Cell and Tissue Research

, Volume 343, Issue 1, pp 227–235 | Cite as

The complement system

  • J. Vidya Sarma
  • Peter A. WardEmail author


The complement system consists of a tightly regulated network of proteins that play an important role in host defense and inflammation. Complement activation results in opsonization of pathogens and their removal by phagocytes, as well as cell lysis. Inappropriate complement activation and complement deficiencies are the underlying cause of the pathophysiology of many diseases such as systemic lupus erythematosus and asthma. This review represents an overview of the complement system in an effort to understand the beneficial as well as harmful roles it plays during inflammatory responses.


Complement Activation pathways Anaphylatoxins 


  1. Blom AM, Hallström T, Riesbeck K (2009) Complement evasion strategies of pathogens-acquisition of inhibitors and beyond. Mol Immunol 46(14):2808–2817CrossRefPubMedGoogle Scholar
  2. Bottazzi B, Doni A, Garlanda C, Mantovani A (2010) An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 28:157–183CrossRefPubMedGoogle Scholar
  3. Botto M, Kirschfink M, Macor P, Pickering MC, Würzner R, Tedesco F (2009) Complement in human diseases: Lessons from complement deficiencies. Mol Immunol 14:2774–2783CrossRefGoogle Scholar
  4. Cain SA, Monk PN (2002) The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). J Biol Chem 277:7165–7169CrossRefPubMedGoogle Scholar
  5. Carroll MC (2004) The complement system in B cell regulation. Mol Immunol 41(2-3):141–146CrossRefPubMedGoogle Scholar
  6. Cestari Idos S, Krarup A, Sim RB, Inal JM, Ramirez MI (2009) Role of early lectin pathway activation in the complement-mediated killing of Trypanosoma cruzi. Mol Immunol 47(2–3):426–437CrossRefPubMedGoogle Scholar
  7. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M (2009) C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 15(2):69–78CrossRefPubMedGoogle Scholar
  8. Davis AE 3rd, Mejia P, Lu F (2008) Biological activities of C1 inhibitor. Mol Immunol 45(16):4057–4063CrossRefPubMedGoogle Scholar
  9. Dunkelberger JR, Song WC (2010) Complement and its role in innate and adaptive immune responses. Cell Res 20(1):34–50CrossRefPubMedGoogle Scholar
  10. Eisen DP (2010) Mannose-binding lectin deficiency and respiratory tract infection. J Innate Immun 2(2):114–122CrossRefPubMedGoogle Scholar
  11. Flierl MA, Rittirsch D, Nadeau BA, Day DE, Zetoune FS, Sarma JV, Huber-Lang MS, Ward PA (2008) Functions of the complement components C3 and C5 during sepsis. FASEB J 22(10):3483–3490CrossRefPubMedGoogle Scholar
  12. Guo RF, Riedemann NC, Ward PA (2004) Role of C5a-C5aR interaction in sepsis. Shock 21(1):1–7CrossRefPubMedGoogle Scholar
  13. Heeger PS, Lalli PN, Lin F, Valujskikh A, Liu J, Muqim N, Xu Y, Medof ME (2005) Decay-accelerating factor modulates induction of T cell immunity. J Exp Med 201(10):1523–1530CrossRefPubMedGoogle Scholar
  14. Holers VM, Kulik L (2007) Complement receptor 2, natural antibodies and innate immunity: Inter-relationships in B cell selection and activation. Mol Immunol 44(1-3):64–72CrossRefPubMedGoogle Scholar
  15. Huang Y, Qiao F, Abagyan R, Hazard S, Tomlinson S (2006) Defining the CD59-C9 binding interaction. J Biol Chem 281(37):27398–27404. doi: 10.1074/jbc.M603690200 CrossRefPubMedGoogle Scholar
  16. Huber-Lang M, Younkin EM, Sarma JV, Riedemann N, McGuire SR, Lu KT, Kunkel R, Younger JG, Zetoune FS, Ward PA (2002) Generation of C5a by phagocytic cells. Am J Pathol 161(5):1849–1859PubMedGoogle Scholar
  17. Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12(6):682–687CrossRefPubMedGoogle Scholar
  18. Inal JM, Sim RB (2000) A Schistosoma protein, Sh-TOR, is a novel inhibitor of complement which binds human C2. FEBS Lett 470(2):131–134CrossRefPubMedGoogle Scholar
  19. Ingram G, Hakobyan S, Robertson NP, Morgan BP (2009) Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol 155(2):128–139CrossRefPubMedGoogle Scholar
