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Complement system

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In the late 19th century, Hans Ernst August Buchner found that blood serum contained a "factor" or "principle" capable of killing bacteria. In 1896, Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, demonstrated that this principle had two components: one that maintained this effect after being heated, and one that lost this effect after being heated. The heat-stable component was responsible for the immunity against specific microorganisms, whereas the heat-sensitive (heat-labile) component was responsible for the non-specific antimicrobial activity conferred by all normal serum. This heat-labile component is what we now call "complement."



Functions of the ComplementEdit

File:Complement death.PNG

The following are the basic functions of the complement

  1. Opsonization - enhancing phagocytosis of antigens
  2. Chemotaxis - attracting macrophages and neutrophils
  3. Cell Lysis - rupturing membranes of foreign cells
  4. Clumping of antigen-bearing agents


The proteins and glycoproteins that constitute the complement system are synthesized by the liver hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinal tract and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antigen:antibody complexes for activation (specific immune response), whereas the alternative and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory cells. C3a is the precursor of an important cytokine (adipokine) named ASP and is usually rapidly cleaved by carboxypeptidase B. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction. C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9.[2] MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

Classical pathwayEdit

Main article: Classical complement pathway
C2 fragment nomenclature
Different assignment for the fragments C2a and C2b, as to which is larger or smaller, is found below in several current text books in immunology; however, we might safely make assignment that the former is smaller. In a literature below, in the publishing year of as early as 1994,[3] they commented that the larger fragment of C2 should be designated C2b. In the 4th edition of their book, they say that:[4]


This nomenclature is used in another literature:[5]


The assignment is mixed in the latter literature, though.

Literature[6][7][8][9][10][11][12][13][14] can be found where the larger and smaller fragments are assigned to be C2a and C2b, respectively, and literature[15][3][4][16][17] can be found where the opposite assignment is made. However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b. It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition[13] they withdraw the stance to indicate the larger fragment of C2 as C2b.




Alternative pathwayEdit

Main article: Alternative complement pathway



Lectin pathwayEdit

Main article: Lectin pathway


Activation of complements by antigen-associated antibodyEdit




Regulation of the complement systemEdit


Role in diseaseEdit

Main article: Complement deficiency

It is thought that the complement system might play a role in many diseases with an immune component, such as Barraquer-Simons Syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, and ischemia-reperfusion injuries.[18][19] and rejection of transplanted organs.[20]

The complement system is also becoming increasingly implicated in diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions such as spinal cord injuries.[21][22][23]


Mutations in the complement regulators factor H and membrane cofactor protein have been associated with atypical haemolytic uraemic syndrome.[24][25] Moreover, a common single nucleotide polymorphism in factor H (Y402H) has been associated with the common eye disease age-related macular degeneration.[26] Polymorphisms of complement component 3, complement factor B, and complement factor I, as well as deletion of complement factor H-related 3 and complement factor H-related 1 also affect a person's risk of developing age-related macular degeneration.[27] Both of these disorders are currently thought to be due to aberrant complement activation on the surface of host cells.




Modulation by infectionsEdit


See alsoEdit


  1. 1.0 1.1 Abbas AK, Lichtman AH, Pillai S (2010). Cellular and Molecular Immunology., 6th, Elsevier.
  2. Goldman AS, Prabhakar BS (1996). The Complement System. in: Baron's Medical Microbiology (Baron S et al., eds.), 4th, Univ of Texas Medical Branch. (via NCBI Bookshelf).
  15. Janeway CA Jr., Travers P, Walport M, Shlomchik MJ (2001). Immunobiology., 5th, Garland Publishing. (via NCBI Bookshelf).
  18. Arumugam et al. (2004). The role of the complement system in ischemia-reperfusion injury. Shock 21 (5): 401–9.
  19. Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh SC, Kambham N, Lerut E, Salvatierra O, Butte AJ, Sarwal MM. (2009). Expression of Complement Components Differs Between Kidney Allografts from Living and Deceased Donors. J. Am. Soc. Nephrol. 20 (8): 1839–1851.
  20. Sacks S et al. (2003). Role of the complement system in rejection. Curr. Opin. Immunol. 21 (5): 487–92.
  21. Galvan MD, Luchetti S, Burgos AM, et al. (December 2008). Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury. J. Neurosci. 28 (51): 13876–88.
  22. Nguyen HX, Galvan MD, Anderson AJ (2008). Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury. J Neuroinflammation 5: 26.
  23. Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ (February 2010). Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 133 (Pt 2): 433–47.
  24. Dragon-Durey MA, Frémeaux-Bacchi V (2005). Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. Springer Semin. Immunopathol. 27 (3): 359–74.
  25. Zipfel PF, Misselwitz J, Licht C, Skerka C (2006). The role of defective complement control in hemolytic uremic syndrome. Semin. Thromb. Hemost. 32 (2): 146–54.
  26. Mooijaart SP, Koeijvoets KM, Sijbrands EJ, Daha MR, Westendorp RG (2007). Complement Factor H polymorphism Y402H associates with inflammation, visual acuity, and cardiovascular mortality in the elderly population at large. Experimental Gerontology 42 (11): 1116–22.
  27. DOI:10.1038/eye.2011.37
  28. Datta PK, Rappaport J (2006). HIV and complement: Hijacking an immune defence. Biomedicine and Pharmacotherapy 60 (9): 561–568.

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