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at infection. The lectin pathway and the alternative pathway are, therefore, participates in the
innate arm of the immune system, whereas the classical pathway participates in acquired arm.
All three pathways lead to the production of C3b, the central molecule of the complement
cascade. The presence of C3b on the surface of a microbe marks it as foreign and targets it for
destruction. C3b has two important functions: (1) It combines with other complement
components to generate C5 convertase, the enzyme that leads to the production of the Membrane
Attack Complex(MAC) and (2) it opsonize (opsonin) bacteria because phagocytes(neutrophils
¯ophages) have receptors for C3b on their surface named(CD35,CR1).
1-The classical pathway
Antigen–antibody complexes activate C1 to form a protease, which cleaves C2 and C4 to form
C4b2a complex. The latter is C3 convertase, which cleaves C3 molecules into two fragments,
C3a and C3b. C3a, an anaphylatoxin which increases vascular permeability and causes
vasodilation .
C3b forms a complex with C4b2a, producing a new enzyme, C5 convertase (C4b,C2aC3b),
which cleaves C5 to form C5a and C5b. C5a is an anaphylatoxin and a chemotactic factor.
C5b binds to C6 and C7 to form a complex that interacts with C8 and C9 to produce the
membrane attack complex (C5b,6,7,8,9), which causes cytolysis.
Note that the "b" fragment of complement proteins continues in the main pathway, whereas the
"a" fragment is split off and has other activities.
Only IgM and IgG fix complement. One molecule of IgM can activate complement; however,
activation by IgG requires two cross-linked IgG molecules. C1consist of three proteins: C1qC1r
&C1s. C1 is bound to a site located in the Fc region of the heavy chain(CH2)of IgG&IgM. Of the
IgGs, only IgG1, IgG2, and IgG3 subclasses fix complement; IgG4 does not.
2-The lectin pathway
Mannan-binding lectin (MBL) (also known as mannose-binding protein) binds to the surface of
microbes bearing mannan (a polymer of the sugar, mannose). This activates proteases associated
with MBL that cleave C2 and C4 components of complement and activate the classic pathway.
Note that this process bypasses the antibody-requiring step and so is protective early in infection
before antibody is formed.
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5
Regulation of the Complement System ((Complement control proteins))
1-The first regulatory step in the classic pathway is at the level of the antibody itself. The
complement-binding site on the heavy chain of IgM and IgG is unavailable to the C1 component
of complement if antigen is not bound to these antibodies. This means that complement is not
activated by IgM and IgG despite being present in the blood at all times. However, when antigen
binds to its specific antibody, a conformational shift occurs and the C1 component can bind and
initiate the cascade.
Several serum proteins regulate the complement system at different stages.
2-C1 inhibitor is an important regulator of the classic pathway. It inactivates the protease activity
of C1. Activation of the classic pathway proceeds past this point by generating sufficient C1 to
overwhelm the inhibitor.
3-Protection of human cells from lysis by the membrane attack complex of complement is
mediated by decay-accelerating factor (DAF, CD55), a glycoprotein located on the surface of
human cells. DAF acts by binding to C3b and C4b and limiting the formation of C3 convertase
and C5 convertase.
Biologic Effects of Complement
1-Opsonization
Microbes, such as bacteria and viruses are phagocytized much better in the presence of C3b
because there are C3b receptors on the surface of many phagocytes.
2-Chemotaxis
C5a attracts neutrophils which migrate well toward C5a. C5a also enhances the adhesiveness of
neutrophils to the endothelium.
3-Anaphylatoxin
C3a,C4a and C5a(Anaphylatoxin) cause degranulation of mast cells with release of mediators,
e.g., histamine, leading to increased vascular permeability and smooth muscle contraction,
especially contraction of the bronchioles leading to bronchospasm. Anaphylatoxins can also bind
directly to smooth muscle cells of the bronchioles and cause bronchospasm. C5a is the most
potent of these anaphylatoxins.
Assistant Prof. Dr.Ahmed Adil “Immunology” 3rd class-college of Medicine
6
4-Cytolysis
Insertion of the C5b,6,7,8,9 complex into the cell membrane leads to killing or lysis of many
types of cells including erythrocytes, bacteria, and tumor cells. Cytolysis is not an enzymatic
process; rather, it appears that insertion of the complex results in disruption of the membrane and
the entry of water and electrolytes into the cell.
5-Enhancement of Antibody Production
The binding of C3b to its receptors on the surface of activated B cells greatly enhances antibody
production compared with that by B cells that are activated by antigen alone.