  20. Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K (2005) C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem 280(25):23936–23944CrossRefPubMedGoogle Scholar
  21. Kemper C, Atkinson JP (2007) T-cell regulation: with complements from innate immunity. Nat Rev Immunol 7(1):9–18CrossRefPubMedGoogle Scholar
  22. Kemper C, Atkinson JP, Hourcade DE (2010) Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol 28:131–155CrossRefPubMedGoogle Scholar
  23. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46(14):2753–2766CrossRefPubMedGoogle Scholar
  24. Kolev MV, Ruseva MM, Harris CL, Morgan BP, Donev RM (2009) Implication of complement system and its regulators in Alzheimer's disease. Curr Neuropharmacol 7(1):1–8CrossRefPubMedGoogle Scholar
  25. Kourtzelis I, Markiewski MM, Doumas M, Rafail S, Kambas K, Mitroulis I, Panagoutsos S, Passadakis P, Vargemezis V, Magotti P, Qu H, Mollnes TE, Ritis K, Lambris JD (2010) Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 116(4):631–639CrossRefPubMedGoogle Scholar
  26. Lalli PN, Strainic MG, Yang M, Lin F, Medof ME, Heeger PS (2008) Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 112:1759–1766Google Scholar
  27. Lambris JD, Ricklin D, Geisbrecht BV (2008) Complement evasion by human pathogens. Nat Rev Microbiol 6(2):132–142CrossRefPubMedGoogle Scholar
  28. Langlois PF, Gawryl MS (1988) Accentuated formation of the terminal C5b-9 complement complex in patient plasma precedes development of the adult respiratory distress syndrome. Am Rev Respir Dis 138:368–375PubMedGoogle Scholar
  29. Laudes IJ, Chu JC, Huber-Lang M, Guo RF, Riedemann NC, Sarma JV, Mahdi F, Murphy HS, Speyer C, Lu KT et al (2002) Expression and function of C5a receptor in mouse microvascular endothelial cells. J Immunol 169:5962–5970PubMedGoogle Scholar
  30. Liebman HA, Feinstein DI (2003) Thrombosis in patients with paroxysmal nocturnal hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. Thromb Res 111(4–5):235–238CrossRefPubMedGoogle Scholar
  31. Markiewski MM, DeAngelis RA, Lambris JD (2006) Liver inflammation and regeneration: two distinct biological phenomena or parallel pathophysiologic processes? Mol Immunol 43(1–2):45–56CrossRefPubMedGoogle Scholar
  32. Molina H, Holers VM, Li B, Fung Y, Mariathasan S, Goellner J, Strauss-Schoenberger J, Karr RW, Chaplin DD (1996) Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc Natl Acad Sci USA 93(8):3357–3361CrossRefPubMedGoogle Scholar
  33. Ohno M, Hirata T, Enomoto M, Araki T, Ishimaru H, Takahashi TA (2000) A putative chemoattractantreceptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. Mol Immunol 37:407–412CrossRefPubMedGoogle Scholar
  34. Okinaga S, Slattery D, Humbles A, Zsengeller Z, Morteau O, Kinrade MB, Brodbeck RM, Krause JE, Choe HR, Gerard NP et al (2003) C5L2, a nonsignaling C5A binding protein. Biochemistry 42:9406–9415CrossRefPubMedGoogle Scholar
  35. Patel SN, Berghout J, Lovegrove FE, Ayi K, Conroy A, Serghides L, Min-oo G, Gowda DC, Sarma JV, Rittirsch D, Ward PA, Liles WC, Gros P, Kain KC (2008) C5 deficiency and C5a or C5aR blockade protects against cerebral malaria. J Exp Med 205(5):1133–1143CrossRefPubMedGoogle Scholar
  36. Pettigrew HD, Teuber SS, Gershwin ME (2009) Clinical significance of complement deficiencies. Ann N Y Acad Sci 1173:108–123CrossRefPubMedGoogle Scholar
  37. Qu H, Ricklin D, Lambris JD (2009) Recent developments in low molecular weight complement inhibitors. Mol Immunol 47(2–3):185–195CrossRefPubMedGoogle Scholar
  38. Ricklin D, Lambris JD (2007) Complement-targeted therapeutics. Nat Biotechnol 25(11):1265–1275CrossRefPubMedGoogle Scholar
  39. Riedemann NC, Guo RF, Sarma VJ, Laudes IJ, Huber-Lang M, Warner RL, Albrecht EA, Speyer CL, Ward PA (2002) Expression and function of the C5a receptor in rat alveolar epithelial cells. J Immunol 168:1919–1925PubMedGoogle Scholar
