Activation of the complement system plays an important role in our natural ability to ward off infection and in the pathogenesis of infection and inflammation. Anaphylatoxins produced as the result of complement activation play a role in a number of infectious and inflammatory conditions including sepsis, ischemia-reperfusion injury, immune complex diseases, and hypersensitivity diseases like asthma. Anaphylatoxins are also thought to be important in the pathogenesis of allergy, autoimmunity, neurodegenerative diseases, and cancer.
Complement activation can occur through three separate mechanisms. The first mechanism to be discovered, referred to as the classical complement cascade, is activated by antigen-antibody complexes. This was the basis for the name of this system as they serve to "complement" humoral immunity. Alternatively, the complement cascade can be activated directly by contact with bacterial cell surface molecules, including lipopolysaccharide from gram-negative outer membranes, teichoic acid from gram-positive cell walls, zymosan from fungal and yeast cell walls, and some parasite surface molecules. Recently, a third activation mechanism has been characterized in which mannose-binding lectin synthesized by the liver in response to inflammatory macrophage cytokines stimulates the activation of complement.
Complement cascade activation results in the formation of complement split products C3a, C4a, and C5a. These proteins, referred to as anaphylatoxins, facilitate the phagocytosis of immune complexes, viral particles, toxic cell debris and apoptotic corpses. Anaphylatoxins promote an inflammatory response by binding to complement receptors on granulocytes and macrophages. Anaphylatoxins also bind to receptors on mast cells, which trigger the release of histamine, increasing blood vessel permeability and smooth muscle contraction. They control the local inflammatory response through activation of leukocytes and stimulating their chemotaxis to the site of infection.
Complement C4a levels can become increased in any condition associated with inflammation. Normal human pregnancy is associated with evidence of complement activation, with an increase in concentrations of the anaphylatoxins C3a, C4a, and C5a in the maternal circulation. Levels of anaphylatoxins C3a and C4a have also been found to be elevated in patients with antiphospholipid syndrome relative to healthy controls. Ingram and associates have shown that levels of C4a are increased in patients with multiple sclerosis, especially during relapse.
Complement activation split products are present only in trace amounts in normal plasma in vivo. It is crucial that samples be collected and stored properly in order to avoid in vitro activation. Blood must be drawn directly into tubes containing EDTA at a final concentration of at least 10 mM. Citrate and heparin do not block complement activation efficiently and should not be used. The addition of nafamostat mesilate (Futhan, FUT-175) further reduces in vitro complement activation.
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