Complement system is a major effector of the humoral branch of the immune system,
acting to protect the host from microorganisms such as bacteria.
Complement components are designated by numerals (C1-C9), by letter symbols (e.g.,
Complement factor I (Factor I)), or by other trivial names.
Peptide fragments formed by the activation of a component are denoted by small letters
[1], [2].
In most cases, the smaller fragment resulting from cleavage of a Complement component
is designated 'a' and the larger fragment designated 'b' (e.g.,
C3a, C3b; note that Complement
component C2 is an exception: C2a is the larger cleavage
fragment) [1].
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
(CR3aR) and Complement component 5a receptor 1
(CR5aR) [3], [4], [5]
at different sites. Complement fragments named opsonins, i.e.,
C1q, C3b,
C3dg, and iC3b, interact with
the cell surface receptors, such as CD93 molecule (C1qRp),
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 [3], [6].
Complement fragments also interact with each another to form functional complexes.
Complement activation by the classical pathway commonly begins with the formation of
soluble antigen-antibody complexes (immune complexes) or with the binding of an antibody
(Immunoglobulins such as IgG1 and
IgM) to an antigen on a suitable target, such as a bacterial
cell.
The initial stage of activation involves Complement components
C1, C2,
C3 and C4, which are present in
the plasma in functionally inactive forms.
Formation of an antigen-antibody complex induces conformational changes in the Fc part
of the IgM molecule that expose a binding site for the
Complement component C1. C1
present in serum is represented by a macromolecular complex (also called
C1qr2s2). It consists of three protein subunits: Complement
component 1 q subcomponent (C1q), Complement component 1 r
subcomponent (C1r) and Complement component 1 s subcomponent
(C1s). Components of the complex are stabilized by Ca(2+)
ions [7], [8].
Serpin peptidase inhibitor clade G member 1 (C1
inhibitor) inhibits activated C1r and
C1s and thus regulates complement activation [9]. Complement component 1, q subcomponent binding protein
(GC1QBP) binds and inhibits C1q
[10].
C1r cleaves and activates
C1s, which translates the activation of the Complement
component C1 complex into complement activation via cleavage
of C4 and C2 to form a
C3 convertase (C2aC4b).
C3 convertase (C2aC4b) cleaves
C3.
C5 convertase (C2aC4bC3b) is involved in classical
pathway and is composed of two proteins, C4b and
C2a, and additional C3b
molecules. The CD55 molecule decay accelerating factor for
complement (DAF) inhibits the assembly of the complement
system C3/C5 convertases by forming a complex with C4b and
C3b [11], [12].
Factor I is a major regulator of the complement system.
As a protease, it has very restricted specificity, cleaving only
C3b or C4b in the presence of a
cofactor such as Complement factor H (Factor H). Cleavage of
C3b by Factor I yields
iC3b, a major opsonin [13]. The CD46 molecule, a
complement regulatory protein (MCP) is a cofactor for the
Factor I -mediated degradation of
C3b and C4b deposited on host
cells [14].
Smaller fragments resulting from complement cleavage, C3a
and C5a, called anaphylatoxins, bind to their cognate
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 [3].
The terminal sequence of complement activation involves Complement components
C5b, C6,
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 the
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 [15].
The last step of complement activation is also controlled by the membrane-associated
complement regulatory protein CD59 which prevents the
formation of the Membrane attack complex at the terminal step of complement activation
cascade [16], [17]. The plasma complement regulatory protein
Clusterin can also interfere with the formation of the
Membrane attack complex pore [18]