COMPLEMENT
It is an important component of the host’s innate immune defense system. This
system consists of approximately 20 proteins which are present in human and
animal serum. When antigen interacts with specific antibody and forms a
complex, complement is activated and produces biologically significant
consequences.
A. Components of Complement:
The complement consists of 9 components named from C1 to C9. This system is
present in an inactive form but gets activated by formation of antigen-antibody
complexes or by molecules such as endotoxin. The various components of the
complement get activated in a sequential manner by the classical or alternate
pathway. The final outcome of these pathways is the lysis or damage of the target.
Classical Pathway: (Figure 1)
When complement components react in a specific sequential manner following
activation of C1 component and ends in immune cytolysis, it is known as the
classical pathway.
Step 1:
This pathway begins with the C1 component (C1q, C1r, C1s) binding to the
antigen-antibody complex (represented as EA). C1q binds to the Fc portion of
IgM or IgG. Once C1q binds in presence of calcium ions, it activates C1r and
C1s.
Step 2:
C1s, which is an esterase, cleaves C2 and C4 to form a C4b, 2b complex called
as C3 convertase.
Step 3:
C3 convertase cleaves C3 into C3a and C3b. C3a is an anaphylatoxin whereas
C3b complexes with C3 convertase to form C5 convertase.
Step 4:
C5 convertase cleaves C5 into C5a and C5b. C5a is an anaphylatoxin whereas
C5b binds to C6 and C7 to form a complex.
Step 5:
This complex interacts with C8 and C9 to form the membrane attack complex
(C5b, 6, 7, 8, 9). This complex brings about immune cytolysis.
Alternative Pathway: (Figure 1)
This pathway is activated by bacterial lipopolysaccharides (endotoxin), fungal
cell walls, viral envelopes, IgA and cobra venom factor. This pathway contributes
to anti-microbial defence without requiring specific antibodies. In this pathway,
C3 is activated without prior formation of C3 convertase.
The first step is the binding of C3b to an activator.
Bound C3b interacts with a serum protein called Factor B in presence of
magnesium ions to form C3bB. This complex is cleaved by another serum protein
called as Factor D. C3bB is cleaved by factor D into Ba and Bb.
Bb fragment binds to C3b to form C3bBb which is the C3 convertase of the
alternative pathway. This enzyme is labile and stabilized by factor P or properdin.
This stabilized enzyme splits more C3 into C3a and C3b and the pathway
proceeds in a similar cascade as in the classical pathway.
Figure 1: Classical and Alternate pathway of Complement activation
Biological effects of complement:
1. Opsonization- enhancement of phagocytosis
2. Chemotaxis- generates mediators which attracts inflammatory cells
3. Anaphylatoxins- causes degranulation of mast cells and release of
inflammatory mediators
4. Cytolysis- kill or lyse cells such as RBCs, bacteria and tumour cells.
Complement deficiency states:
1. Angioneurotic edema- inherited deficiency of C1 inhibitor
2. Severe recurrent pyogenic infections- deficiency of C3 and C3b inactivator
3. Bacteremia with gram negative diplococci- deficiency of C5 to C8
4. SLE and acute glomerulonephritis- deficiency of C1, C2 and C4.
QUESTIONS:
Major questions:
a. Describe the classical pathway of complement activation.
b. Describe the alternate pathway of complement activation.
Short notes:
a. Biological effects of complement
b. Complement deficiency states