Page 307 - Color Atlas of Biochemistry

298 Tissues and organs
Complement system
The complement system is part of the innate
immune system (see p. 294). It supports non-
specific defense against microorganisms. The
system consists of some 30 different proteins,
the “complement factors,” which are found in
the blood and represent about 4% of all
plasma proteins there. When inflammatory
reactions occur, the complement factors enter
the infected tissue and take effect there.
The complement system works in three
different ways:
Chemotaxis. Various complement factors
attract immune cells that can attack and
phagocytose pathogens.
Opsonization. Certain complement factors
(“opsonins”) bind to the pathogens and
thereby mark them as targets for phagocytos-
ing cells (e. g., macrophages).
Membrane attack. Other complement fac-
tors are deposited in the bacterial membrane,
wherethey createpores that lyse the patho-
gen (see below).
A. Complement activation
Thereactions that take placein the comple-
ment system can be initiated in several ways.
During the early phase of infection, lipopoly-
saccharides and other structures on the sur-
face of the pathogens trigger the alternative
pathway (right). If antibodies against the
pathogens become available later, the anti-
gen–antibody complexes formed activate the
classic pathway (left). Acute-phase proteins
(see p. 276) are also able to start the comple- able pore in the bacterial membrane, which
ment cascade (lectin pathway, not shown).
Factors C1 to C4 (for “complement”) belong
to the classic pathway, while factors B and D
form the reactive components of the alterna-
tive pathway. Factors C5 to C9 are responsible
for membrane attack. Other components not
shown here regulate the system.
As in blood coagulation (see p. 290), the
early components in the complement system
are serine proteinases, which mutually acti-
vate each other through limited proteolysis.
They create a self-reinforcing enzyme cas-
cade.Factor C3, the products of which are
involved in several functions, is central to
the complement system.
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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The classic pathway is triggered by the for-
mation of factor C1 at IgG or IgM on the sur-
face of microorganisms (left). C1 is an 18-part
molecular complex with three different com-
ponents (C1q, C1r, and C1s). C1q is shaped like
a bunch of tulips, the “flowers” of which bind
to the F c region of antibodies (left). This acti-
vates C1r, a serine proteinase that initiates the
cascade of the classic pathway. First, C4 is
proteolytically activated into C4b, which in
turn cleaves C2 into C2a and C2b. C4B and
C2a together form C3 convertase [1], which
finally catalyzes the cleavage of C3 into C3a
and C3b. Small amounts of C3b also arise from
non-enzymatic hydrolysis of C3.
The alternative pathway starts with the
binding of factors C3b and B to bacterial lipo-
polysaccharides (endotoxins). The formation
of this complex allows cleavage of B by factor
D, giving rise to a second form of C3 conver-
tase (C3bBb).
Proteolytic cleavage of factor C3 provides
two components with different effects. The
reaction exposes a highly reactive thioester
group in C3b, which reacts with hydroxyl or
aminogroups. This allows C3b tobind cova-
lently to molecules on the bacterial surface
(opsonization, right). In addition, C3b initiates
a chain of reactions leading to the formation
of the membrane attack complex (see below).
Together with C4a and C5a (see below), the
smaller product C3a promotes the inflamma-
tory reaction and has chemotactic effects.
The “late” factors C5 to C9 are responsible
for the development of the membrane attack
complex (bottom). They create an ion-perme-
leads to lysis of the pathogen. This reaction is
triggered by C5 convertase [2]. Depending on
the type of complement activation, this en-
zyme has the structure C4b2a3b or C3bBb3b,
and it cleaves C5 into C5a and C5b. The com-
plex of C5b and C6 allows deposition of C7 in
the bacterial membrane. C8 and numerous C9
molecules—which form the actual pore—then
bind to this core.