  40. Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Köhl J, Gerard C, Sarma JV, Ward PA (2008a) Functional roles for C5a receptors in sepsis. Nat Med 14(5):551–557CrossRefPubMedGoogle Scholar
  41. Rittirsch D, Flierl MA, Ward PA (2008b) Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8(10):776–787CrossRefPubMedGoogle Scholar
  42. Rooijakkers SH, van Strijp JA (2007) Bacterial complement evasion. Mol Immunol 44(1–3):23–32CrossRefPubMedGoogle Scholar
  43. Sarma VJ, Huber-Lang M, Ward PA (2006) Complement in lung disease. Autoimmunity 39(5):387–394CrossRefPubMedGoogle Scholar
  44. Scola AM, Johswich KO, Morgan BP, Klos A, Monk PN (2009) The human complement fragment receptor, C5L2, is a recycling decoy receptor. Mol Immunol 46(6):1149–1162CrossRefPubMedGoogle Scholar
  45. Silver KL, Higgins SJ, McDonald CR, Kain KC (2010) Complement driven innate immune response to malaria: fuelling severe malarial diseases. Cell Microbiol 12(8):1036–1045, Epub 2010 Jun 11CrossRefPubMedGoogle Scholar
  46. Sjöberg AP, Trouw LA, Blom AM (2009) Complement activation and inhibition: a delicate balance. Trends Immunol 30(2):83–90CrossRefPubMedGoogle Scholar
  47. Sørensen R, Thiel S, Jensenius JC (2005) Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Semin Immunopathol 27(3):299–319CrossRefGoogle Scholar
  48. Stengaard-Pedersen K, Thiel S, Gadjeva M, Møller-Kristensen M, Sørensen R, Jensen LT, Sjøholm AG, Fugger L, Jensenius JC (2003) Inherited deficiency of mannan-binding lectin-associated serine protease 2. N Engl J Med 349(6):554–560CrossRefPubMedGoogle Scholar
  49. Strainic MG, Liu J, Huang D, An F, Lalli PN, Muqim N, Shapiro VS, Dubyak GR, Heeger PS, Medof ME (2008) Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28(3):425–435CrossRefPubMedGoogle Scholar
  50. Thiel S, Steffensen R, Christensen IJ, Ip WK, Lau YL, Reason IJ, Eiberg H, Gadjeva M, Ruseva M, Jensenius JC (2007) Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun 8(2):154–163CrossRefPubMedGoogle Scholar
  51. Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL (2000) Viral subversion of the immune system. Annu Rev Immunol 18:861–926CrossRefPubMedGoogle Scholar
  52. Wagner E, Frank MM (2010) Therapeutic potential of complement modulation. Nat Rev Drug Discov 9(1):43–56CrossRefPubMedGoogle Scholar
  53. Wallis R (2007) Interactions between mannose-binding lectin and MASPs during complement activation by the lectin pathway. Immunobiology 212(4–5):289–299CrossRefPubMedGoogle Scholar
  54. Walport MJ (2001) Complement. First of two parts. N Engl J Med 344(14):1058–1066, ReviewCrossRefPubMedGoogle Scholar
  55. Ward PA (2008) Sepsis, apoptosis and complement. Biochem Pharmacol 76(11):1383–1388CrossRefPubMedGoogle Scholar
  56. Ward PA, Zvaifler NJ (1973) Quantitative phagocytosis by neutrophils. II. Release of the C5-cleaving enzyme and inhibition of phagocytosis by rheumatoid factor. J Immunol 111(6):1777–1782PubMedGoogle Scholar
  57. Wasowska BA (2010) Mechanisms involved in antibody- and complement-mediated allograft rejection. Immunol Res 47(1–3):25–44CrossRefPubMedGoogle Scholar
  58. Wetsel RA (1995) Expression of the complement C5a anaphylatoxin receptor (C5aR) on non-myeloid cells. Immunol Lett 44:183–187CrossRefPubMedGoogle Scholar
  59. Wills-Karp M (2007) Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc 4(3):247–251CrossRefPubMedGoogle Scholar
  60. Zhang L, Jacobsson K, Vasi J, Lindberg M, Frykberg L (1998) A second IgG-binding protein in Staphylococcus aureus. Microbiology 144(Pt 4):985–991CrossRefPubMedGoogle Scholar
  61. Zipfel PF, Würzner R, Skerka C (2007) Complement evasion of pathogens: common strategies are shared by diverse organisms. Mol Immunol 44(16):3850–3857CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of PathologyThe University of Michigan Medical SchoolAnn ArborUSA

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