DEVU SYAM

COORDINATION OF CLASSICAL AND

ALTERNATIVE METHOD OF COMPLEMENT

SYSTEM

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.

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.

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

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.

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

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.

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 canbind the C3b-coated cell or particle preparatory tophagocytosis.

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 triggeringthem to release their vasoactive contents (e.g., histamine).Because of the role of these materials in anaphylaxis, C3a iscalled an anaphylatoxin.

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.

C5a is the most anaphylatoxine.

C5b initiate the assembly of the terminal complementcomponent.

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

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.

C3 convertase enzyme is stabilized by properdin or factor P.

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

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.