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1. COORDINATION OF CLASSICAL AND
ALTERNATIVE METHOD OF COMPLEMENT
SYSTEM
DEVU SYAM

2. Important effector in both innate and acquired immunity.
Discovered in 1894 by Jules bordet as a heat labile component of
the normal plasma which complement the antibacterial activity of the
antibody.
The term “complement” was coined by Paul Ehrlich: “the activity of
blood serum that completes the action of antibody”.
It consist of more than 30 distinct serum proteins which act as
cascade.
Synthesized by liver hepatocytes, blood monocytes, tissue
macrophages and the epithelial cells of the gastrointestinal and
genitourinary tracts.
Circulate in serum as zymogens.

3. Four important functions:
•Lysis of cells, bacteria and viruses.
•Opsonization, which promotes the phagocytosis of
particulate antigens.
•Activation of inflammatory response.
•Immune clearance, which removes immune complexes
from the circulation and deposits them in the spleen and
liver.

4. C1(C1q, C1r, C1s )
C2(C2a, C2b)
C3(C3a, C3b)
C4(C4a, C4b)
C5(C5a, C5b)
C6
C7
C8
C9
Factor B
Factor D
DAF, CD55
CR1, CD35
Factor H
Factor I

5. NOMENCLATURE
Designated by numerals : C1-C9
By letter symbols: factor D, factor B etc
Smaller fragments resulting from cleavage of a component is
designated “a” and larger fragment designated “b” except for C2
Those complexes that have enzymatic activity are designated by
a bar over the number or symbol.

6. 1-classical pathway which is activated by Ab bound
to Ag
2- the lectin pathway activated by carbohydrates
3-Alternative pathway activated in the presence of
various microbial pathogen

8. CLASSICAL PATHWAY
Begins with the formation of antigen-antibody
complex.
IgM and IgG are involved.
Conformational change in the Fc portion expose
binding site for C1 component.
C1 consist of C1q and two molecules each of C1r and
C1s, held together in a complex (C1qr2s2) stabilized by
Ca2+ ions.

13. C4b2a cuts C3 into two major fragments:
C3b is the main effector molecule of the complement system.
It coat the pathogen surface.
Macrophages and neutrophils have receptors for C3b and can
bind the C3b-coated cell or particle preparatory to
phagocytosis.
This effect qualifies C3b as an opsonin
C3a, the small fragment is released into the surrounding fluids.
It can bind to receptors on basophils and mast cells triggering
them to release their vasoactive contents (e.g., histamine).
Because of the role of these materials in anaphylaxis, C3a is
called an anaphylatoxin.

14. A single C3 convertase molecule can generate over 200
molecules of C3b, resulting in tremendous amplification at
this step of the sequence.
Many C3b molecules bind to the microbial surface.
A labile internal thioester bond in C3 is activated as C3b is
formed, allowing the C3b fragment to bind to free hydroxyl
or amino groups on the cell membrane.

17. C5a is the most anaphylatoxine.
C5b initiate the assembly of the terminal complement
component.
C5b, which serves as the anchor for the assembly of a single
molecule each of
•C6
•C7 and
•C8
The resulting complex C5b•6•7•8 guides the polymerization of
as many as 18 molecules of C9 into a tube inserted into the lipid
bilayer of the plasma membrane. This tube forms a channel
allowing the passage of ions and small molecules. Water enters
the cell by osmosis and the cell lyses

20. The complement system can also be triggered without antigen-antibody
complexes.
Hydrolysis of C3 initiates alternative pathway. C3 is abundant in
plasma.
C3b is produced at a significant rate by spontaneous cleavage
(trickover) through spontaneous hydrolysis of the thioester in the C3 to
form C3b(H2O), allowing binding of factor B.
factor D plasma protease cleave factor B (Bb $ Ba) to form
C3b(H2O)Bb a fluid-phase C3 convertase, and can cleave C3 to C3a
and C3b.
This results in the formation of alternative pathway C3 convertase,
C3bBb.

23. C3 convertase enzyme is stabilized by properdin or factor P.

26. INFLAMMATION
many of the released fragments help develop an inflammatory
response.
C3a, C4a, C5a- anaphylotoxins bind to receptors on mast cells
and basophils; degranulation, smooth muscle contraction; capillary
dilation; fluid influx.
C5a is also effective chemoattractants that initiate accumulation
of complement and phagocytic cells to the site of infection or
antigen-presenting cells to lymph nodes. C5a play key role in
increasing migration and adherence of neutrophils and monocytes
to vessels walls

28. Regulation of complement system
Because it is nonspecific, several regulatory mechanisms are
involved (otherwise there would be a lot of “collateral
damage”).
Many components are very labile.
Many regulatory proteins block activity through binding to
target.