Tanta Faculty of Medicine
Internal medicine Department
Role of Complement System in
Diseases
Introduction
Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces.
Soluble complement components form the proteolytic cascade , whose activation leads to the generation of
complement effectors that target various cells involved in the immune response.
Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit
complement activation to the surfaces of pathogens and damaged or activated host cells.
The multiple interconnections among complement proteins ,immune cells , and mediators provide an excellent
mechanism to protect the organism against infections and support the repair of damaged tissues
The activation of complement can significantly contribute to inflammation-mediated tissue damage ,
whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity
Complement was discovered approximately 100 years ago as a heat-sensitive component of plasma that
enhances the opsonization of bacteria by antibodies and facilitates antibody-dependent killing of bacteria
Acute Inflammatory Response
Inflammation is currently viewed as a complex pathophysiologic process that engages literally
hundreds of mediators and different cell types and tissues and can be initiated by any stimulus
causing cell injury.
In fact, the activation of complement occurs immediately with high efficiency when the system
encounters appropriate stimuli. For example, in infection induced by Leishmania, approximately
90% of promastigotes are lysed by complement in just 2.5 minutes after contact with human blood.
Therefore, complement effectors generated as a result of this activation can participate in the earliest
events of an inflammatory reaction.
Complement Activation
Complement is activated through the
CLASSICAL
LECTIN
ALTERNATIVE PATHWAYS
Activation
The classical pathway initiated by antibodies produced during the humoral response, by natural
antibodies, and by other molecules that are generated as a result of an inflammatory reaction .
The binding of C1q to antigen-antibody complexes initiates the proteolytic cleavage of complement
components in the classical pathway.
The lectin pathway begins with the recognition and binding of pathogen-associated molecular
patterns by lectin proteins, including MBL.
both the classical and lectin pathways require C2 and C4 complement
components for the generation of the C3 convertase.
The alternative pathway differs significantly from the classical and lectin pathways because it is
initiated by the spontaneous hydrolysis of C3.
Activation
C3 convertases that cleave C3 to C3a and C3b.
C3b contributes to the formation of the C5 convertase, which in turn cleaves C5 to C5a and C5b.
Complement anaphylatoxins C3a, C4a, and C5a are potent inflammatory mediators,
and C5b initiates the formation of C5b-9 terminal complement complex, which is incorporated into
bacterial cell walls and induces the lysis of pathogens.
Complement in Acute Inflammation
Complement components that are activated in plasma and body fluids are engaged in the regulation
of virtually all phases of an acute inflammatory reaction, including changes in vascular flow
and caliber, the increase in vascular permeability, extravasation of leukocytes, and
chemotaxis
Increased Vascular Permeability
The hemodynamic changes and the increased permeability of the endothelial barrier lead to the
formation of an inflammatory exudate, which contains protein-rich fluid and inflammatory cells.
These include the formation of endothelial gaps in venules
Leukocyte Extravasation
leukocytes leave the blood stream and migrate into the interstitial space.
Anaphylatoxins, mainly C5a, participate in endothelial activation
Chemotaxis
Leukocytes that cross the walls of blood vessels migrate toward the site of injury,
directed by chemotactic mediators along a chemical gradient.
Anaphylatoxins, and particularly C5a, are well-established chemotactic factors
that affect leukocyte migration
”Waste Disposal“
Inflammation is usually associated with host tissue damage of various degrees of
severity.
Apoptotic and necrotic cells are known to activate complement, and several
complement components significantly facilitate the clearance of dead cells by a
system involving phagocytes.
Autoimmune Disorders
Autoimmune diseases occur when a specific adaptive immune response is directed
against self-antigens
This “decomplementation” is often a result of deposition of complement
components in host tissues, associated with the deposition of immune complexes
that activate complement through the classical pathway.
Complement effectors that are generated as a result of this activation enhance the
inflammatory reaction in affected host tissue, thereby exacerbating the tissue injury
Dysfunction of Complement Regulators
Alterations in the expression of the complement regulators that limit the activation
of complement in the healthy individual can lead to unregulated and excessive
complement activation, resulting in tissue injury.
References
1. Bordet J, Gengou O: Sur l’existences de substance sensibilisatricesdans la plupart des serum antimicrobiens. French. Ann
Inst Pasteur 1901,15:289 -302
2. Carroll MC: The complement system in regulation of adaptive immunity. Nat Immunol 2004, 5:981-986
3. Mastellos D, Lambris JD: Cross-disciplinary research stirs new challenges into the study of the structure, function and
systems biology of complement. Current Topics in Complement. Edited by JD Lambris.
New York, Springer Science and Business Media, LLC, 2006, pp1-16
4. Mastellos D, Morikis D, Isaacs SN, Holland MC, Strey CW, LambrisJD: Complement: structure, functions, evolution, and
viral molecular mimicry. Immunol Res 2003, 27:367-385
5. Nathan C: Points of control in inflammation. Nature 2002, 420:846- 852
6. Collins T: Acute and chronic inflammation. Pathologic Basis of Disease. Edited by RS Cotran, V Kumar, T Collins.
Philadelphia, W.B. Saunders, 1999, pp 50 - 88
7. Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (Eds): Innate immunity. Immunobiology. New York, Garland
Publishing, 2005, pp
37-100
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