, 75 kDa



single chain, 120 kDa



single chain, 110 kDa



3 chains: α, 65 kDa, β, 65 kDa γ, 22 kDa



single chain, 69kDa


The proteins that constitute the classical, alternative, and membrane attack pathways are listed together with their approximate concentration in plasma. Modified from: Morgan, B.P. and Harris, C. L. (1999) Complement Regulatory Proteins.Academic, London.


Systemic Lupus Erythematosus Alternative Pathway Lectin Pathway Immune Complex Deposit Meningococcal Meningitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Turner M. W. (1991) Deficiency of mannan binding protein—a new complement deficiency syndrome. Clinic. Experiment. Immunol. 86, 53–56.CrossRefGoogle Scholar
  2. 2.
    Reid K. B. and Turner M. W. (1994) Mammalian lectins in activation and clearance mechanisms involving the complement system. Springer Sent. Immunopathol 15, 307–326.CrossRefGoogle Scholar
  3. 3.
    Loos M. (1988) “Classical” pathway of activation, in The Complement System (Rother K. and Till G. O., eds.), Springer, Berlin, pp. 136–154.Google Scholar
  4. 4.
    Reid K. B. (1986) Activation and control of the complement system. Essays in Biochem. 22, 27–68.Google Scholar
  5. 5.
    Reid K. B. and Day A. J. (1989) Structure-function relationships of the complement components. Immunol. Today 10, 177–180.PubMedCrossRefGoogle Scholar
  6. 6.
    Schreiber R. D. and Muller-Eberhard H. J. (1974) Fourth component of human complement: description of a three polypeptide chain structure. J. Exp. Med. 140. 1324–1335.PubMedCrossRefGoogle Scholar
  7. 7.
    Janatova J. and Tack B. F. (1981) Fourth component of human complement: studies of an a mine-sensitive site comprised of a thiol component. Biochemistry 20, 2394–2402.PubMedCrossRefGoogle Scholar
  8. 8.
    Campbell R. D., Dunham I., and Sargent C. A. (1988) Molecular mapping of the HLA-linked complement genes and the RCA linkage group. Experiment. Clinic. Immunogenet. 5, 81–98.Google Scholar
  9. 9.
    Campbell R. D. (1988) The molecular genetics of components of the complement system. Baillieres Clinic. Rheumatol. 2, 547–575.CrossRefGoogle Scholar
  10. 10.
    Lambris J. D. (1988) The multifunctional role of C3, the third component of complement. Immunol. Today 9, 387–393.PubMedCrossRefGoogle Scholar
  11. 11.
    Kozono H., Kinoshita T., Kim Y. U., Takata-Kozono Y., Tsunasawa S. Sakiyama F., et al. (1990) Localization of the covalent C3b-binding site on C4b within the complement classical pathway C5 convertase, C4b2a3b. J. Biohg. Chem. 265, 14,444–14,449.Google Scholar
  12. 12.
    Ebanks R. O., Jaikaran A. S., Carroll M. C, Anderson M. J., Campbell R. D., and Isenman D. E. (1992) A single arginine to tryptophan interchange at betachain residue 458 of human complement component C4 accounts for the defect in classical pathway C5 convertase activity of allotype C4A6. Implications for the location of a C5 binding site in C4. J. Immunol. 148, 2803–2811.PubMedGoogle Scholar
  13. 13.
    Gotze O. (1986) The alternative pathway of activation, in The Complement System (Rother K. and Till G. O., eds.), Springer, Berlin, pp. 154–168.Google Scholar
  14. 14.
    Weiler J. M., Daha M. R., Austen K. F., and Fearon D. T. (1976) Control of the amplification convertase of complement by the plasmaproteinbetalH. Proc. Natl. Acad Sci. USA 73, 3268–3272.PubMedCrossRefGoogle Scholar
  15. 15.
    Fearon D. T., Daha M. R., Weiler J. M., and Austen K. F. (1976) The natural modulation of the amplification phase of complement activation. Transplant. Rev. 32, 12–25.PubMedGoogle Scholar
  16. 16.
    Minta J. O. and Lepow I. H. (1974) Studies on the subunit structure of human properdin. Immunochemistry 11, 361–368.PubMedCrossRefGoogle Scholar
  17. 17.
    Lachmann P. J. and Hughes-Jones N. C. (1984) Initiation of complement activation. Springer Sent. ImmunopathoL 7, 143–162.CrossRefGoogle Scholar
  18. 18.
    Law S. K. and Dodds A. W. (1990) C3, C4 and C5: the thioester site. Biochem. Soc. Trans. 18, 1155–1159.PubMedGoogle Scholar
  19. 19.
    Holmskov U., Malhotra R., Sim R. B., and Jensenius J. C. (1994) Collectins: collagenous C-type lectins of the innate immune defense system. Immunol. Today 67–74.Google Scholar
  20. 20.
    Matsuhita M. and Fujita T. (1992) Activation of the classical complement pathway by mannose-binding protein in association with a novel Cls-like serine protease. J. Exp. Med. 176, 1497–1502.CrossRefGoogle Scholar
  21. 21.
    Tamura N., Shimada A., and Chang S. (1972) Further evidence for immune cytolysisby antibody and the first eight components of complement. Immunology 22, 131–140.PubMedGoogle Scholar
  22. 22.
    Davis A. E. (1988) Cl inhibitor and hereditary angioneurotic edema. Anna. Rev. Immunol. 5, 595–628.CrossRefGoogle Scholar
  23. 23.
