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Complement System

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RONAK LASHKARI
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82 views

Complement System

Uploaded by

RONAK LASHKARI
Copyright
© © All Rights Reserved
Available Formats
Download as PPT, PDF, TXT or read online on Scribd
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Discovery of Complement

1890s Jules Bordet observed:


1. Sheep antiserum to the bacterium Vibrio cholerae
caused lysis of the bacteria.
2. Heating the antiserum destroyed its bacteriolytic
activity.
Bacteriolytic activity requires 2 different substances:
a. the specific antibacterial Abs, which are resistant to the
heating process
b. heat-sensitive component responsible or the lytic activity
c. 56˚C, 30 min will inactivate complement
Paul Ehrlich in Berlin carried out similar
experiments and named the substance
complement,defining it as “the activity of
serum that completes the action of Ab.”

Bordet won the Nobel Prize in 1919 –


Complement-mediated bacteriolysis
Complement Plays a Key Role in Both
Innate and Adaptive Immunity

- The complement system is the major effector


of the humoral branch of the immune system.
- Although the discovery of complement and
most early studies were linked to the activity
of complement following Ab binding, a major
role for this system is the recognition and
destruction of pathogens based on recognition
of pathogen-associated molecular patterns, or
PAMPs, rather than on Ab specificity.
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
Complement Activation
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
General Properties of Complement
• Primary role is cell lysis
• Activity of complement destroyed by heating sera to 56 C for
30 minutes.
• IgM and IgG are the only immunoglobulin capable of
activating complement (classical pathway).
• Complement activation can be initiated by complex
polysaccharides or enzymes (alternative or properdin
pathway).
• Portions of the complement system contribute to chemotaxis,
opsonization, immune adherence, anaphylatoxin formation,
virus neutralization, and other physiologic functions
Sequential interaction of
complement components
• Cleavage of components generates a
small fragment which is released, and a
larger molecule which attaches to cell
surface and continues in reaction
sequence.
• Sequence of activation referred to as a
cascade reaction.
Classical Pathway Begins with Ag-Ab Binding
C1 molecule
soluble Ag-Ab or bacteria-Ab
↓
conformational changes in the
Fc portion of Ig
↓
expose a binding site on the
the Fc portion for the C1
component of the
complement system
C1q binds to Ag-bound Ab
↓
Binding of C1q to Fc induces a conformational change in C1r
↓ __
C1qr2s2 stabilized by Ca++
C1r converts to an active serine protease enzyme, C1r, __
which cleaves C1s to a similar active enzyme, C1s
__
C1s has two substrates, C4 and C2
__ ↓
C1s hydrolyzes C4 into C4a and C4b,
and hydrolyze C2 into C2b and C2a
↓ ___
C4b and C2a form a C4b2a complex, also called C3
convertase,
referring to its role in converting the C3 into an active form.

an anaphylatoxin*,
or C2a
C4b
a mediator of inflammation

* Anaphylaxis ( )
____
C4b2a (C3 convertase) hydrolyzes C3 into C3b and C3a ☺
↓ ____ ______
C3b binds to C4b2a and form C4b2a3b (C5 convertase)
_______ ↓
C4b2a3b cleaves C5 into C5b and C5a

opsonization inflammatory
responses
inflammatory
responses

©
Membrane Attack
Unit (C5,6,7,8,9)
• In the presence of C5b, molecules of C6, C7, C8
and a variable number of C9 molecules assemble
themselves into aggregates.
• This molecular complex causes a change in
membrane permeability.
• Exact cause of lysis unknown, one theory is change
in lipid membrane causes exchange of ions and
water molecules across membrane.
• Cells can lyse without C9 but it’s slower.
The Alternative Pathway Is
Ab-independent
- 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.
plasma C3, with an unstable thioester
bond, can be hydrolyzed
spontaneously into C3a and C3b.
C3b attaches to the surface of bacteria,
yeasts, viruses (or even host’s own
cells ®).
Mg++

Ba
(stabilization
of C3bBb) ___
analogous to the C4b2a complex in the
classical pathway

©
Lectin Pathway
• Activation of the lectin pathway begins when mannan-
binding protein (MBP) binds to the mannose groups of
microbial carbohydrates.

• This forms an enzyme similar to C1 of the classical


complement pathway that is able to cleave C4 and C2 to
form C44bC2a, the C3 convertase capable of enzymatically
splitting hundreds of molecules of C3 into C3a and C3b
Lectin Pathway
Activation of the lectin pathway begins when mannan-binding protein (MBP)
binds to the mannose groups of microbial carbohydrates.
The beneficial results are the same as in the classical complement pathway:
Trigger inflammation (C5a>C3a>C4a);
Chemotactically attract phagocytes to the infection site (C5a);
Promote the attachment of antigens to phagocytes via enhanced attachment
or opsonization (C3b>C4b;
Serves as a second signal for the activation of naive B-lymphocytes (C3d);
Cause lysis of gram-negative bacteria and human cells displaying foreign
epitopes (MAC).
 And remove harmful immune complexes from the body (C3b>C4b).
The Three Complement Pathways Converge at the
Membrane-attack Complex

The three complement


pathways converge at
the production of an
active C5 convertase
↓
C5b6789
membrane-attack
complex (MAC)
Formation of C5b6789,
Membrane-attack Complex

C5b attaches to C6, then to C7, and the


C5b67 complex inserts into the
membrane.
↓
binding of C8 to membrane-bound
C5b67 induces a 10 Å pore.
↓
binding and polymerization of C9, a
perforin-like molecule, to C5b678
↓
The completed membrane-attack
complex (MAC) has a tubular form and
functional pore size of 70 – 100 Å
Formation of Membrane-attack Complexes
(MAC) on the cell surface

Poly-C9 complex Complement-induced lesions


formed in vitro on the membrane of a RBC
Lysis of an E. coli by Complement
Strict Regulation of the Complement System

- Discrimination between microorganisms and self

- Passive mechanisms of regulation: highly labile


components that undergo spontaneous inactivation if they
are not stabilized by reaction with other components

- A series of specific regulatory proteins: inactivate


various components
Biological Effects Mediated by Complement

1. Cell lysis
The membrane-attack complex can lyse a broad spectrum of cells:
G(-ve) 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.
2. Inflammatory response
- Various peptides generated during activation of
complement play a decisive role in the development of
an effective inflammatory response.
- C3a, C4a, C5a (called anaphylatoxin) bind to
complement receptors on mast cells and basophils and
induce degranulation with release of histamine and other
mediators.
- The anaphylatoxins also induce smooth-muscle
contraction, increased vascular permeability,
extravasation, and chemoattraction (induced by C5a, C3a,
and C5b67)
3. Opsonization
- C3b is the major opsonin of the complement system,
although C4b and iC3b also have opsonizing activity.

binds to the surface of microbes

C3 convertase
Opsonization by Ab and complement
4. Viral neutralization
- 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.
5. Clearance of
immune complexes

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