s e c t io n 35.10
Via C3 Thioester
F;it:k.n B, Fih Ivt D
C3 C onvertase
Factor I
Factor H
C 3 (-* -C 3 b ,C 3 a )
C5 Convertase
C5 (-►CSh, C5a)
Ag-Ab Complex
Via(C1q,' 1 ■
C4, C2
C1 Inactivator
C3 C onvertase
Via № P, MAS*.
C4, C2
C3 C onvertase
(C4b, 2a)
C3 ( -►
C5 Convertase
C5 (-*-C5b, C5a)
_______ I
(C5b, C6, C7, C8, C9)
Membrane Attack Complex
FIGURE 35-22
(Also see color figure.) Initiation of actron by complement occurs via three
pathways: classical, alternative (properdin), and lectin pathways.
Action of the complement system has many conse-
quences: lysis of bacterial cells, recruitment of phagocytic
cells to the site(s) of invasion, opsonization (marking for
phagocytic attack and removal) of foreign cells, and re-
moval of immune complexes. Initiation of action by com-
plement can occur via three distinct pathways: the “classi-
cal” pathway, the“alternative” or properdin pathway, and
the lectin pathway (Figure 35-22).The physiological sig-
nificance of the first two pathways has been established;
however, the importance of the lectin pathway is not yet
fully known. The lectin pathway has only been investi-
in vitro.
The Alternative Pathway
The principal pathway of complement activation, which
is part of the innate immunity of the organism, is the al-
ternative pathway. The designation of this pathway as “al-
ternative” reflects order of discovery and acceptance, not
physiological importance.
Initiation of complement activation occurs during the
“spontaneous” reaction of C3, the most prevalent com-
plement protein with nucleophilic chemical groups on the
surface of invading organisms. This reaction involves a rel-
atively uncommon organic chemical in nature, a thioester
that is found on C3, C4, and on one of the plasma pro-
tein inhibitors, a
-macrogIobulin. Reaction between the
thioster and a cell surface nucleophile, i.e., an amino, hy-
droxyl, or thiol group, results in the covalent attachment
of C3 to the cell surface. Spontaneous hydrolysis of the
C3 thioester also produces a functionally active form of
C3, C3(H
0). C3(H
0) forms a complex with factor B
and makes factor B susceptible to proteolysis by factor D,
a proteinase from adipocytes. Factor B is converted to Bb
by factor D, becoming a proteolytic enzyme itself. The
combined product of this reaction, C3b, Bb forms the en-
zyme C3 convertase (specifically the alternative pathway
C3 convertase). C3 convertase proteolytically converts cir-
culating C3 molecules to C3b and C3a. The C3 conver-
tase has a short life time because the C3b and Bb disso-
ciate rapidly. Factor H, another circulating complement
protein, can bind to C3b and replaces Bb in the C3 con-
vertase. C3b that is bound to factor FI also becomes very
susceptible to the complement proteinase factor I. Upon
cleavage of C3b by factor I, C3b loses its ability to func-
tion in the C3 convertase complex. Proteolytically cleaved
C3b (iC3b) still retains its ability to opsonize cells and thus
mark them for attack by phagocytes. The product C3a is an
anaphylatoxin, i.e., it causes histamine release from mast
cells and increases vascular permeability through vasodi-
lation. Increased permeability facilitates phagocyte access
to pathogens in the tissues surrounding the blood vessels.
C3a is also chemotactic for eosinophils suggesting an as-
sociation with allergic responses and asthma.
P (properdin) can also bind to the C3 convertase. Its
role is to stabilize the complex and hence it is consid-
ered a cofactor-activator in the alternative pathway. These
components plus additional C3b molecules form the C5
convertase, an enzyme complex that peoteolytically con-
verts C5 to C5a and CSb. Properdin stabilizes C3b and
Bb in the complex and protects these proteins from pro-
teolytic inactivation by factor I. Factor H competes for
Bb in the C5 convertases, the same as it does in the C3
convertase. The alternative pathway has also been called
the properdin pathway because of properdin’s participa-
tion in alternative pathway C3 and C5 convertases. C5b is
a component in the terminal complex of the complement
activation process, the MAC. The MAC is composed of a
self-assembled, noncovalent complex of C5b, C
, C7, C
and C9. Together these components produce a pore-like
structure that makes the membrane of the cell to which it is
attached permeable and causes cell death. Under the elec-
tron microscope the MAC appears like an impact crater
similar to those observed on the surface of the moon. C5a
is also an anaphylatoxin like C3a, but it is more potent.
C5a is also a chemokine and attracts phagocytic cells to
the site of complement activation.
The Classical Pathway
The classical pathway of complement activation is closely
linked to acquired immunity because it is initiated by
antigen-antibody complexes binding to Cl, the first com-
ponent of this pathway. Antigen-antibody complexes that
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