Course: ImmunologyLecturer: Dr. Weam Saad
Lecture: Complement System
The Complement SystemThis system includes over than 20 proenzymes (glycoproteins)
components inactive state found in the blood. When the complement
components are activated, serial, rapid cascad events occur. Historically, the
term complement (C) was used to a heat -labile seru m component able to
lyse bacteria and its activity is destroyed (or inactivated) by heating serum
at 56 C ᵒ for 30 min.
1. Synthesis and metabolism of complement components.Complement glycoproteins are synthesized by liver cells
(hepatocytes) and macrophages and many other cells (e.g. gut
epithelial cells). All normal individuals have complement
components in their blood. The synthetic rates for the complement
glycoproteins i ncrease when complement is activated and consumed.
2. Activation of the complement system.This system can be activated by:
a) Antigen -antibody complexes containing IgG or IgM activate
complement by the classical pathway that starts with C1
b) Membranes and cell walls of microbial organisms (e.g.
Lipopolyccharides layer [LPS] of gram –ve bacteria) and many other
substances can activate complement by the alternative pathway.
c) Proteolytic enzymes released either from microbes or from host cells
du ring immune defense mechanisms , can also activate the
complement system by breaking down critical components.
3. The complement cascade induction. When the complement componentis activated, it continues activating the next component by:
or becomes bound to an activated component or complex of
4. Function of the complement system:The complement system has role in both specific and non -specific
immunity . The functions of the complement system are:
1) Binding and neutralizing foreign substances that activate it.
2) Induce the ingestion of complement -coated substances by phagocytic
cells (help in the opsonization process when C3b and C4b linked
with the surface of microorganisms and attach to Complement
receptor on ph agocytic cells then induce phagocytosis).
3) Activation of many cells including PMNs cells and macrophages .
4) Have roles in regulation of antibody responses.
5) Clearance of immune complexes and apoptotic cells.
6) Have roles in inflammation and tissue damage.
7) Some components (C3a, C4a and C5a), have role in Anaphylaxis (a
dangerous case of type I hypersensitivity), hence they are called
8) Some complement components acts as chemotactic factors e.g. C5a.
5. Complement Pathways(The sequence of complement components activation)
A. Classical Pathway:1) C1activation
C1, a multi -subunit protein containing three different proteins (C1q,
C1r and C1s), binds to the Fc region of IgG and IgM antibody
molecules that have interacted with antigen ( it does not bind to free
Ab) , binding requires calcium and magnesium ions. The binding of
C1q results in the activation of C1r which in turn activates C1s. The
result is the formation of an activated “C1qrs”, which is an enzyme
that cleaves C4 into two fr agments C4a and C4b.
2) C4 and C2 activation (generation of C3 convertase).The C4b fragment will stay (usually binds to the binds to the
membrane of bacteria) and the C4a fragment is released. Activated
“C1qrs” also cleaves C2 into C2a and C2b. C2a binds to the
membrane in association with C4b, and C2b is released. The resulti ng
C4bC2a complex is a C3 convertase (acts as enzyme), which cleaves
C3 into C3a and C3b.
3) C3 activation (generation of C5 convertase):C3b binds to the membrane in association with C4b and C2a, and
C3a is released (which acts as anaphylaxis protein and a chemotactic
factor). The resulting C4bC2aC3b is a C5 convertase. The generation
of C5 convertase is the end of the classical pathway. Many products of
the classical pathway have biological activities that support the host
defenses as in the table (1).
B. Lectin PathwayThe lectin pathway is very similar to the classical pathway. It starts with the
binding of mannose -binding lec tin (MBL) to bacterial surfaces. Many serial
events happens resulting C4bC2aC3b formation, which is the C5
convertase . The generation of C5 convertase is the end of the lectin
Table (1) Biological Activity of classical pathway productsComponent Biological Activity
C2b Prokinin ; have role in kinin system, causes edema
Anaphylotoxin ; can activate basophils and mast cells to
degranulate resulting in increased vascular permeability and
contraction of smooth muscle cells, which may lead to
C3b Opsonin ; induces phagocytosis by binding to complement
receptors. Activation of phagocytic cells
C4a Anaphylotoxin (weaker than C3a)
C4b Opsonin ; induces phagocytosis by binding to complement
C.Alternative PathwayActivation of this pathway starts spontaneously and C3 will be cleaved
by the help of Factor B, Factor D, properdin and Mg +2 ions. Cleavage of
C3will release C3a (which acts as anaphylaxis protein) and C3b. when C3b
is formed, Factor B will bind to it and will be cleaved by Factor D. The
resulting C3bBb complex is a C5 convertase and this is the end of the
alternative pathway. Generation of C3b is essential for the activation of the
The component C3b can be formed due to :
a. During normal C3 turnover in blood
b. In the prese nce of bacterial proteases
c. During classical pathway activation (for this reason activation of the
classical pathway is always associated with activation of the
alternative pathway which generating more activated C3).
The alternative pathway of complement activation is importantespecially during the early phase of an infection, when the concentrations of
specific antibody are very low and classical pathw ay activation is limitedand in the presence of large numbers of b acteria. The alternative pathway
provides the non -specific resistance against infection without the need to
antibodies and hence provides a first line of defense against a number of
D. Membrane attack complex Formation :Lytic pathw ay is the end of all the complement system pathways, C5
convertase from all pathways (classical, lectin or alternative) cleaves C5
into C5a and C5b. Then C5b rapidly binds with C6, C7, C8 and C9
molecules . Pore s will be formed in the membrane and lysis occurs due to
physical damage to the membrane. The complex of C5bC6C7C8C9 is
called the membrane attack complex (MAC).
C5a formed in the lytic pathway is the most active anaphylotoxin . It is a
chemotactic factor for neutrophils and stimulates the respiratory burst in
them and it stimulates inflammatory cytokine production by macrophages.
Complement deficiencies and diseasesComponent Disease Mechanis m
C1, C2, C4 SLE
Opsonization of immune complexes help keep
them soluble, deficiency results in increased
precipitation in tissues and inflammation
Factors B or D
pyogenic (pus -
Not enough opsonization of bacteria
C3 Susceptibility to
Lack of opsonization and inability to utilize
the membrane attack pathway
C5, C6, C7 C8,
Inability to attack the outer membrane of
Gram -negative bacteria