The Complement system

Dhruba Acharya
Lecturer/Immunologist
 The complement system
 A complex cascade consisting of at least 20 serum proteins,
which, once activated, acts like a part of the innate immune
defense

 The complement components are present in serum in inactive

form

 The complement is activated in a cascading manner (= each

protein activates that following) and it has widespread
physiologic and pathophysiologic effects

 Complement proteins are synthesized mainly in the liver, but

tissue macrophages and fibroblasts can synthesize some
complement proteins as well
Complement kills microbes in four different ways

1. Opsonization

2. Inflammation

3. Cytolysis

4. Clearance of immune complex

 Three pathways: classical, alternative, & lectin

Final steps identical in all 3 pathways

Classical - Initiated by formation of an Ag-Ab complex

Alternative - Antibody-independent
Part of innate immunity
Initiated by foreign cell surfaces

Lectin - Initiated by host proteins binding microbial

surfaces

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 Classical pathway

Classical was discovered first (but actually evolved

later)

Initiated by:
-formation of a soluble Ag-Ab complex

-binding of antibody to a target such as a bacterial

cell

Only certain antibodies can initiate this

(IgM, some classes of IgG)
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 Building the Membrane Attack complex

C5b on the surface of bacteria binds to C6

The binding of C6 to C5b activates C6 so that it can bind

to C7

C7 binds to C8 which in turn binds so many C9’s

Together these proteins form a circular complex called

the Membrane attack complex (MAC)
 Membrane Attack complex

The MAC causes Cytolysis.

The circular membrane attack

complex acts as a channel in which
cytoplasm can rush out of and water
rushes in.

The cells inner integrity is

compromised and it dies
 Alternative pathway

Four components: C3, factor B, factor D, properdin

Triggering substances may be pathogens or

nonpathogens

bacterial cell wall components,

fungi, viruses, parasites
immune complexes, RBCs, polymers

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 Initiation of The 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
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.
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
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
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.
 Lectin pathway

Lectin is a protein that binds to

carbohydrate

MBL (mannose-binding lectin) binds to

mannose on many bacterial cells
MBL is produced by liver in acute-phase
inflammatory reactions

Once MBL binds to target cell, 2 serine

proteases (MASP-1, MASP-2) bind
Acts like C1
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 p. 176

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 Regulation of complement system

Because it is nonspecific, several regulatory

mechanisms are involved (otherwise there
would be a lot of “collateral damage”)

Many components are very labile

Many regulatory proteins block activity through

binding to target

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 p. 178

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Biological effects of complement activation

Complement fragments must bind to

complement receptors expressed by
various cells

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Amplifies humoral response
Destroys invading bacteria and viruses
(lysis by MAC)

Inflammatory response

Opsonization of antigen (enhances phagocytosis)

Virus neutralization

Clearance of immune complexes

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 Some bacteria can resist lysis

Gram-positive bacteria

Some microbes produce inactivating enzymes

Nucleated cells are harder to lyse

Not particularly effective against tumor cells

(they can endocytose MAC and repair damage)

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Ch. 7 p. 182
Inflammation
many of the released fragments help
develop an inflammatory response

C3a, C4a, C5a- anaphylotoxins

bind to receptors on mast cells and
basophils; degranulation

(smooth muscle contraction; capillary

dilation; fluid influx)

also play a role in blood cell chemotaxis

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p. 184
 Viral neutralization

Some viruses activate alternative or lectin pathway

Antibody-mediated (classical) pathway is more common

Causes aggregation of viruses; can’t infect

host cells; more vulnerable to phagocytes

Enveloped viruses can be lysed

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 p. 186

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Consequences of complement deficiency

Early components of classical pathway (C1,

C4, C2)- immune complex disease
can’t generate C3b, which is needed
for solubilization

Recurrent Staph and Strep infections

(can’t lyse bacteria but seem to control
infections)

Early components of alternative pathway-

not as serious; tendency to infections
by Neisseria
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C3 deficiencies (can’t activate C5 and form MAC)

Recurrent severe bacterial infections

MAC deficiencies- recurrent Neisseria infections

no immune complex disease

Regulatory protein deficiencies

edema
RBC lysis

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