Complement Regulatory Proteins and Related Diseases


Many regulatory proteins exist to prevent excessive complement activation and to protect our cells and tissues from inappropriate damage. The classical and lectin pathways are inhibited by C1 inhibitor (C1 INH) and C4b‐binding protein (C4bp). Deficiencies in C1 INH predispose to hereditary angiooedema (HAE). Factor H(FH) is the main inhibitor of the alternative pathway amplification cascade. Mutations and polymorphisms in FH predispose to meningococcal infections, dense deposit disease (also called membranoproliferative glomerulonephritis type II), partial lipodystrophy, atypical haemolytic uraemic syndrome (aHUS) and age‐related macular degeneration. aHUS can also be the consequence of mutations in factor I (C4b/C3b inactivator) or membrane cofactor protein (CD46). Two other membrane regulators, decay‐accelerating factor (CD55) and protectin (CD59), have glycosylphosphatidylinositol (GPI)‐anchors, whose acquired deficiency from bone marrow‐derived cells can lead to paroxysmal nocturnal haemoglobinuria (PNH). Cell damage and vascular thromboses are characteristic for PNH and aHUS.

Key Concepts:

  • Several complement inhibitors are needed because the complement system has a strong potential to cause inflammation and tissue damage.

  • The default of the complement system – in the absence of regulators – is to become activated and stay in a state of activation.

  • The alternative pathway factor H can discriminate between activators (nonhost) and nonactivators (host) to prevent attack against viable endogenous cells and structures.

  • Loss of complement inhibitor function usually predisposes to a spectrum of distinct diseases.

  • The diseases are characterised by ‘innate autoreactivity’, that is, attack against endogenous cells and tissues.

  • Anaemia, thrombocytopenia and endothelial cell damage are common features and lead, in severe cases, to thrombotic microangiopathy.

  • Inability to control complement activation may also lead to secondary complement deficiency and increased susceptibility to infections.

  • Complement regulators have cross‐inhibitory activity to kinin (C1INH) and coagulation (FH) systems. Loss of function thus predisposes, for example, to bradykinin formation (in HAE) and thrombosis (aHUS).

  • Initiation of complement dysregulation‐related diseases and disease attacks usually requires triggering factors (e.g. infection, trauma, medication and stress).

  • The emergence of therapeutic complement inhibitors and replacement therapy helps in controlling excessive disease‐related complement activation.

Keywords: C1 inhibitor; factor H; MCP; CD59; age‐related macular degeneration; atypical haemolytic uraemic syndrome; glomerulonephritis; hereditary angiooedema

Figure 1.

An overview of complement activation, regulation and diseases caused by deficiencies of complement regulator proteins. The C1r and C1s are serine esterases that are inhibited by the plasma protein C1 inhibitor (C1 INH). C1 INH also inhibits analogous MBL‐associated serine protease, MASP‐2. Activity of the classical pathway C3/C5 convertase, C4b2a, is inhibited by the plasma factor C4b‐binding protein (C4bp). The activity of the alternative pathway C3/C5 convertase, C3bBb, can be enhanced by the only known physiological positive complement regulator, properdin (P). The self‐amplifying process of the AP is inhibited by multiple regulator molecules described in Figure . The five terminal plasma glycoproteins (C5, C6, C7, C8 and C9) bind sequentially to each other to generate the cytolytic membrane attack complex (MAC). Soluble regulators S‐protein and clusterin keep forming terminal C complexes in the fluid phase. On human cell membranes the main inhibitor of MAC is CD59 (protectin). Consequences of major complement regulator deficiencies are indicated by broken arrows. aHUS, atypical haemolytic uraemic syndrome; AMD, age‐related macular degeneration; DDD, dense deposit disease; HAE, hereditary angiooedema and PNH, paroxysmal nocturnal haemoglobinuria.

Figure 2.

Structure of C‐terminal FH domains 19–20 in complex with two copies of C3d. CCP domains are composed of antiparallel beta strands. Both CCP domains carry binding sites for C3d. CCP domain 20 has also important recognition sites for polyanionic surfaces (not shown). The data (2XQW) were obtained from pdb protein databank and the image was produced by Jmol Version 12.2.15 (Kajander et al., ).

Figure 3.

Regulators of the classical (CP) and alternative (AP) pathways of complement. Membrane regulators include decay‐accelerating factor (DAF; CD55), complement receptor type 1 (CR1; CD35), complement receptor of the immunoglobulin superfamily (CRIg) and membrane cofactor protein (MCP; CD46). Soluble regulators include C1 inhibitor (C1 INH), C4b‐binding protein (C4bp) and FH (H).

