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The Complement System

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9 views24 pages

The Complement System

Uploaded by

chidumeaugustina14
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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THE COMPLEMENT

SYSTEM
DR AKPA CHINEDU OBASI
INTRODUCTION

• It is a system of hepatically synthesized plasma proteins


that play a role in immunity and inflammation. It also
interfaces with and enhances adaptive immune responses.
• It comprises over 20 proteins circulating in the blood, tissue
fluids and on cell surfaces.
• Many of the biological activities are mediated by cell
surface complement receptors.
• They can be activated during either innate or adaptive
immune responses
• The complement system helps or “complements” the
ability of antibodies and phagocytic cells to clear
pathogens from an organism
• The molecules normally circulate as inactive precursors
(pro-proteins)
• In response to the recognition of molecular components of
microorganisms they become sequentially activated in an
enzyme cascade – the activation of one protein
enzymatically cleaves and activates the next protein in the
cascade (sequential activation system).
NOMENCLATURE

• The components are named by giving uppercase letter C and


numbers according to order of identification: C1,C2, …….,C9.
• Also include complement factors: factor B, D, H, I and properdin.
• When the products are split, they become active; the active
products are usually designated with a lower-case a or b.
• Example: C2a and C4b or Ba and Bb.
FUNCTIONS

1.Opsonization
2. Clearance of immune complexes.
3. Direct microbial killing (cell lysis).
4. Attraction of phagocytes by chemotaxis.
5. Cellular activation (triggering and amplification of
inflammatory reactions).
6. Priming of antibody response.
COMPLEMENT ACTIVATION PATHWAYS
• Multiple (three) ways to ensure efficient recognition and
clearance of pathogens from the host:
 The classical pathway
The alternative pathway
The lectin pathway
• All the three activation pathways generate homologous
variants of the protease, C3 – Convertase.
• The final stage is the formation of MAC (membrane attack
complex)-lytic stage.
• All the pathways share a set of core elements that includes
C3, C5, and the terminal components C6–C9
• Initiation of each of the pathways requires recruitment or
assembly of a serine protease.
• The critical second step is the cleavage of C3 by C3-
convertase to form the peptide fragments C3a + C3b.
• Then C5 is cleaved by a C5-convertase.
• Amplification at each step results from the cleavage of
multiple substrate molecules by these two convertases
• The three pathways can be distinguished by their
processes of initiation, their unique components, their
unique functions, and how they are regulated
CLASSICAL PATHWAY
• The classical pathway of complement activation is initiated
by antigen–antibody complexes.
1. Only immunoglobulin IgM and IgG antibodies participate
in classical pathway activation
2. Activation begins with the binding of the C1q peptide to
the CH domains of μ and γ heavy chains .
C1q is a hexamer that cross-links two adjacent binding
sites located on the CH domains of μ or γ Ig heavy
chains.
 IgM antibodies are more efficient than IgG antibodies in
binding C1q, because the pentameric nature of IgM
ensures that two CH domains will be in close proximity
to one another.
3. Once bound, C1q recruits two copies each of C1r and C1s
to form an active enzyme.
4. The C1qr2s2 complex can cleave C4 to yield peptides C4a
and C4b
5. C1qr2s2 then cleaves C2 to yield the C2a + C2b peptides.
C2a binds to C4b to produce C4b2a, the classical C3
convertase.
This enzyme complex can cleave C3 to yield C3a + C3b.
Multiple copies of peptides are produced at each
THE ALTERNATIVE PATHWAY

• This pathway is initiated by at least three different


mechanisms:
1. Highly charged microbial surface patterns, including
polysaccharides, can bind C3.
2. In fluid phase, C3 can spontaneously hydrolyze with water
to form an intermediate designated C3(H2O).
3. The C3b peptide, derived from the classical or lectin
pathways, can activate the alternative pathway directly.
4. Bound C3, C3(H2O), or C3b then binds Factor B.
5. Bound B is then cleaved by the constitutively active
enzyme Factor D to produce Ba + Bb.
6. C3Bb, C3(H2O)Bb, and C3bBb are the alternative
pathway C3 convertases.
Whereas C3(H2O)Bb is unstable, the other two complexes
are relatively stable.
C3bBb can be further stabilized by binding Factor P.

7. The ability of the alternative pathway C3 convertases to


generate more C3b constitutes a feedback amplification
loop
• 8. Another unique feature of the alternative pathway is
called C3 tickover.
C3 constantly interacts with H2O in fluid phase to form
C3(H2O), an initiator of alternative pathway activation.
However, the C3(H2O) intermediate is very unstable.
THE LECTIN PATHWAY

• MBL (mannose-binding lectin) is produced by liver in acute


inflammation.
• Antibody-independent pathway activated by binding of MBL to
mannose residues on foreign surface.
• An important innate defense mechanism.
• Utilizes the elements of the classical pathway, except for the C1
proteins.
• MBL binds to mannose on bacterial cells
• Binding activates 2 MBL-associated serine proteases
(MASP-1, MASP-2) that cleave and activate C4 and C2.
Cleaved C4 and C2 generate C3 Convertase like classical
pathway C4b2a
• The activated MASP-1/2 functions as an enzyme with
substrate specificity similar to that of C1qr2s2, causing
cleavage and activation of C4 and C2.
MEMBRANE ATTACK COMPLEX

• The terminal steps in complement activation are shared by


the three pathways.
• C3 convertases are converted to C5 convertases by the
binding of C3b
• The C5 convertases cleave C5 generating C5a + C5b.
• C5a is a biologically active peptide that mediates
chemotaxis and mast cell activation
• C5b is the first component of the membrane attack
complex (MAC)
• C5b on the surface of pathogen binds to C6.
• C6 bind to C7 and C7 binds to C8.
• The assembled C5b678 complex can intercalate into the
lipid membranes of both microbial and host cells.
• The C5b678 complex recruits multiple copies of C9 to form
a stable membrane pore.
• Membrane disruption and rapid cell lysis result.
• Opsonins
C3b, C4b – opsonization (they bind to macrophages and
neutrophils via complement receptors , enhancing phagocytosis.
• Clearance of immune complexes
C3b, C4b – binds immune complexes to erythrocytes via CR1,
taking immune complexes out of plasma to the liver and spleen
facilitating removal by macrophages. (Immune Adherence
Phenomenon)
• Anaphylatoxins
C3a, C4a, C5a bind to receptors on mast cells and
basophils.
 Binding lead to cell activation and degranulation.
Release of their granular substances extracellular.
This leads to anaphylactic reaction (anaphylaxis): Smooth
muscle contraction; capillary dilation; fluid influx.
• Chemotaxis
C3a, Ba, C5a – chemotaxis (attracts phagocytic cells to
sites of inflammation and increases their overall activity)
• Complement Deficiency Diseases
− C1, C4, C2 = (SLE), glomerulonephritis.
− C3 = Severe bacterial infections.
− C6,7,8-C9 = Severe Neisseria infections.
− C1-inhibitor = Hereditary angioedema.
− DAF, CD59 = Paroxysmal Nocturnal Hemoglobinuria

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