The complement system:
Dr. Alaa.s. Alattabi
[Link].B F.I.C.M.S
path/immunity &
microbiology
Behavioral objectives:
1-over view on complement
2- Pathways of complement systems
3- Major biological activities of complement
system
4- Regulation of complement system:
The complement system:
• The complement system is a collection of
circulating and cell membrane proteins that in
normal condition are functionally inactive.
• once activated play important roles in host
defense against microbes and in antibody-
mediated tissue injury .
• The term complement refers to ability of these
proteins to assist ,or complete, the anti
microbial activity of anti bodies.
• That are synthesized predominantly by liver
cells but blood monocyte ,tissue
macrophage and other cells cell types are also
sources of various complement components
at sites of infections and/or inflammation.
• The complement activity is destroyed
(inactivated) by heating serum at 56 degrees C
for 30 minutes .The complement works as a
cascade system.
– Cascade is when one reaction triggers another
reaction which trigger others and so on. These
types of systems can grow exponentially very fast.
Pathways of complement systems:
1-the classical pathway.
2-the alternative pathway.
3-the lectin pathway.
The Membrane Attack Complex
C5a
C5
70-100 Å
C6 C5b C7
C9
C9
C8 C9 C9
C9
C9C9
C9C9
C9
C9
The classical pathway:
it was named classical because it was discovered
characterized first.
Activation:
The classical pathway is activated normally by
complement fixing Abs (Abs that bind to
complement), which are in Ag-Ab complexes
or in which the Ab(IgM,IgG1,IgG2,IgG3,but
IgG4 is not fix complement ) IgM more
efficient than IgG)
Once Ig fix complement activate C1 which compose of
three protein (C1qr2s2),which is cleaved to active
protein C1s¯ which cleaves C2,C4to form complex
C4b2a(C3convertase)which in turn cleaves C3 molecule
into two fragments C3a and C3b ,C3b form complex
with C4b2a to form C4b2a3b(C5 convertase )which
cleave C5 to C5a and C5 b which is bind to C6 and C7 to
form complex that interact with C8 and C9 to produce
membrane attack complex.
•
Components of the Classical
Pathway
C3 C4
C1 complex
Classical Pathway
Generation of C3-convertase
Classical Pathway
Generation of C3-convertase
C4b2a is C3 convertase
C4b
Classical Pathway
Generation of C3-convertase
C4b2a is C3 convertase
C4b
Classical Pathway
Generation of C5-convertase
C4b2a3b is C5 convertase; it leads into the
Membrane Attack Pathway
C3 b
C4b
The alternative pathway:
Many substances like bacterial polysaccharide
(endotoxin), cobra venom factor, fungal cell
walls , viral envelope and IgG ,IgA, and IgE in
complex initiate the pathway by binding C3
and factor B to form complex that is cleaves by
factorD to produce C3bBb( stabilize by
properdin )which acts as C3convertase to
produce C3b.
Components of the
alternative pathway
C3
Spontaneous C3 activation
Generation of C3 convertase
b
C3 i C3 b
C3iBb complex has a very short half life
C3-activation
the amplification loop
If spontaneously-generated C3b
is not degraded
C3b b C3 b
C3-activation
the amplification loop
C3 b b C3b
C3b
C3-activation
the amplification loop
C3b C3b C3b
C3b
The lectin pathway:
Mannan-binding-lectin(MBL)bind to
Carbohydrate residues on surface of a cell or
pathogen. The active complex form by this
association cause cleavage and activation of
C4 and C2.
Components of mannose-binding
lectin pathway
MBL MASP1
Mannose-binding lectin pathway
C4b2a is C3 convertase; it will lead to the
generation of C5 convertase
MASP1
MBL
Note
The classical pathway is important in acquired
immunity because it is required immune complex
(Ag-Ab) for activations while the alternative
pathway and lectin pathway are important in
innate immunity because are not required (Ag-
Ab) for activations. The final steps in all pathway
is formation MAC which make holes and destroys
the membrane of target cell.
Major biological activities of complement
system:
1- opsonization:
Microbial cells, Ag-Ab complexes and other
particles are phagocytose more efficiently in
the presence of C3b due to presence C3b
receptor (CR1) on the phagocytic cells.
2. cytolysis:
Insertion of MAC of complement system into the cell surface
lead to killing or lysis of many types of cells(RBC , bacteria,
tumor cells,….) by direct mechanisms involving formation
punching holes in their membranes.
3-anaphlatoxin :
C3a and C5a act as anaphlatoxins which is small
peptides that cause smooth muscle
contraction,, degranulation of mast cell and
basophiles .C5a most potent than C3a.
4- chemotaxis:
C5a stimulates the movement of nutrophils and
monocytes to the sites of antigen depositions.
5- clearance of immune complex: •
Complement generates C3b that may be
deposited on immune complexes .interaction
of receptor (CR1) present on phagocytes ,
interact with free C3b molecules on the
immune complexes inducing phagocytosis of
the complexes.
Regulation of complement system:
Strict regulatory control of this system is of
critical importance to prevent complement
mediated destruction of host own tissues
.fluid –phase proteins and cell- bound proteins
have evolved to regulate complement
activation:
Fluid phase proteins :
1-C1 inhibitor regulates the classical pathway.
2- Factor H regulate the alternative pathway by
block C3 convertase formation.
3-Factor I regulate classical, alternative and lectin
path way by cleave C4b orC3b.
4-S protein regulate by prevent C5b67 insertion
into cell membrane.
Cell bound proteins:
1-Decay accelerating factor(DAF CD55):regulate
C3 andC5 convertase.
2-Homologous restriction factor (HRF) (CD59)
regulates MAC formation by binding to
C5b678 on autologous cells blocking binding
of C9.
Refrence
Kuby immunology
Review of medical microbiology and
immunology.
USMLE step 1 kaplan.
question?
• Regarding the complement pathway, which one of the following is
the most accurate?
• (A) C3 convertase protects normal cells from lysis by complement.
• (B) C3a is a decay-accelerating factor and causes the rapid decay
and death of bacteria.
• (C) In general, gram-positive bacteria are more likely to be killed by
complement than gram-negative bacteria.
• (D) The membrane attack complex is formed as a result of activation
of the classic pathway but not by activation of the alternative
pathway.
• (E) The first time a person is exposed to a microorganism, the
alternative pathway of complement is more likely to be activated
than the classic pathway
Thank you