Figure 4.

Inhibition of the MAC of complement by protectin (CD59). By binding to the C5b‐8 complex at the C8α chain (a) and C9 (b); CD59 inhibits C9 incorporation and polymerisation in the MAC.



Bork K, Wulff K, Hardt J, Witzke G and Staubach P (2009) Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. Journal of Allergy and Clinical Immunology 124: 129–134.

Cattaneo R (2004) Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens' magnet. Journal of Virology 78: 4385–4388.

Cicardi M, Bork K, Caballero T et al. (2012) Evidence‐based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 67: 147–157.

Cicardi M and Zanichelli A (2010a) Acquired angioedema. Allergy, Asthma, and Clinical Immunology 6: 14.

Cicardi M and Zanichelli A (2010b) The acquired deficiency of C1‐inhibitor: lymphoproliferation and angioedema. Current Molecular Medicine 10: 354–360.

Cugno M, Zanichelli A, Foieni F, Caccia S and Cicardi M (2009) C1‐inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends in Molecular Medicine 15: 69–78.

Dahlback B (2011) C4b‐binding protein: a forgotten factor in thrombosis and hemostasis. Seminars in Thrombosis and Hemostasis 37: 355–361.

Ekser B, Gridelli B, Veroux M and Cooper DK (2011) Clinical pig liver xenotransplantation: how far do we have to go? Xenotransplantation 18: 158–167.

Falgarone G and Chiocchia G (2009) Chapter 8: Clusterin: A multifacet protein at the crossroad of inflammation and autoimmunity. Advances in Cancer Research 104: 139–170.

Ferreira VP, Pangburn MK and Cortes C (2010) Complement control protein factor H: the good, the bad, and the inadequate. Molecular Immunology 47: 2187–2197.

Fremeaux‐Bacchi V, Moulton EA, Kavanagh D et al. (2006) Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. Journal of the American Society of Nephrology 17: 2017–2025.

Haines JL, Hauser MA, Schmidt S et al. (2005) Complement factor H variant increases the risk of age‐related macular degeneration. Science 308: 419–421.

He JQ, Wiesmann C and van Lookeren Campagne M (2008) A role of macrophage complement receptor CRIg in immune clearance and inflammation. Molecular Immunology 45: 4041–4047.

Helmy KY, Katschke KJ Jr, Gorgani NN et al. (2006) CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124: 915–927.

Hillmen P, Young NS, Schubert J et al. (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine 355: 1233–1243.

Høgåsen K, Meri S and Jansen JH (1998) Membranoproliferative glomerulonephritis type II – factor H dysfunction nephritis. Immunologist 6: 23–28.

Jalanko H, Peltonen S, Koskinen A et al. (2008) Successful liver‐kidney transplantation in two children with aHUS caused by a mutation in complement factor H. American Journal of Transplantation 8: 216–221.

Kajander T, Lehtinen MJ, Hyvarinen S et al. (2011) Dual interaction of factor H with C3d and glycosaminoglycans in host‐nonhost discrimination by complement. Proceedings of the National Academy of Sciences of the USA 108: 2897–2902.

Kavanagh D and Goodship T (2010a) Genetics and complement in atypical HUS. Pediatric Nephrology 25: 2431–2442.

Kavanagh D and Goodship TH (2010b) Atypical hemolytic uremic syndrome. Current Opinion in Hematology 17: 432–438.

Khera R and Das N (2009) Complement receptor 1: disease associations and therapeutic implications. Molecular Immunology 46: 761–772.

Kim DD and Song WC (2006) Membrane complement regulatory proteins. Clinical Immunology 118: 127–136.

Kimberley FC, Sivasankar B and Paul Morgan B (2007) Alternative roles for CD59. Molecular Immunology 44: 73–81.

Korotkova N, Cota E, Lebedin Y et al. (2006) A subfamily of Dr adhesins of E. coli bind independently to decay‐accelerating factor and the N‐domain of carcinoembryonic antigen. Journal of Biological Chemistry 281: 29120–29130.

Laine MJH, Seitsonen S, Haapasalo K et al. (2007) Y402H polymorphism of complement factor H affects binding affinity to C‐reactive protei. Journal of Immunology 178: 3831–3836.

Lambris JD, Ricklin D and Geisbrecht BV (2008) Complement evasion by human pathogens. Nature Reviewa Microbiology 6: 132–142.

Le Friec G, Sheppard D, Whiteman P et al. (2012) The CD46‐Jagged1 interaction is critical for human T(H)1 immunity. Nature Immunology 13: 1213–1221.

