Complement: The Alternative Pathway


The alternative pathway of complement is a powerful and evolutionarily old defence system of innate immunity that recognises and destroys invading infectious microbes and also targets and eliminates modified self cells. For survival in an immunocompetent host, pathogenic microbes provide strategies to interfere with alternative pathway activation at their surface and they evade complement immune recognition. Recent evidence shows that mutations and sequence variations of important regulators of the alternative pathway cause a variety of autoimmune diseases, including age‐related macular degeneration (AMD) of the retina and kidney diseases in the form of atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathy (C3G). On the basis of its central relevance in immunity targeting, the complement system by specific therapeutic agents is a promising approach to treat autoimmune diseases and inflammatory disorders.

Key Concepts

  • Alternative pathway is a spontaneous self‐amplifying initiator of complement
  • AP is activated by default in blocked by inhibitors
  • Defective AP regulation results in serve autoimmune disease
  • Mutations in regulators and autoimmune forms cause diseases
  • Pathogenic infectious microbes block AP action by mimicking intact host surfaces
  • The C3 convertase of the AP is the central hub for complement activation
  • AP is controlled in fluid phase and on biological surfaces
  • Targeting AP action is a promising option to treat inflammatory autoimmune disorders
  • Animal behaviourists must participate in conservation planning to protect the future of biodiversity
  • Lipid bilayers provide the fundamental architecture of biological membranes.

Keywords: alternative pathway; innate immunity; microbial immune evasion; factor H ; autoimmune diseases

Figure 1. Formation and control of C3 at the cell surface. C3 is continuously activated by the alternative complement pathway and attaches to surfaces in the form of C3b in a random manner. When activation occurs, factor B (B) binds to C3b and is subsequently cleaved by factor D (D) into fragments Bb and Ba. The resulting C3 convertase (C3bBb) is stabilized by binding of properdin (P) and, in an amplification loop, generates more C3b molecules which deposit in the vicinity of the convertase. A powerful amplification reaction results in surface deposition of C3b (opsonization) and formation of C5 convertases, followed by the induction of the lytic complement pathway and cell lysis. Complement regulators existing in the fluid phase and on the cell membrane determine the fate of the newly formed C3b molecule. The activity is shown here for the fluid‐phase regulators factor H and reconectin/FHL‐1. These regulators either direct the dissociation of the C3/C5 convertases or they inhibit the formation of these convertases by controlling factor B binding, that is, decay‐accelerating activity. In addition, they act as cofactors for factor I and cause the inactivation of the C3b protein to the inactive form iC3b.
Figure 2. Processing of C3 in the alternative pathway. A continuously and spontaneously formed C3 convertase cleaves plasma C3 to C3b and the anaphylactic C3a fragment. The thioester of C3b interacts with molecules in its vicinity and binds to cell surfaces. C3b is inactivated by factor I in combination with various cofactors in several steps. The first cleavage results in the inactive form of iC3b and the release of fragment C3f. A second cleavage liberates the large C3c fragment and leaves the smaller C3dg fragment attached to particles or biomolecules. Further cleavage forms the C3d fragment. The various fragments represent ligands for several C3‐binding proteins and specific C3 receptors.


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Further Reading

Józsi M and Zipfel PF (2008) Factor H family proteins and human diseases. Trends in Immunology 29: 380–387.

Noris M and Remuzzi G (2008) Therapies of renal diseases associated with complement factor H abnormalities: atypical haemolytic uraemic syndrome and membranoproliferative glomerulonephritis. Clinical and Experimental Immunology 151: 199–209.

Reid KBM and Day AJ (1996) Complement. Oxford: IRL Press.

Rodríguez de Córdoba S , Esparza‐Gordillo J , Goicoechea de Jorge E , Lopez‐Trascasa M and Sánchez‐Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Molecular Immunology 41: 355–367.

Smith RJ , Alexander J , Barlow PN , et al. (2007) Dense deposit disease focus group: new approaches to the treatment of dense deposit disease. Journal of American Society of Nephrology 18: 2447–2456.

Volonakis JE and Frank MM (1997) The Human Complement System in Health and Disease. New York: Marcel Dekker.

Zipfel PF (2005) Complement and Kidney Disease. Basel: Birkhäuser Verlag.

Zipfel PF , Heinen S , Józsi M and Skerka C (2006) Complement and diseases: defective alternative pathway control as a cause for kidney – and eye diseases. Molecular Immunology 43: 97–106.

Zipfel PF , Hallström T and Riesbeck K (2013) Pathogenic microbes – tipping the balance. Molecular Immunology 56: 152–160.

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Zipfel, Peter F, and Skerka, Christine(Jul 2015) Complement: The Alternative Pathway. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000509.pub3]