2. The Functions of Complement
1. Lysis of cells, bacteria, and viruses – the major effector
of the humoral branch of the immune system
2. Opsonization, which promotes phagocytosis of
particulate Ags
3. Binding to specific complement receptors on cells of
the immune system, triggering specific cell functions,
inflammation, and secretion of immunoregulatory
molecules
4. Immune clearance, which removes immune complexes
from the circulation and deposits them in the spleen
and liver
3. Complement consists of more than 20 proteins present in plasma and on cell
surfaces that interact with each other to produce biologically active
inflammatory mediators that promote cell and tissue injury
Nomenclature:
a. the first component of complement
is named C1 (etc.)
other components are designated by
capital letters and
names: Factor B, Properidin
b. when cleaved: fragments of
complement components
are designated by small letters (e.g.
C3a and C3b)
C3
C3a
C3b
Factor B Ba + Bb
Factor H
Factor I
4. Complement Activation
complement activation involves 3 pathways which forms separate
homologous varients of C3 convertase
1. Classical Pathway – begins with the formation of Ag-Ab
complex
2. Alternative Pathway – is initiated by cell-surface
constituents that are foreign to
the host
– Ab-independent
3. Lectin Pathway – is activated by the binding of mannose-
binding lectin (MBL) to mannose
residues on glycoproteins or
carbohydrates on the surface of
microorganisms
– Ab-independent
5. C1 complex
C1 exists in blood serum as
a molecular complex
containing:
•6 molecules of C1q
•2 molecules of C1r
•2 molecules of C1s
•The constant regions of mu
chains (IgM) and some gamma
chains (IgG) contain a binding
site for C1q.
The first protein in the classical pathway is C1
6. • IgG
The C1 must bind to at
least two IgG molecules
that are close enough
together so that it can
bind to both of them at
the same time.
• IgM
The C1 must bind at
least 2 CH3 domains of
one IgM molecule to be
activated.
IgM is the best
complement activator
because it is a pentamer.
7. The building of a C3 activation
complex
• Once C1 is activated, it activates 2
other complement proteins, C4
and C2 by cutting them in half
• C4 is cleaved into C4a and C4b
• C2 is cleaved into C2a and C2b
• Both C4b and C2b bind together
on the surface of the bacteria
• C4a and C2a diffuse away
8. C3 Activation complex
• C4b and C2b bind
together on the surface
to form a C3 activation
complex
• The function of the C3
activation complex is to
activate C3 proteins.
– This is done by cleaving C3
into C3a and C3b
9. C3b
• Many C3b molecules are produced by
the C3 activation complex.
• The C3b bind to and coat the surface of
the bacteria.
• C3b is an opsonin
– Opsonins are molecules that bind both to
bacteria and phagocytes
– Opsonization increases phagocytosis by 1,000
fold.
Opsonins
Macrophages and neutrophils have receptors for C3b and can
bind the C3b-coated cell or particle preparatory to phagocytosis.
10. C3a
C3a increases the inflammatory response by binding
to mast cells and causing them to release histamine
This small fragment is released into the surrounding fluids. It can
bind to receptors on basophils and mast cells triggering them to
release their vasoactive contents (e.g., histamine). Because of the
role of these materials in anaphylaxis, C3a is called an
anaphylatoxin.
11. the C5 activation complex
• Eventially enough C3b is cleaved that the
surface of the bacteria begins to become
saturated with it.
• C2b and C4b which make up the C3 activation
complex has a slight affinity for C3b and C3b
binds to them
• When C3b binds to C2b and C4b it forms a
new complex referred to as the C5 activation
complex
12. The C5 activation complex
The C5 activation complex (C2b, C4b, C3b)
activates C5 proteins by cleaving them into
C5a and C5b
Many C5b proteins are produced by the
C5activation complex. These C5b begin to
coat the surface of the bacteria.
13. The function of C5a
C5a disperses away from the bacteria.
› Binds to mast cells and increases inflammation.
