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The Complement system
The complement system is an alarm and a
weapon against infection, especially
bacterial infection.
 activated directly by bacteria and bacterial
products binding to sugars on the
bacterial cell surface, or by complexes
of antibody and antigen

The complement system

consists of a series of heat-labile serum proteins that are
activated in turn.

The components normally exist as soluble inactive
precursors; once activated, a complement component may
then act as an enzyme cleaves several molecules of the next
component in the sequence (rather like the clotting cascade).

Each precursor is cleaved into two or more fragments.

The major fragment has two biologically active sites:
-one for binding to cell membranes or the triggering
complex and
-other for enzymatic cleavage of the next
complement component
Complement pathways
The two complement pathways differs but both
form C3 and C5 converses and ultimately
generate common membrane –attack complex
(MAC)
 1. Alternative pathway (properdin system)
most commonly is activated by microbial
surface and cell-surface components (eg LPS)
generate earl, innate response that dies not
require antibody for activation
 2. Classical pathway: is activated primarily by
antigen antibody complexes containing IgM or
IgG. This constitute a major effect mechanism of
Humoral Immunity.

Biological activities of Complement Product
1. Membrane attack complex (MAC) act as a
molecule drill to puncture cell membranes
a) Formation of MAC begins with cleavage of
C5by C5 convetases formed in both
pathway.
b) Sequential additional of C6.7 and C8 to
C5byiles C5b678 a complex that inserts
stably into cell membranes but has limited
cytotoxic ability
c) binding of multiple C9 molecules produces
ahighly cytotoxic MAC (C5b6789) that
forms holes in the cell membrane killing the
cell.
2. Complement cleavage products promote
inflammatory response, opsonization and
other effect. Some of the effect depend the
presence complement receptors on specific
target cells.
Regulation of complement
CI inhibitor: prevent inappropriate
activation of the classical pathway
 Inactivation of C3 and C5 convertases
include decal: accelerating factor (DAF)
factor H, and factor I.
 Anaphylotoxin inhibitor blocks
anaphylactic activity of C3a and C5a.

The complement system
Control of the sequence involves
spontaneous decay of any expose
attachment sites and specific inactivation
by complement inhibitors.
 Minor fragments (usually prefixed
‘a’) generated by cleavage of
components have important biological
properties in the fluid phase, such as the
chemotactic activity of C5a.

Complement functions
• Host benefit:
–
–
–
–
–
–
opsonization to enhance phagocytosis
phagocyte attraction and activation
lysis of bacteria and infected cells
regulation of antibody responses
clearance of immune complexes
clearance of apoptotic cells
• Host detriment:
– Inflammation, anaphylaxis
The complement system
The major purpose of the complement pathways
is to provide a means of removing or destroying
antigen, regardless of whether or not it has
become coated with antibody
 The key function of complement is probably the
opsonization of microorganisms and
immune complexes; microorganisms coated
(i.e. opsonized) with immunoglobulin and/or
complement are more easily recognized by
macrophages and more readily bound and
phagocytosed through IgG:
 Fc and C3b receptors

Pathways of complement
activation
CLASSICAL
PATHWAY
LECTIN
PATHWAY
ALTERNATIVE
PATHWAY
antibody
independent
antibody
Dependent
Activation of C3 and
generation of C5 convertase
activation
of C5
LYTIC ATTACK
PATHWAY
The complement system

Similarly, immune complexes are opsonized by their activation of
the classical complement pathway
 Individuals who lack one of the classical pathway components suffer
from immune complex diseases .

Soluble complexes are transported in the circulation from
the inflammatory site by erythrocytes bearing CR1 which bind
to the activated C3 (C3b) in the immune complex.

Once in the spleen or liver, these complexes are removed from the
red cells, which are then recycled
role of C3 in complement activation is underlined by
patients with a deficiency of C3, who cannot opsonize
pathogens or immune complexes, predisposing them to
bacterial infection as well as immune complex diseases.

Complement…
Activation by either pathway initiates a cascade of
proteolytic events that cleave the proteins into “a”
and “b” subunits.
The “a” subunits (C3a, C5a)
• attract (chemotactic factors) phagocytic and inflammatory
cells to the site
• Allow access to soluble molecules and cells by increasing
vascular permeability (anaphylactic C3a, C4a, C5a)
• activate responses.
The “b” subunits are bigger
• bind to the agent to promote their phagocytosis (opsonization)
and elimination
• build a molecular drill that can directly kill the infecting agent
classical pathway


The first to be described.
It is activated by a number of substances, the
most widely recognized being antigen–antibody
complexes where the antibody is either IgM or
IgG .

The reaction of IgM or IgG with its antigen causes
a conformational change in the Fc region of the
antibody to reveal a binding site for the first
component in the classical pathway, C1q.

