Alternative complement pathway
Complement system is a major effector of humoral branch of the immune system, acting
to protect the host from microorganisms, such as bacteria.
Complement components are designated either by numerals
(C1-C9), letter symbols (e.g.,
Complement factor I (Factor I)), or by names. Peptide
fragments formed by activation of a component are denoted with small letters .
In most cases, the smaller fragment resulting from cleavage of a component is
designated 'a' and the larger fragment designated 'b' (e.g.,
C3a, C3b; note that
C2 is an exception: Complement component C2a
is the larger cleavage fragment) .
Larger fragments bind to targets near activation sites, while smaller fragments,
called anaphylatoxins, diffuse from the site and may initiate localized inflammatory
responses by binding to specific receptors, such as Complement component 3a receptor 1
Complement component 5a receptor 1 (CR5aR)
, , . Complement fragments named
opsonins, i.e., C3b, C3dg, and
iC3b, interact with the cell surface receptors, such as
Complement component receptor 1
(CR1), Complement component receptor 2
(CD21), Integrins alpha-M/beta-2
integrin and alpha-X/beta-2 integrin, to
promote phagocytosis .
Complement fragments interact with each another to form functional complexes.
Alternative complement pathway is independent of antibodies and other molecules that
bind to Complement component 1 q subcomponent (C1q). It is
activated by molecules, such as bacterial lipopolysaccharides .
Complement component C3b present on the surface of
foreign cells can bind another serum protein called Complement factor B
(Factor B) to form a complex. C3b
binding exposes a site on Factor B that
serves as a substrate for enzymatically active serum protein called Complement factor D
(Factor D). Factor D cleaves
Factor B, releasing a small fragment Factor
Ba and the larger fragment Factor Bb.
Complement component C3b and Factor Bb
form the enzymatically active complex C5 convertase
(C3bBb). Subsequently, Complement factor
Properdin (also called Factor P) binds to C5
convertase (C3bBb) and stabilizes it. The C5 convertase
(C3bBb) complex has C3 convertase activity
and thus is analogous to the C3 convertase (C2aC4b) complex in the classical pathway.
C5 convertase (C3bBb) make a complex with
C3b, which exhibits C5 convertase activity, analogous to the
C5 convertase (C2aC4bC3b) complex in the classical pathway , .
Regulatory molecule of the alternative pathway is a Factor
I. Factor I cleaves
C3b. CD46 molecule, complement regulatory protein
(MCP) is a cofactor for Factor
I-mediated degradation of C3b.
Complement factor H (Factor H) accelerates
the destructive action of Factor
I . CD55 molecule decay accelerating factor
for complement (DAF) also regulates the complement system
activity by accelerating the decay of the C3/C5-convertase activity of the alternative
Smaller fragments resulting from complement cleavage, Complement components
C3a and C5a, called
anaphylatoxins, bind to receptors (CR3aR and
CR5aR) on the surface of mast cells and blood basophils and induce
degranulation upon release of histamine and other biologically active mediators .
The terminal sequence of complement activation involves
C7, C8, and
C9, which interact sequentially to form a macromolecular
structure called Membrane attack complex. This complex
creates pores in the cell membrane and induces cell lysis.
C5b initiates assembly of Membrane attack
complex by binding of C6 and
C7 resulting in C5b/C6/C7 hydrophobic complex. It inserts
into the lipid bilayer of cell membranes, where it becomes a high-affinity receptor for
C8 molecules (C8alpha, C8beta,
C8gamma). C5b/C6/C7/C8 complex has a limited ability to lyse
cells. The formation of fully active Membrane attack complex
is accomplished by binding of C9 to C5b/C6/C7/C8 complex.
This fully active Membrane attack complex forms a large
channel through the membrane of the target cell, enabling ions and small molecules to
diffuse freely across the membrane .
The latest step of complement activation is also controlled by the membrane-associated
complement regulatory protein CD59 that prevents the
formation of the Membrane attack complex at the terminal
step of complement activation cascade , . Plasma
complement regulatory protein Clusterin can also interfere
with formation of the Membrane attack complex pore .
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