COMPLEMENT SYSTEM
DR MUSARRAT
ZAHRA
LEARNING OBJECTIVES
Define complement system
Outline different types of pathways in complement system
Describe the functions of complement system
Functions of membrane attack complex
HISTORY
Research in complement started in 1890s when Jules
Bordet at the Institut Pasteur of Paris conducted
experiment using sheep antiserum.
He named those substances as
Alexins.
Paul Ehrlich coined the
e
tm
r complement.
INTRODUCTION
It is named “complement system” because it was first
identified as
a heat-labile component of serum that “complemented”
antibodies
in the killing of bacteria.
Consists of serum and cell surface proteins involved in
defense
against pathogens and tissue damage mediated by antibodies
The Complement system is the major effector of
humoral branch of immune system.
Functions of the
complement
system
Opsonisation
Chemotaxis
Cell lysis
Immune clearance
Activation of inflammatory response
The components of
complement
system
Over 30 serum and cell surface proteins:
- Complement components
(in serum inactive, activated sequentially as a cascade)
- Complement receptors
(cell surface, recognize activated components)
- Regulatory proteins of complement
(both in serum and cell surface, inhibit activated
components)
Components are designated by numbers (E.g. ; C1 – C9) or
latters (E.g. : Factor D).
They are mainly synthesized by hepatocytes
Also produced by blood monocytes, tissue macrophages and
epithelial cells of he gastrointestinal and genitourinary tract.
Complement proteins: Made as zymogens - activation by
cleavage.
Exampl C
e: 4
C4 C4
a b
a = smaller b= larger fragment.
fragment Diffusion remains bound to
& signaling microbe
Exception: C2a = large
C2: fragment C2b =
small fragment
Three pathways for
Complement
activation:
1. Classical Pathway
2. Alternative Pathway
3. Lectin or MBL Pathway
Pathways for activation require multiple
steps categorized as:
1. Recognition Unique proteins
2. Enzyme for 1st 2 steps
activation
common
3. Biological
proteins
THE CLASSICAL PATHWAY
Part of immune system
Relies on Ag – Ab complex to get
activated
The classical pathway is initiated by:
[Link] binding to the pathogen.
2. C1 proteins binds to the Fc of
Ab.
C1 Protein
C1q- 18 polypeptides
6 arms with globular heads-
Binds Fc on IgG or IgM to get
activated
2 C1r + 2 are activated
C1s
by activated
C1q.
Pathoge Pathoge
n n
Cleavage of C3 reveals a thioester bond
and it will bind to cell surface of
pathogen.
C3
b
C3b is an opsonin
microb
e
Opsonins are molecules
that bind both to
bacteria and
phagocytes
Opsonization
phagocytosis increases
by 1,000
C3b s attached
to microbial fold.
surface
C4b-2a-3b functions as the
classical C5 convertase:
FORMATION OF MEMBRANE ATTACK COMPLEX
C5
b
Cell
membrane
Pathoge
n
C
6
Cell
membrane
Pathoge
n
C
7
Cell
membrane
Pathoge
n
Cell
membrane
C
8
Cell
membrane
Pathoge
n
C
9
Cell
membrane
Pathoge
n
Cell
membrane
Pathoge
n
Cell
membrane
Pathoge
n
Cell
membrane
Pathoge
n
Cell
membrane
Pathoge
n
Cell
membrane
Pathoge
n
Cell
membrane
Pathoge
n
Functions of C3a
and C5a
Neutrophi
Granules l
containin
g
inflammat
o ry
agents
like
histamine
Macrophag
e
C3a and C5a increases the inflammatory response by binding to
mast cells and causing them to release histamine.
Most powerful chemotactic factor known for leukocytes.
The Alternative
Pathway
Also called as Properdin pathway
Part of innate immunity.
Antibody Independent.
The alternative pathway is slower
than h
te Classical pathway.
Molecules of C3 undergo cleavage at
continuous low level in normal plasma.
Activation of
Alternative
pathway
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
Factor
B
C3b on the surface of
a foreign cells binds
to another plasma
protein called factor
B
This binding of Factor
B results in the
exposure of a binding
site for another
enzyme called Factor
D
Factor
D
The binding of factor B
to C3b 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.
The complex C3bBb
B
is C3 convertase a
of alternative
pathway
Properdin-
Factor P
Stabilizes C3b-Bb so it may cleave more
C3.
May cleave over a million C3 molecules!
Protects Bb-C3b from inactivation
by complement control
C5
activation
C3b-C3b-Bb functions as the C5 convertase in
the alternative pathway.
MAC
formation
Lectin Binding
Pathway
Independent of antibodies.
Lectins are proteins that bind to specific cb
targets.
Activated by Mannose binding lectin (MBL) –
lectin h
tat binds to mannose residues on the
microbes.
MBL is similar to C1q in structure and function.
Activation of
lectin
pathway
First step is binding of Mannose
Binding Lectin (MBL) to mannose
residue on the surface of microbes.
To the MBL bound to microbe, MBL –
Associated Serine Proteases (MASP – 1
and MASP – 2) will bind.
MASP 1 and 2 is similar in structure
and function to C1s andC1r
This complex will cleave C4 and C2
Effector functions of
complement
system
1. Facilitates Opsonization :
Extremely important when pathogen
carries a
capsule.
[Link]
lysis
3. Immune complex
clearance
4. Inflammatory response and
chemotaxis
and
C3b
OVERVIEW