The Complement
System
Andrew E Thompson MD FRCPC
Fellow in Rheumatology
University of British Columbia
Overview
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The complement system is part of the
innate immune system (vs adaptive)
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
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It is now known that it consists of over 30
proteins and contributes 3 g/L to overall
serum protein quantities
“Classical” Pathway
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Begins with antibody binding to a cell surface and ends
with the lysis of the cell
The proteins in this pathway are named C1-C9 (the order
they were discovered and not the order of the reaction)
When complement is activated it is split into two parts
– a – smaller of the two
– B – larger part and usually the active part (except with factor 2)
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Remember 3 Key Words
– ACTIVATION
– AMPLIFICATION
– ATTACK
“Classical Pathway”
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ACTIVATION
– C1q portion of C1 attaches to the Fc portion of
an antibody
– Only IgG and IgM can activate complement
– Once activated C1s is eventually cleaved which
activates C4 and C2
– C4b & C2a come together to form the C4b2a
which is the C3 convertase
– C3 convertase activates C3 to C3a and C3b
“Classical Pathway”
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ACTIVATION
– C3a binds to receptors on basophils and
mast cells triggering them to release
there vasoactive compounds (enhances
vasodilation and vasopermeability)
– C3a is called an anaphylatoxin
– C3b serves as an opsonin which
facilitates immune complex clearance
“Classical Pathway”
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AMPLIFICATION
– Each C1s creates many C4b and C2b
fragments
– Each C4bC2a creates many C3b (activated
C3)
– Each C3b goes on to create many Membrane
Attack Complexes
– Example
1 C1S makes 100 C4bC2b
 100 C4bC2b makes 10,000 C3b
 10,000 C3b makes 1,000,000 MAC
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“Classical Pathway”

ATTACK
– Most C3b serves an opsonin function
– Some C3b binds to C4bC2a to form the
C5 convertase C4bC2aC3b
– C5 convertase cleaves C5 leading to the
formation of the Membrane attack
Complex (C5-C6-C7-C8-C9)
– The MAC “punches holes” in cell walls
resulting in lysis
C5a is a:
C2
C4
C1q
C3
1. Potent anaphylatoxin
2. Chemoattractant for
neutrophils
4a
2a
2b
4b
C3a binds to receptors on
basophils and mast cells
triggering them to release
there vasoactive compounds
(enhances vasodilation and
vasopermeability) ANAPHYLATOXIN
C3a
C3b
C5
C5bC5a
C3-convertase
C5-Convertase
C7
C9
Classical
Pathway
C8
C6
“Alternative Pathway”

Requires no specific recognition of
antigen in order to cause activation
“Alternative Pathway”
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ACTIVATION
– Spontaneous conversion from C3 to C3b
occurs in body
– Normally, C3b is very short lived and
quickly inactivated by proteins on the
surface of the body’s own cell walls
– However, bacteria or other foreign
material may lack these surface proteins
allowing C3b to bind and stay active
“Alternative Pathway”
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AMPLIFICATION
– Factor B binds to C3b
– Factor B is then cleaved by factor D into
Ba and Bb
– C3bBb remains which acts as a C3
convertase (C3  C3a and C3b)
– C3bBbC3b is formed which acts as a C5
convertase
“Alternative Pathway”
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ATTACK
– C5 is cleaved to C5a and C5b
– C5b then starts the assembly of the
Membrane Attack Complex
C3a
C3
C3b
C3
C5
Anaphylatoxin
Alternative
Pathway
C3-Convertase
C5-Convertase
C7
C9
C8
C6
C3b
C3a
C5b C5aD
Bb
B Ba
Summary - Activation
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Complement can be activated by the binding
of antibody (Classical) or by the adherance
of C3b to foreign material (Alternative)
The two pathways converge at the
formation of the C5 convertase (C4b2a3b or
C3bBbC3b)
The final common pathway is the formation
of the membrane attack complex
Summary - Function
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Opsonization – C3b
Chemotaxis – C5a (attracts
neutrophils)
Increases vasodilation &
permeability of capillary beds via
mast cell and basophil activation – C3a
& C5a (Anaphylatoxins)
Cellular Lysis via the MAC
Laboratory Measures
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C3 – Quantitative measure (nephelometry)
C4 – Quantitative measure (nephelometry)
CH50
– Functional assay of entire Classical Pathway
– Measures the ability of the patients serum to
lyse 50% of a standard suspension of sheep
erythrocytes coated with rabbit antibody
– A low CH50 suggests either
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CONSUMPTION OF COMPLEMENT COMPONENTS
DEFICIENCY OF COMPLEMENT COMPONENTS
AH50
The Role of Complement in
the Rheumatic Diseases
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The Double Edged Sword!
Needed for proper handling of immune
complexes
Also mediates tissue damage, especially in
the setting of autoantibodies and excessive
immune complex formation
Just as the complement system can destroy
a microbe, it can lyse and erythrocyte,
phagocytose a platelet, or disrupt a
basement membrane
Autoimmunity and Inherited
Complement Deficiencies
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Inherited deficiencies of complement
components can result in autoimmunity,
especially SLE
– C1q deficiency – 90% have SLE
– C4 deficiency – 75-80% have SLE
– C2 deficiency – 10-40% have SLE
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Early age of onset, prominent cutaneous
manifestations, and presence of anti-Ro
antibodies are features suggestive of a
complement deficiency
Autoimmunity and Inherited
Complement Deficiencies
QUIZ TIME
 Q:How
Dendritic
CellsSLE
present
antigen
with
MHC Class I or MHC
does
form
with
complement
Class II?
 A:deficiencies?
MHC Class II – It is an APC (antigen presenting cell)
 Q: –
MHC
Classto
II molecules
present antigen
derived from
Failure
clear autoantigens
(apoptotic
cells)
intracellular or extracellular processes?
– Immature(e.g.
dendritic
cells
uptake the antigen in the
 A: Extra-cellular
apoptotic
cells)
 Q: MHC
Class II molecules
stimulatecytokines
CD4 or CD8causing
cells
presence
of inflammatory
them
 A: CD4 (IIx4=8, Ix8=8)
to mature into antigen presenting dendritic cells –
 Q: In this scenario with the APC being a dendritic cell – the CD4
Presents
to T-Cellwith is a Th1 or Th2?
T-lymphocyte
it interacts
 A: Th1
is chiefly involved
in cellular
immunity
Th2
– Autoreactive
B-Cells
take mediated
up antigen
fromand
apoptotic
is chiefly involved in humoral mediated immunity – Th2
cells and (with the help CD4+ Th2-Cells) transform
into plasma cells that secrete autoantibody
Indirect Laboratory uses of
Complement – Detection of
Immune Complexes
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C1q binding Assay
– Normally C1q has a very weak affinity for
monomeric IgG and IgM
– When IgG or IgM are part of an immune
complex the Fc portion undergoes a
conformational change
– This results in a much higher affinity for C1q
– This test is an ELISA which looks for immune
complexes in a patients serum capable of
binding C1q
Indirect Laboratory uses of
Complement – Detection of
Immune Complexes
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Raji Cell Preparation
– Raji cells are a human lymphoblastoid cell derived from a
patient with Burkitt’s lymphoma
– They are unique because
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They have surface receptors for C1q, C3b, C3bi, and C3d
Lack of surface immunoglobulin
Surface IgG receptors are low in number and avidity
– Therefore, immune complexes containing complement can
bind to surface receptors on Raji Cells!
– This can then help to detect immune complexes capable of
binding complement
– Sensitive test, however, warm reactive anti-lymphocyte
antibodies and anti-ds-DNA antibodies may cause false
positive results