SERUM COMPLEMENT
CLASSICAL PATHWAY: Antibody-dependent activation of complement.
• INITIATION: C1 has an Fc-Receptor that is activated when IgG and/or IgM cross-link the Fc-Receptors.
o One molecule of IgM, because its pentameric is sufficient to activate complement.
o ~1000 molecules of IgG are required in order to achieve high enough concentration to get the needed cross-
linking.
• C1qr2s2 then activates C4 and, separately, C2.
o C4 ------> C4a + C4b
C4a is then released as anaphylatoxin.
o C2 ------> C2a, which then catalyzes formation of C3-Convertase.
• C3-CONVERTASE is then formed by C4b2a. C1 is sloughed off.
• C3-Convertase then catalyzes C3 ------> C3a + C3b
o C3b then participates in both classical and alternative C5-Convertases.
o C3a is then released as anaphylatoxin.
• C5-CONVERTASE is then formed by C4b2a3b
o C5 ------> C5a + C5b
C5a is released as anaphylatoxin and chemotactic factor.
C5b hooks to complement receptors and forms the initial part of the Membrane-Attack Complex
(MAC).
ALTERNATIVE PATHWAY: Antibody-independent activation of complement.
• INITIATION: Initiation occurs whenever C3b and the necessary accessory enzymes are present. Alternative pathway is
subject to a positive feedback loop.
o C3 Slow Spontaneous Hydrolysis ------> C3a + C3b
o FACTOR-B ------> Ba + Bb
Ba is sloughed off.
o C3-CONVERTASE: Bb then binds to C3b to form C3bBb, which is C3-CONVERTASE.
Binding of Bb to C3b is catalyzed by FACTOR-D
The C3-Convertase is very unstable (5-min half life) unless it is stabilized by binding of
PROPERDIN.
o AMPLIFICATION / POSITIVE FEEDBACK: C3-CONVERTASE can then generate more C3b by cleaving
C3 ------> C3a + C3b
o C5-CONVERTASE: C3-Convertase (C3bBb) can bind to another C3b to form the C5-Convertase: C3bBb3b.
C5 ------> C5a + C5b
Again, C5a is given off as chemotactic factor
Again, C5b forms beginning of MAC.
MEMBRANE-ATTACK COMPLEX (MAC): C5b6789
• INITIATION: C5b binds to the target-cell by means of a complement-receptor. It provides the binding site for the
subsequent addition of other factors.
• C5b6 exposes hydrophobic regions of complex that nudge their way into the membrane.
• C9 is a perforin-like molecule that can polymerize, and add 15 or more subunits to C5b678.
• The final MAC simply pierces the membrane.
Complement Regulation:
• C1 INHIBITOR (C1Inh): Glycoprotein that can block the Classical Pathway by preventing initial reaction of C1q,
preventing activation of C2 and C4.
• C3-CONVERTASE REGULATORS: Family of proteins that inhibit C3-Convertase.
o CR1: Classical and Alternative C3-Convertase Inhibition. Since this is complement receptor Type-I, this acts
as a form of negative feedback.
It also acts to accelerate decay of alternative C3-Convertase.
o MEMBRANE-COFACTOR PROTEIN (MCP): Classical and Alternative C3-Convertase inhibitor.
o C4b BINDING-PROTEIN (C4bp): Classical C3-convertase inhibitor. Binds to C4b and prevents its
association with C3a, preventing formation of Classical C3-Convertase.
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