IgA, IgD and IgE do not activate the
classical pathway
classical pathway…

Once C1q is activated, C1r and C1s are sequentially bound to
generate enzyme activity (C1 esterase) for C4 and C2 ,
splitting both molecules into “a” and “b” fragments.

The complex C4b2b is the classical pathway C3 convertase.
Other fragments released are C4a, C2a and a vasoactive peptide
released from C2.

C4b2b cleaves C3 into two fragments, C3a possessing
anaphylotoxic and chemotactic activity and C3b that binds to the
initiating complex and promotes many of the biological properties
of complement.

The C4b2b3b complex so generated is an enzyme, C5
convertase, which initiates the final lytic pathway (the ‘attack’
sequence).
Alternate Pathway

The alternate pathway is activated directly by bacterial cell surfaces and their components
(e.g., endotoxin, microbial polysaccharides), as well as other factors.

This pathway can be activated before the establishment of an
immune response to the infecting bacteria because it does not
depend on antibody and does not involve the early complement
components (C1, C2, and C4).

The initial activation of the alternate pathway is mediated by
properdin factor B binding to C3b and then with properdin factor D,
which splits factor B in the complex to yield the Bb active fragment
that remains linked to C3b (activation unit).

The C3b sticks to the cell surface and anchors the complex.

The complement cascade then continues in a manner analogous to
the classical pathway
Lectin Pathway

The lectin pathway is also a bacterial and fungal defense
mechanism.

Mannose-binding protein is a large serum protein that
binds to nonreduced mannose, frucose, and glucosamine on
bacterial, fungal, and other cell surfaces.

Mannose-binding protein resembles and replaces the C1q
component of the classical pathways and on binding to
bacterial surfaces, activates the cleavage of the mannose
binding protein–associated serine protease.

Mannose binding protein–associated serine protease cleaves
the C4 and C2 components to produce the C3 convertase,
the junction point of the complement cascade.
The complement system….

The three activation pathways of
complement coalesce at a common
junction point, the activation of the C3
component
Membrane Attack Complex

The terminal stage of the classical pathway involves creation of the
membrane attack complex (MAC), which is also called the
lytic unit.

The five terminal complement proteins (C5 through C9)
assemble into an MAC on target cell membranes to mediate injury.
Initiation of the MAC assembly begins with C5 cleavage into C5a
and C5b fragments.




A (C5b,6,7,8)1(C9)n complex forms and drills a hole in the
membrane, leading to apoptosis or the hypotonic lysis of cells.
Neisseria bacteria are very sensitive to this manner of killing, while
gram-positive bacteria are relatively insensitive.
The C9 component is similar to perforin, which is produced by
cytolytic T cells and NK cells
Biologic Activities of Complement
Components

Cleavage of the C3 and C5 components produces important
factors that enhance clearance of the infectious agent by
promoting access to the infection site and reactions.

C3b is an opsonin that promotes clearance of bacteria by
binding directly to the cell membrane to make the cell more
attractive to phagocytic cells, such as neutrophils and macrophages,
which have receptors for C3b.

C3b can be cleaved further to generate C3d,which is an activator
of B lymphocytes.

Complement fragments C3a, C4a, and C5a serve as powerful
anaphylatoxins that stimulate mast cells to release histamine and
tumor necrosis factor-α (TNF-α), which enhances vascular
permeability and smooth muscle contraction
Bio.. Activities of Complement ……
C3a and C5a also act as attractants (chemotactic
factors) for neutrophils and macrophages by increasing
adhesion protein expression of the capillary lining near the
infection.
 These proteins are powerful promoters of inflammatory
reactions.
 For many infections, these responses provide the major
antimicrobial function of the complement system.


The complement system also interacts with the clotting
cascade. Activated coagulation factors can cleave C5a, and a
protease of the lectin pathway can cleave prothrombin to
result in production of fibrin and activation of the clotting
cascade.
Regulation of Complement Activation
Humans have several mechanisms for preventing
generation of the C3 convertase to protect against
inappropriate complement activation.
These include C1 inhibitor, C4 binding protein, factor H,
factor I, and the cell surface proteins, which are decayaccelerating factor (DAF) and membrane cofactor protein.
 In addition, CD59 (protectin) prevents formation of the
MAC.
 Most infectious agents lack these protective mechanisms and
remain susceptible to complement.


A genetic deficiency in these protection systems can result in
disease.
control of any cascade sequence is
extremely important

The control of any cascade sequence is
extremely important, particularly when it
results in the production of potentially selfdamaging mediators of inflammation.

The complement pathway is controlled by three
mechanisms

These mechanisms ensure that the potentially
harmful effects of complement activation remain
confined to the initiating antigen without
damaging autologous (host) cells.