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The Complement System

060525

沈

弘

德

台北榮總教研部

Innate and adaptive immunity

Cytokines
APCs
DCs
ADCC

Abbas AK & Lichtman AH
...
2003

Types of adaptive immunity

(CD4+)

(CD8+)

Abbas AK & Lichtman AH
...
2003

The differentiation and functions of TH1 and TH2 subsets
of CD4+ helper T lymphocytes

IL-12

IL-4

Abbas AK & Lichtman AH
...
2003

Opsonization
- Deposition of opsonins on an antigen, thereby
promoting a stable adhesive contact with an
appropriate phagocytic cell
...
g
...


Schematic representation of the roles of C3b and
antibody in opsonization
...
, Immunology 2003

Complement
• 1890

Jules Bordet, Paul Ehrlich

• Bacteriolytic activity requires two different substances
...

• Evolved as part of the innate immune system
...


Kuby J et al
...


• Most circulate in the serum in functionally inactive forms
as proenzymes (zymogens)
...

• Peptide fragments formed by activation of a component
- the larger fragments: bind to the target near the site of activation
- the smaller fragments: local inflammation
• Complexes with enzymatic activity are designated by
a bar over the number or symbol
...


Kuby J et al
...


Abbas AK & Lichtman AH
...
2003

Structure of the C1 macromolecular complex
C1q molecule

(b)

Kuby J et al
...


Each C1 molecule must bind by its
C1q globular heads to at least two
Fc sites for a stable C1-Ab interaction
to occur
...
Cellular and Molecular Immunology 5th ed
...
, Immunology 2003

Electron micrographs of IgM antiflagellum antibody bound to
flagella, showing the planar form (c) and stape form (d)

(c)

(d)

Kuby J et al
...

C1q binds antigen-bound antibody
...


Kuby J et al
...

C1s cleaves C4 and C2
...
C4
binds the surface near C1 and C2 binds C4, forming C3 convertase
...
, Immunology 2003

Schematic diagram of intermediates in the classical
pathway of complement activation (3)
...
Some combine with
C3 convertase to form C5 convertase
...


Kuby J et al
...


Kuby J et al
...


Cleavage of C4 exposes a highly
reactive thioester bond on the C4b
molecule that allows it to bind
covalently to molecules in the
immediate vicinity of its site of
activation
...

Abbas AK & Lichtman AH
...
2003

_____

Hydrolysis of C3 by C3 convertase C4b2a
(a labile internal
thioester bond)

The membranes of most mammalian cells have high levels of sialic acid,
which contributes to the rapid inactivation of bound C3b molecules on host cells;
consequently this binding rarely leads to further reactions on the host cell membrane
...
, Immunology 2003

Overview of the complement activation pathways
...
, Immunology 2003

The alternative pathway
• does not depend on antibody for its activation
• being initiated in most cases by cell-surface
constituents that are foreign to the host

Schematic diagram of intermediates in the formation of bound C5b by the
alternative pathway of complement activation
1
...

b
2
...
Cleavage generates
C3bBb, which has C3 convertase activity
...
Binding of properdin stabilizes convertase
...
Convertase generates C3b; some binds
to C3 convertase activating C5’ convertase
...

*More than 2 x 106 molecules of C3b can be deposited on an
antigenic surface in less than 5 minutes
...
, Immunology 2003

Schematic representation of the roles of C3b and
antibody in opsonization
...
, Immunology 2003

Overview of the complement activation pathways
...
, Immunology 2003

The mannose-binding lectin pathway
• does not depend on antibody for its activation
• originates with host proteins (MBL) binding
microbial surfaces

The mannose-binding lectin (MBL) pathway
-

MBL, an acute phase protein, binds to mannose residues, and to
certain other sugars on many pathogens
...

- When the MBL complex binds to a pathogen surface, MASP-2
is activated to cleave C4 and C2
...

- The MBL pathway is of importance in innate host defense
mechanisms in early childhood
...


*MBL is an acute phase protein
produced in inflammatory responses
...


On vertebrate cells, these
mannose residues are covered by
other sugar groups, especially by
sialic acid while avoiding
complement activation on
host cell surfaces
...


Kuby J et al
...

The C3b component of C5 convertase binds C5, permitting C4b2a
to cleave C5
...

