Complement System
The complement system consists of a number of small proteins found in
the blood, made by the liver. Normally they circulate as inactive precursors.
The complement system helps or “complements” the ability of antibodies
and phagocytic cells to clear pathogens from an organism.
Complements are soluble proteins and glycoproteins.
More than 20 types of complements are present in serum
Main functions of the Complement System
1. Opsonization: Increases phagocytosis by opsonins.
2. Chemotaxis: Attracts macrophages and neutrophils via inflammation.
3. Cell lysis: Ruptures membranes due to formation of a membrane attack
complex (MAC)
4. Agglutination: Causes clustering and binding of pathogens
Pathways
Complement proteins in the circulation are activated when triggered a
bacterial cell, a virus, an immune complex, damaged tissue or other
substance not usually present in the body.
Complement activation is a cascading event.
The circulating proteins have been grouped into three activation
pathways, based on the types of substances and proteins that initiate
the activation ie,
1. Classical Pathway
2. Lectin Pathway
3. Alternative Pathway
The Classical Complement Pathway
1. The classical complement pathway is activated when a complement protein complex
called C1 interacts with antibody molecules (IgG or IgM) bound to specific antigen.
2. The C1 complex is composed of three complement proteins called C1q, C1r, and
C1s.
The binding of C1q activates the C1r portion of C1 which, in turn, activates C1s. This
activation gives C1s enzymatic activity to cleave complement protein C4 into C4a and
C4b .
3. C2 is cleaved by C1 into C2a and C2b
4. C4b and C2a combine to form C4b2a, the C3 convertase. C3 convertase can cleave
C3 into C3a and C3b .
5. Some molecules of C3b bind to C4b2a, the C3 convertase, to form C4b2a3b, a C5
convertase that cleaves C5 into C5a and C5b.
6. C5b binds to the surface of the target cell and subsequently binds C6, C7, C8, and a
number of monomers of C9 to form C5b6789, the Membrane Attack Complex (MAC)
The Lectin Pathway
1. The lectin pathway is activated by the interaction of microbial carbohydrates with
mannose-binding lectin (MBL) found in the plasma and tissue fluids. (Lectins are
carbohydrate-binding proteins.)
2. Mannose-binding lectin (MBL) form complexes with MBL-associated serine
proteases called MASP1 and MASP2.
3. The binding of the MBL to MASP2 give it the enzymatic activity to split C4 into C4a
and C4b .
4. C2 then binds to C4b and is cleaved by MASP2 into C2a and C2b .
5. C4b and C2a combine to form C4b2a, the C3 convertase. C3 convertase cleave C3
into C3a and C3b .
6. Some molecules of C3b bind to C4b2a, the C3 convertase, to form C4b2a3b, a C5
convertase that cleaves C5 into C5a and C5b .
7. C5b binds to the surface of the target cell and subsequently binds C6, C7, C8, and a
number of monomers of C9 to form C5b6789n, the Membrane Attack Complex.
The Alternative Complement Pathway
1. Activation of the alternative complement pathway begins when C3b (or C3i) binds to
the cell wall and other surface components of microbes.
2. Protein Factor B then combines with the cell-bound C3b to form C3bB.
3. Factor D then splits the bound Factor B into Bb and Ba, forming C3bBb. This
functions as a C3 convertase capable of splitting C3 into C3a and C3b.
4. Some of the C3b subsequently binds to some of the C3bBb to form C3bBb3b, a C5
convertase capable of splitting molecules of C5 into C5a and C5b . From here, the
alternative complement pathway is identical to the other complement pathways.
Complement Regulation
The complement system has the potential to be extremely damaging to host
tissues; hence regulatory mechanisms are required to restrict the complement
pathway. Various plasma and cell membrane proteins regulate complement
activation.
The complement system is diffusely active within the body, and deficiencies or
dysregulation results in immune system deficiencies, autoimmune disorders,
or bleeding disorders.
The complement system plays a critical role in inflammation and defence
against some bacterial infections.
Complement may also be activated during reactions against incompatible
blood transfusions, and during the damaging immune responses that
accompany autoimmune disease.