Longhurst H and Cicardi M (2012) Hereditary angio‐oedema. Lancet 379: 474–481.

Meri S (2007) Loss of self‐control in the complement system and innate autoreactivity. Annals of the New York Academy of Sciences 1109: 93–105.

Meri S, Jordens M and Jarva H (2008) Microbial complement inhibitors as vaccines. Vaccine 26(Suppl. 8): I113–117.

Meri S, Koistinen V, Miettinen A, Tornroth T and Seppala IJ (1992) Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. Journal of Experimental Medicine 175: 939–950.

Meri S, Waldmann H and Lachmann PJ (1991) Distribution of protectin (CD59), a complement membrane attack inhibitor, in normal human tissues. Laboratory Investigation. 65: 532–537.

Mikesch JH, Schier K, Roetger A et al. (2006) The expression and action of decay‐accelerating factor (CD55) in human malignancies and cancer therapy. Cellular Oncology 28: 223–232.

Ni Choileain S and Astier AL (2012) CD46 processing: a means of expression. Immunobiology 217: 169–175.

Paixao‐Cavalcante D, Lopez‐Trascasa M, Skattum L et al. (2012) Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation. Kidney International 82: 1084–1092.

Parker CJ (2012) Paroxysmal nocturnal hemoglobinuria. Current Opinion in Hematology 19: 141–148.

Preissner KT and Reuning U (2011) Vitronectin in vascular context: facets of a multitalented matricellular protein. Seminars in Thrombosis and Hemostasis 37: 408–424.

Pu JJ and Brodsky RA (2011) Paroxysmal nocturnal hemoglobinuria from bench to bedside. Clinical and Translational Science 4: 219–224.

Rautemaa R, Rautelin H, Puolakkainen P et al. (2001) Survival of Helicobacter pylori from complement lysis by binding of GPI‐anchored protectin (CD59). Gastroenterology 120: 470–479.

Richards A, Kemp EJ, Liszewski MK et al. (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proceedings of the National Academy of Sciences of the USA 100: 12966–12971.

Saifuddin M, Hedayati T, Atkinson JP et al. (1997) Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol‐anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement‐mediated destruction. Journal of General Virology 78(Pt 8): 1907–1911.

Skerka C and Zipfel PF (2008) Complement factor H related proteins in immune diseases. Vaccine 26(Suppl. 8): I9–I14.

Smith RJ, Harris CL and Pickering MC (2011) Dense deposit disease. Molecular Immunology 48: 1604–1610.

Vakeva A, Laurila P and Meri S (1993) Regulation of complement membrane attack complex formation in myocardial infarction. American Journal of Pathology 143: 65–75.

Weismann D, Hartvigsen K, Lauer N et al. (2011) Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478: 76–81.

Wiesmann C, Katschke KJ, Yin J et al. (2006) Structure of C3b in complex with CRIg gives insights into regulation of complement activation. Nature 444: 217–220.

Yamashina M, Ueda E, Kinoshita T et al. (1990) Inherited complete deficiency of 20‐kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine 323: 1184–1189.

Zuber J, Fakhouri F, Roumenina LT, Loirat C and Fremeaux‐Bacchi V (2012) Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nature Reviews Nephrology 8: 643–657.

Further Reading

Banerji A (2011) Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy and Asthma Proceedings 32: 403–407.

Dragon‐Durey MA, Blanc C, Garnier A et al. (2010) Anti‐factor H autoantibody‐associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS. Seminars in Thrombosis and Hemostasis 36 633–640.

Heeger PS and Kemper C (2012) Novel roles of complement in T effector cell regulation. Immunobiology 217: 216–224.

Kraiczy P and Wurzner R (2006) Complement escape of human pathogenic bacteria by acquisition of complement regulators. Molecular Immunology 43: 31–44.

Pickering M and Cook HT (2011) Complement and glomerular disease: new insights. Current Opinion in Nephrology and Hypertension 20: 271–277.

Suzuki KG, Kasai RS, Hirosawa KM et al. (2012) Transient GPI‐anchored protein homodimers are units for raft organization and function. Nature Chemical Biology 8: 774–783.

Zipfel PF, Lauer N and Skerka C (2010) The role of complement in AMD. Advances in Experimental Medicine and Biology 703: 9–24.

Zipfel PF and Skerka C (2009) Complement regulators and inhibitory proteins. Nature Reviews Immunology 9: 729–740.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Meri, Seppo, and Jarva, Hanna(Jun 2013) Complement Regulatory Proteins and Related Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001434.pub3]