Complement is a serum protein found in human and vertebrate serum and tissue fluids that is not heat-resistant and enzymatically active upon activation, including more than 30 soluble and membrane-bound proteins, also known as the Complement System, mediates the immune response and inflammatory response. It can be activated by antigen-antibody complexes or microorganisms, leading to lysis or phagocytosis of pathogenic microorganisms.
 

Complement System Components

The complement system is a multimolecular system containing more than 30 soluble proteins, membrane-bound proteins, and complement receptors. Due to the large variety of complement molecules are named according to the order of their discovery: C1q, C1r, C1s, C2, C3, C4, etc.
 

Biological Effects of Complement

Enhances phagocytosis, enhances phagocyte chemotaxis, increases vascular permeability, neutralizes viruses, and cytolytic effects, and regulates immune response.
 

Function of Complement

1. Causing lysis of cells (e.g., bacteria, viruses, xenografts, and tumor cells);
2. Producing mediators involved in triggering specific cellular functions, inflammation, and secretion of immunomodulatory molecules;
3. Facilitating osmosis, a process in which bacteria are more readily and efficiently engulfed by phagocytes;
4. Causing immune clearance, a process in which immune complexes are removed from the circulation and transported to the spleen and liver.

 

Pathways of Complement Activation

The complement system can be activated through three pathways that are both independent and intersecting: the classical pathway, the alternative pathway, and the lectin pathway.
  1.Classical pathway:
A pathway in which activation is initiated by the binding of C1q by a complex formed by an antibody (IgG or IgM) and antigen. The activator first binds to C1q and sequentially activates C1r, C1s, C4, C2, and C3 to form C3 converting enzyme (C4b2a) and C5 converting enzyme (C4b2a3b).
 
Activator: antibody-antigen complex. 
 
Participating components: C1, C2, C3, C4, C5, C6, C7, C8, C9. 
 
2.Alternative pathway:
An activation process in which contact surfaces are provided by pathogenic microorganisms, etc., and in which factors C3 and D are directly involved. The process requires neither antigen-antibody complexes nor activation of C1, C2 and C4.
 
Activator: mainly pathogen cell wall components, such as lipopolysaccharide, peptidoglycan, phosphoglycolic acid, etc., as well as condensed IgA and IgG4.
 
Participating components: in addition to C3, C5, C6, C7, C8, and C9, there are also B factors, D factors, and P factors.
 
3.Lectin pathway:
Direct recognition of sugar structures on the surface of pathogenic microorganisms by mannose-binding lectin (MBL) in plasma, which in turn activates MASP1, MASP2, C4, C2, and C3 sequentially to form a cascade enzymatic reaction process between C3 converting enzyme and C5 converting enzyme.
 
Activators: pathogenic microorganisms with mannose and glucose on their surface.
 
Participating components: MBL, C-reactive protein, C2, C3, C4, C5, C6, C7, C8, C9.
 
The C5 converting enzyme formed by the three pathways can cleave C5 into C5a and C5b fragments. C5b combines with C6 and C7 in the liquid phase to form C5b67, which is embedded in the hydrophobic lipid layer of the cell membrane and then polymerizes with C8 and several C9 molecules to form the C5b6789n complex, i.e. the membrane attack complex (MAC). The MAC can form a pore of 11 nm in diameter, which allows water, ions, and soluble small molecules to enter and exit freely, and makes it difficult for large molecules to escape, leading to the reduction of intracellular osmotic pressure and cell degradation.
 

Complement C3, C4

Complement C3 and C4 are most easily detected in the human body, of which the content of Complement C3 is the highest, followed by Complement C4.
 
Complement C3 can induce phagocytes to move directionally to promote phagocytosis, promote B cell proliferation, and have a solubilizing effect on soluble immune complexes.
 
Complement C4 is an important component of the classical activation pathway of complement and is divided into two major categories, C4a and C4b. C4a release induces histamine release from mast cells and increases vascular permeability causing localized exudative inflammation. C4b primarily plays a role in mediating the complement cascade response. It also plays a role in promoting phagocytosis, participating in preventing the deposition of immune complexes, and neutralizing viruses.
 

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