Complement System

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Complement system is the major effector of immune system. It plays an important functions in both innate and adaptive immunity. Complement system has more than 20 serum glycoproteins synthesized mainly by hepatocytes. Some complements are synthesized by monocytes, macrophages and epithelial cells.

Complement system plays several functions:

  1. Lysis of cell
  2. Opsonization
  3. Inflammation
  4. Immune clearance

Complement Components

Many complement components circulate in serum. They are proenzyme (inactive). Proteolytic cleavage is necessary to activate the complement components. It involves enzymatic cascade. The complement components are cleavaged into large (designated as “b”) and small fragment (designated as “a”). Larger fragment binds to the surface of the substrate. The smaller fragment diffuses away from the site and trigger inflammation. The complement components are not working separately, They works together in the system. Some complement components join together and show enzymatic activity where bar over the number or symbol is included.

Complement Activation

Complement system has three activation pathways:

  1. Classical pathway
  2. Alternative pathway
  3. Lectin pathway

Initial activation for three pathways are different. But, they share the common final step where the membrane attack complex is formed.

Classical Pathway

Classical pathway is activated when antibodies (Ig G or Ig M) bind to the antigen. C1 is a complex consists of one C1q and two C1s and C1r molecules. C1 binds to antibodies and activate the classical pathway. Activationc causes C1r and C1s are activated. C1s activates C4, then binds to C2 and activates C2. Then, C3 convertase is formed.

C3a, C4a and C5a released act as anaphylatoxins or mediators of inflammation.

C3b functions as opsonin.

classical pathway, complement system

Classical Pathway of Complement System


Alternative Pathway

C3 hydrolyze spontaneously to form C3b. C3b deposits on host and microbial antigens. Factor B is activated by factor D results the formation of C3 convertase.

Lectin Pathway

Mannan-binding lectin binds to MBL-associated serine protease (MASP). When MBL binds to carbohydrate of bacteria, MASP is activated. MASP acts as C4 and C2 to form C3 convertase.

Common Final Steps

C3 convertase that formed from classical, alternative and lectin pathways cleavages the C5 to C5b. C5b binds to C6, C7 and C8. C5b67 inserts into the plasma membrane and the C8 binds to the complex. C9 forms the perforin-like molecule and binds to C5b678, which called membrane attack complex (MAC). MAC creates an ion-permeable pore, results osmotic lysis of the cell.

membrane attack complex

Membrane Attack Complex
Image credit: Wikimedia Commons