    Davis A. E. (1989) Hereditary and acquired deficiencies of Cl inhibitor. Immunodef. Rev. 1, 207–226.PubMedGoogle Scholar
  24. 24.
    Vik D. P., Munoz-Canoves P., Chaplin D. D., and Tack B. F. (1990) Factor H. Curr. Topics Microbiol. Immunol. 153, 147–162.Google Scholar
  25. 25.
    Gigli I., Fujita T., and Nussenzweig V. (1979) Modulation of the classical pathway C3convertaseby the plasma proteins C4 binding protein and C3b inactivator. Proc. Natl Acad. Sci. USA 76, 6596–6600.PubMedCrossRefGoogle Scholar
  26. 26.
    Pillemer L., Blum L., Lepow I. H., Ross O. A., Todd E. W., and Wardlaw A. C. (1954) The properdin system and immunity. I. demonstration of a new serum protein, properdin, and its role in immune phenomena. Science 120, 279–285.PubMedCrossRefGoogle Scholar
  27. 27.
    Smith C. A., Pangburn M. K., Vogel C-W., and Muller-Eberhard H. J. (1984) Molecular architecture of human properdin, a positive regulator of the alternative pathway of human complement. J. Biol. Chem. 259, 4582–4588.PubMedGoogle Scholar
  28. 28.
    Pangburn M. K. (1986) The alternative pathway, in lmmunobiology of the complement system (Ross G. D., ed.), Academic, New York, pp. 45–62.Google Scholar
  29. 29.
    Lachmann P. J. (1991) The control of homologous lysis. Immunol. Today 12. 312–315.PubMedCrossRefGoogle Scholar
  30. 30.
    Davies A. and Lachmann P. J. (1993) Membrane defence against complement lysis the structure and biological properties of CD59. Immunol. Res. 12, 258–275.PubMedCrossRefGoogle Scholar
  31. 31.
    Andrews B. S., Shadforth M., Cunningham P., and Davis J. S. (1981) Demonstration of a Clq receptor on the surface of human endothelial cells. J. Immunol. 127, 1075–1080.PubMedGoogle Scholar
  32. 32.
    Ghebrehiwet B. (1989) Functions associated with the Clq receptor. Behring Inst. Mitt. 84, 204–215.PubMedGoogle Scholar
  33. 33.
    Sim R. B. and Malhotra R. (1994) Interactions of carbohydrates and lectins with complement. Biochem. Soc. Trans. 22, 106–111.PubMedGoogle Scholar
  34. 34.
    Eggleton P., Gehebrehewit B., Sastry K. N., Coburn J. P., Zaner K. S., Reid K. B., and Tauber A. I. (1995) Identification of a gClq-binding protein (gClq-R) on the surface of human neutrophils. Subcellular localisation and binding properties in comparison with the cClq-R. J. Clin. Invest. 95, 1569–1578.PubMedCrossRefGoogle Scholar
  35. 35.
    Fearon D. T. and Wong W. W. (1983) Complement ligand-receptor interactions that mediate biological responses. Ann. Rev. Immunol. 1, 243–271.CrossRefGoogle Scholar
  36. 36.
    Fearon D. T., Klickstein L. B., Wong W. W., Wilson J. G., Moore F. D., Jr.; Weis J. J., Weis, et al. (1989) Immunoregulatory functions of complement: structural and functional studies of complement receptor type 1 (CR1; CD35) and type 2 (CR2; CD21). Progr. Clln. Biohg. Res. 297, 211–220.Google Scholar
  37. 37.
    Rothlein R. and Springer T. A. (1985) Complement receptor type three-dependent degradation of opsonized erythrocytes by mouse macrophages. J. Immunol. 135, 2668–2672.PubMedGoogle Scholar
  38. 38.
    Larson R. S. and Springer T. A. (1990) Structure and function of leukocyte integrins. Immunolog. Rev. 114, 181–217.CrossRefGoogle Scholar
  39. 39.
    Chenoweth D. E. and Goodman M. G. (1983) The C5a receptor of neutrophils and macrophages. Agents de Actions—Suppl. 12, 252–273.Google Scholar
  40. 40.
    van Epps D. E. and Chenoweth D. E. (1984) Analysis of the binding of fluorescent C5a and C3a to human peripheral blood leukocytes. J. Immunol. 132, 2862–2867.PubMedGoogle Scholar
  41. 41.
    Gerard N. P. and Gerard C. (1991) The chemotactic receptor for human C5a anaphylatoxin. Nature 349, 614–617.PubMedCrossRefGoogle Scholar
  42. 42.
    Ames R. S., Li Y., Sarau H. M., Nuthulaganti P., Foley J. J., Ellis C, et al. (1996) Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J. Biol. Chem. 271, 20,231–20,234.PubMedCrossRefGoogle Scholar
  43. 43.
    Morgan B. P. and Walport M. J. (1991) Complement deficiency and disease. Immunol. Today 12, 301–306.PubMedCrossRefGoogle Scholar
  44. 44.
    Colten H. R. and Rosen F. S. (1992) Complement deficiencies. Ann. Rev. Immunol 10, 809–834.CrossRefGoogle Scholar
  45. 45.
    Figueroa J., Andreoni J., and Densen P. (1993) Complement deficiency states and meningococcal disease. Immunolog. Res. 12, 295–311.CrossRefGoogle Scholar
  46. 46.
    Fukumori Y., Yoshimura K., Ohnoki S., Yamaguchi H., Akagaki Y., and Inai S. (1989) A high incidence of C9 deficiency among healthy blood donors in Osaka. Japan. Int. Immunol. 1, 85–89.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2000

Authors and Affiliations

  • B. Paul Morgan
    • 1
  1. 1.Department of Medical BiochemistryUniversity of Wales College of Medicine

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