The C5b component becomes
inactive within 2 minutes unless
C6 binds to it and stabilizes
its activity
...
, Immunology 2003

Schematic diagram of intermediates in the classical
pathway of complement activation (5)
...


The MAC complex forms a large channel
through the membrane of the target cell,
enabling ions and small molecules to
diffuse freely across the membrane
...
, Immunology 2003

Late steps of complement activation and formation of the
MAC (membrane attack complex)

(10-17 molecules)

Abbas AK & Lichtman AH
...
2003

(a)

poly-C9 complex

(b) Complement-induced lesions on the
membrane of a red blood cell

Kuby J et al
...


Kuby J et al
...


Kuby J et al
...
, Immunology 2003

Schematic representation of the roles
of C3b and antibody in opsonization
...
, Immunology 2003

Opsonins: C3b, C4b, iC3b

CR1: 5,000/resting phagocytes
50,000/activated cells

Clearance of circulating immune complexes
Erythrocytes account for about 90% of the CR1 in the blood
(~ 5 x 102/RBC)
...


Defects in complement activation
↓
Failure to clear circulating immune complexes
↓
Deposition in blood vessel walls & tissues
↓
(eg
...
, Immunology 2003

Scanning electron micrographs of E
...


(a)

(b)

(c)
Kuby J et al
...
, Immunology 2003

The complement system neutralizes viral infectivity
• formation of larger viral aggregates
- reduce the net number of infectious viral particles
• a coating of Ab and/or complement to the surface
of a viral particle
- blocking attachment to susceptible host cells
- facilitate binding of the viral particle to cells
possessing Fc or CR1
- lysing most enveloped viruses

Electron micrographs of negatively stained preparations of EB virus
(a)

(b)

Control
without
antibody

(c)

Antibodycoated
particles

Particles coated with
antibody and complement
Kuby J et al
...

• A series of regulatory proteins
(regulators of complement activation [RCA]
gene cluster - chromosome 1 in humans)
...
, Immunology 2003

Regulation of the complement system by regulatory proteins (1)
1
...


2
...


(serine protease inhibitor)

3
...

(serine
protease)

4
...


5
...


Kuby J et al
...
, Immunology 2003

Regulation of the complement system by regulatory proteins (2)
C3 convertases are dissociated by C4bBP, CR1, Factor H, and decayaccelerating Factor (DAF or CD55)
...
, Immunology 2003

Regulation of the complement system by regulatory proteins (3)
1
...


2
...


Kuby J et al
...
, Immunology 2003

Complement-binding receptors
• Many

of the biological activities of the complement system
depend on the binding of complement fragments to
complement receptors, which are expressed by various cells
...
, Immunology 2003

Role of complement in B cell activation

104 molecules of mIgM had to be engaged by
antigen for B-cell activation to occur when the
co-receptor was not involved
...


Abbas AK & Lichtman AH
...
2003

NK cells use a variety of receptors to identify
target cells to be killed

Doan et al
...


•

The defect identified in PNH lies early in the path to formation
of a GPI anchor and residues in the pig-a gene
...
Complement deficiencies
1
...
deficiencies in components of the alternative pathway
(properdin, factor D, C3)
3
...
deficiencies in complement regulatory proteins
(abnormal complement activation)
5
...
Pathologic effects of a normal complement system
- The immune complexes produced in autoimmune diseases
may bind to vascular endothelium and kidney glomeruli
and activate complement (MAC generation)
...

- Some of the late complement proteins may activate
prothrombinases in the circulation that initiate thrombosis
...

- Crry may block maternal alloantibody-mediated damage
through the classical pathway of complement activation
...


Summary
1
...

2
...

3
...

4
...


5
...
These pathways are initiated by reaction of
complement proteins with surface molecules of
microorganisms
...
In addition to its key role in cell lysis, the complement system
mediates opsonization of bacteria, activation of inflammation,
and clearance of immune complexes
...
Interactions of complement proteins and protein fragments
with receptors on cells of the immune system control both
innate and acquired immune responses
...
Because of its ability to damage the host organism, the
complement system requires complex passive and
active regulatory mechanisms
...
Clinical consequences of inherited complement
deficiencies range from increases in susceptibility to
infection to tissue damage caused by immune
complexes

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