› Most powerful chemotactic factor known for leukocytes
14. MAC: a lytic complex of the terminal
components of the complement cascade,
including C5,6,7,8 and multiple copies of C9,
that forms in the membrane of target cells. The
MAC causes lethal ionic and osmotic changes
in cells.
Membrane Attack complex
26. The Lectin Pathway
Lectin: proteins that bind to a carbohydrate
MBL (mannose-binding lectin):
- an acute phase protein which binds to
mannose
residues on glycoproteins or carbohydrates on
the surface of microorganisms.
MASP-1 & MASP-2: MBL-associated serine protease
MB-lectin forms a complex with two protease : MBL
associated serine protease; MASP-1 and MASP-2
Closely homologous to C1r and C1s and activated to
cleave C4 and C2
27. MBL binds to mannose on glycoproteins
on the surface of microorganisms. Then MASPs
bind to it.
MASP-1MASP-1
MASP-2MASP-2
MASP = mannose associated serine protease
- MBL is induced during inflammatory
responses.
- Thus, the lectin pathway is Ab-independent.
It is
an important innate defense mechanism
comparable
to the alternative pathway, but utilizing the
elements
of the classical pathway, except for the C1
proteins
29. The alternative pathway
• The alternative pathway is part of the non-specific defense
because it does not need antibodies to initiate the
pathway.
- The activation of alternative pathway doesn’t need Ab; thus,
it is a component of the innate immune system.
- It is initiated by cell-surface constituents that are foreign
to the host, e.g., bacterial cell wall.
- C1, C4 and C2 are not involved in the alternative pathway.
- Four serum proteins, C3, factor B, factor D, and properdin,
are involved in this pathway.
31. C3 contains in unstable
thioester bond.
This unstable bond makesC3
subject to slow spontaneous
hydrolysis to C3b and C3a
The C3b is able to bind to
foreign surface antigens.
Mammalian cells contain
sialic acid which inactivates
C3b
Initiation of The Alternative pathway
32. Factor B
• C3b on the surface of a
foreign cells binds to
another plasma protein
called factor B
33. Factor D
• The binding of C3b to
factor B allows a protein
enzyme called Factor D
to cleave Factor B to Ba
and Bb.
• Factor Bb remains
bound to C3b while Ba
and Factor D disperse
away.
34. The C3 activation complex
• Properdin, also called factor P, binds to the C3bBb
complex to stabilize it.
• C3bBbP make up the C3 activation complex for the
alternative pathway
35. The C3 activation Complex
• The C3 activation
complex causes the
production of more
C3b.
• This allows the initial
steps of this pathway to
be repeated and
amplified
• 2X106 molecules can be
generated in 5 minutes
36. C5 activation complex
• When an additional C3b
binds to the C3 activation
complex it converts it into a
C5 activation complex.
• The C5 activation complex
cleaves C5 into C5a and
C5b.
• C5b begins the production
of the MAC.
41. 1. Cell lysis
The membrane-attack complex can lyse a broad spectrum
of cells:
G(-) bacteria
parasites
viruses
erythrocyte
nucleated cells (tumor cells)
Because the activation of alternative and lectin pathways is
Ab-independent, these pathways serve as important innate
immune defenses against infectious microorganisms.
Biological Effects Mediated by Complement
42. • anaphylatoxins: C3a and C5a: mast
cell degranulation
– smooth muscle contraction
– mast cell degranulation mediator
release (histamine, leukotrienes)
– vascular changes: dilation, increased
permeability (edema)
– C5a also leukocyte adhesion and chemotaxis
(recruitment)
• opsonization: C3b, C3bi, C3d: (binding to
complement receptors and enhanced
phagocytosis by neutrophils and macrophages)
• clearance of circulating immune
complexes
43. - Formation of larger viral aggregates reduces the
net number of infectious viral particles
- The deposits of Ab and complement on viral
particle neutralizes viral infectivity by blocking
attachment to susceptible host cells and facilitates
binding of the viral particle to cells possessing
FcR or CR1.
Viral neutralization
