COMPLEMENT
Complement is a system of plasma proteins that interact with bound antibodies and surface
receptors to aid the elimination of pathogens.
In the humoral immune response, the binding of IgM or most classes of IgG to a pathogen
activates the complement cascade.
Complement is also an important part of innate immunity.
The entire complement system consists of 17 plasma proteins whose designations conform to 2
conventions:
1. The classical pathway components: Plasma proteins responsible for the lysis of
cells that are coated with antibody specific to cell surface antigens. They are symbolised
with a capital C and a number designating the component, e.g. C1, C4, C2, C3, and C5
through to C9. They are activated by antibody binding to the antigen.
2. The Alternative pathway factors: which lead into a lytic terminal sequence without
a requirement for antibody, are denoted with a capital letter e.g. B, D, and P (Properdin).
A bar over a letter or number as in C and D indicates enzymatically active form of the protein.
Cleavage fragments are suffixed with lower case letters e,g. C3a and C3b with the suffix b
generally noting the larger of the two fragments. The alternative pathway can be activated when
a spontaneously activated complement component binds to the surface of a pathogen. The central
event of complement activation is the cleavage of C3.
There are three pathways for the cleavage of C3, leading to the activation of the effective
functions of complement.
3. The lectin pathway: is initiated by the binding of a serum lectin, to mannose-
containing proteins of carbohydrates on the bacteria or viruses.
The alternative pathway provides an amplification loop for the classical pathway of complement
activation because one of the activated components of the classical pathway can also initiate the
alternative pathway. The amplification mechanism comprised of alternative protein which
augments C3 cleavage once the initial C3b has been generated, and a final common effector
sequence which all the pathways activate after C3b generation.
The Classical Pathway for C3 Cleavage
There are 3 stages of classical pathway for C3 cleavage.
Recognition,
Enzymatic activation
Membrane Attack Complex – leading to death.
The Recognition
The Recognition unit is the C1 complex which is a complex of 3 different proteins C1q, C1 r and
C1s. The tri-molecular complex is held together by non-covalent forces. C1 fixation occurs when
the C1q subcomponent binds directly to immunoglobulin which has bound to its cognate antigen
on the surface of the cell. C1r and C1s do not bind on the immunoglobulin but are involved in the
fixation. C1q fixes to the CH2 domain of the IgG, C1r and C1s are activated in sequence still
attached to the C1q.
C1s splits a 6 K peptide from the N-terminal part of the α-chain of C 4 and release C4a into the
medium, leaving the larger fragment C4b in the fluid phase of the plasma. C4b is highly active
against C2 which has complexed with C4 b molecules in the presences of Mg 2+ ions. C4b binds to
the adjacent membrane and is split by C1 s, releasing C2a to the surrounding medium. The larger
C2b fragment joins with C4b to form C4b2b. C4b2b is the classical pathway enzyme, C3
convertase which splits C3 into C3a and C3b.
C3a: are Anaphylatoxins
Anaphylatoxins are small peptides released during complement activation which cause histamine
release from mast cells and smooth muscle contraction thereby mimicking anaphylatoxin
reactions. They also show chemotactic activity for Neutrophils, Polymorphonuclear Leucocytes
(Polymorphs), phagocytes, but relatively weakly.
C3b:
C3b molecules bind to C4b2b complex, to form C4b2b3b which is the classical pathway C5
convertase. C4b2b3b cleaves C5 from the ∝−¿chain of C5, a 15k peptide. C5 b fixation initiates
the events leading to formation of the membrane attack complex.
A membrane binding site is then released on the C5b.
C3b receptors are present on Neutrophils, Eosinophils, Monocytes and Macrophages, including
Kupfer cells, Monocytes and alverolar Macrophages. C3 b coated particles adhere to the
phagocytic cell and mediate immune adherence (opsonisation).
Biological Effects of C5a:
C5a is 10-20 times more active than C3a in these biological properties.
1. Smooth muscle contraction
2. Mast cell degranulation
3. Neutrophil activation
4. Marginal and chemotaxis of neutrophils
5. Smooth muscle is further affected by histamine released following mast cell
degranulation.
Membrane Attack Complex Formation:
The fixation of C5b to biological membranes is followed by sequential addition of 4 more
proteins C6, C7, C8 and C9. When they are fully assembled in the correct molar ratio, they form
the membrane attack complex. The C5b – 6 complex is hydrophilic, but the addition of C7
complex makes the complex stable. It interacts with C8 to yield C5b678 on the cell membrane,
which has some effect in disrupting the membrane, and also causes the polymerization of C9 to
form tubules traversing the membrane. The tube may remain associated with the C5b678 and is
referred to as a membrane attack complex (MAC). Disruption of the membrane by this structure
permits this free exchange of solute, responsible for cell lysis.
The Alternative Pathway:
C3b and Factor B combine to form C3b.B which is converted into an active C3 convertase called
[Link] by the release of the small fragment, Ba, through the action of the enzyme Factor D.
[Link] then converts more C3 to C3b. C3b then bind more Factor B, forming a feedback cycle
called the Amplification loop. The uptake of Factor B on to C3b occurs when C3b is bound to an
activator surface.
However, C3b in the fluid phase or attached to a non-activator will preferentially bind Factor H
and prevent C3b.B formatting.
The alternative pathway can be initiated when a spontaneously activated complement component
binds on to the surface of a pathogen. It provides an amplification loop for the classical pathway
of complement activation because one of the activated components of the classical pathway can
also initiate the alternative pathway.
The C3 Convertase occupies a central position in the complement cascade. Each pathway
generates a C3 convertase by a different route, but two of the three Convertases are identical, all
are homologous and have the same activity, so the principal effector molecules and the late
events are the same for all three pathways.
CLASSICAL LECTIN ALTERNATIVE
PATHWAY PATHWAY PATHWAY
Lectin binding to
Ag: Ab Complex Pathogen surfaces
pathogen surfaces
Complement Activation
Recruitment of Opsonisation of Killing of
Inflammatory cells pathogen Pathogens
SUMMARY OF THE ACTIONS OF COMPLEMENT AND ITS ROLE IN THE ACUTE
INFLAMMATORY REACTION:
Increased vascular permeability due to the actions of C3a and C5a on smooth muscle and mast
cells allows exudation of plasma protein. C3 facilitates both the localization of complexes in
germinal centres and the opsonisation and phagocytosis of bacteria. Neutrophils which are
attracted to the area of Inflammation by chemotaxis, phagocytose the opsonized microorganisms.
The membrane attack Complex C5-9 is responsible for the lysis of bacteria and other cells
recognized as foreign.
