COMPLEMENT SYSTEM

Abstract:

The complement system consists of a tightly regulated network of proteins that play an
important role in host defence and inflammation. Complement activation results in
opsonisation of pathogens and their removal by phagocytes, as well as cell lysis.
Inappropriate complement activation and complement deficiencies are the underlying cause
of the pathophysiology of many diseases such as systemic lupus erythematous and asthma.
This review represents an overview of the complement system in an effort to understand the
beneficial as well as harmful roles it plays during inflammatory responses.

Introduction:

Complement was discovered many years ago as a heat-labile component of normal plasma
that augments the opsonisation of bacteria by antibodies and allows antibodies to kill some
bacteria. This activity was said to complement the antibacterial activity of antibody, hence
the name. Although first discovered as an effector arm of the antibody response, complement
can also be activated early in infection in the absence of antibodies. Indeed, it now seems
clear that complement first evolved as part of the innate immune system, where it still plays
an important role.

The complement system is made up of a large number of distinct plasma proteins that react
with one another to opsonize pathogens and induce a series of inflammatory responses that
help to fight infection. A number of complement proteins are proteases that are themselves
activated by proteolysis cleavage. Such enzymes are called zymogens and were first found in
the gut. The digestive enzyme pepsin, for example, is stored inside cells and secreted as an
inactive precursor enzyme, pepsinogen, which is only cleaved to pepsin in the acid
environment of the stomach.

There are three distinct pathways through which complement can be activated on pathogen
surfaces. These pathways depend on different molecules for their initiation, but they converge
to generate the same set of effector molecule. There are three ways in which the complement
system protects against infection. First, it generates large numbers of activated complement
proteins that bind covalently to pathogens, opsonizing them for engulfment by phagocytes
bearing receptors for complement. Second, the small fragments of some complement proteins
act as chemo attractants to recruit more phagocytes to the site of complement activation, and
also to activate these phagocytes. Third, the terminal complement components damage
certain bacteria by creating pores in the bacterial membrane.
Figure 1(a) Schematic overview of the complement cascade

There are three pathways of complement activation: the classical pathway, which is triggered
by antibody or by direct binding of complement component C1q to the pathogen surface; the
MB-lectin pathway, which is triggered by mannan-binding lectin, a normal serum constituent
that binds some encapsulated bacteria; and the alternative pathway, which is triggered
directly on pathogen surfaces. All of these pathways generate a crucial enzymatic activity
that, in turn, generates the effector molecules of complement. The three main consequences
of complement activation are opsonisation of pathogens, the recruitment of inflammatory
cells, and direct killing of pathogens.

Classical pathway:

The Classical Complement Pathway is a component of the innate immune system. The
innate immune system serves as a constant non-specific defense against foreign pathogens
including bacteria, viruses, fungi, and parasites. Complement is a part of that system but it
cannot act independently. Classical complement as discussed here relies on the actions of B
cells to produce antibodies specific to different pathogens, as well as other components of the
innate immune system such as Mast cells or Macrophages. It is an important aspect of our
immune system and malfunction of complement can result in a compromised immune
system. Complement deficiency has also been linked with autoimmune diseases and
immunosuppression. Without complement we are unable to utilize the full strength of our
immune system as macrophages and mast cells rely on it to phagocytose and release
histamine respectively. While both of these cells are capable of functioning independently,
the signal amplification that complement provides greatly increases their effectiveness.

Alternative pathway:

The alternative pathway of the complement system is an innate component of the immune
system's natural defense against infections.
The alternative pathway is one of three complement pathways that opsonize and kill
pathogens. The pathway is triggered when the C3b protein directly binds a microbe. It can
also be triggered by foreign materials and damaged tissues.

Figure 1(c) complement cascade

Figure 1(b) Functional protein classes in the complement system

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 Effector Functions of Complement:
Cell lysis is only one function (and probably not the most important one) of the complement
system. The complement system acts in several ways to mobilize defense mechanisms.

Opsonization by C3b targets foreign particles for phagocytosis.

Chemotaxis by C5a attracts phagocytic cells to the site of damage.
This is aided by the increased permeability of the capillary beds mediated
by C3a and C5a.
The early complement components are also important for solubilizing antigen-
antibody complexes assisting in their catabolism and elimination from the body.
Failure of this function can lead to immune complex disorders.
Lysis of antibody-coated cells. (In some cases, this causes more harm than good;
complement-mediated lysis can cause such serious disorders as
o Rh disease
o immune hemolytic anemia

Regulation of Complement Activity

The explosive potential of the complement system requires that it be kept under tight control.
At least 12 proteins are known that do this. Three examples:

Factor H removes Bb from the alternative pathway C3 convertase breaking the

positive feedback loop.
Factor I inactivates C3b.
C1 inhibitor (C1INH) binds to sites on activated C1r and C1s shutting down their
proteolytic activity. So when C1 is activated by antigen-antibody complexes, there is
only a brief interval during which it can cleave C4 and C2 before it is deactivated by
C1INH.

Summary

The complement system is one of the major mechanisms by which pathogen recognition is
converted into an effective host defense against initial infection. Complement is a system of
plasma proteins that can be activated directly by pathogens or indirectly by pathogen-bound
antibody, leading to a cascade of reactions that occurs on the surface of pathogens and
generates active components with various effector functions. There are three pathways of
complement activation: the classical pathway, which is triggered directly by pathogen or
indirectly by antibody binding to the pathogen surface; the MB-lectin pathway; and the
alternative pathway, which also provides an amplification loop for the other two pathways.
All three pathways can be initiated independently of antibody as part of innate immunity. The
early events in all pathways consist of a sequence of cleavage reactions in which the larger
cleavage product binds covalently to the pathogen surface and contributes to the activation of
the next component. The pathways converge with the formation of a C3 convertase enzyme,
which cleaves C3 to produce the active complement component C3b. The binding of large
numbers of C3b molecules to the pathogen is the central event in complement activation.
Bound complement components, especially bound C3b and its inactive fragments, are
recognized by specific complement receptors on phagocytic cells, which engulf pathogens
opsonized by C3b and its inactive fragments. The small cleavage fragments of C3, C4, and
especially C5, recruit phagocytes to sites of infection and activate them by binding to specific
trimeric G protein-coupled receptors. Together, these activities promote the uptake and
destruction of pathogens by phagocytes. The molecules of C3b that bind the C3 convertase
itself initiate the late events, binding C5 to make it susceptible to cleavage by C2b or Bb. The
larger C5b fragment triggers the assembly of a membrane-attack complex, which can result in
the lysis of certain pathogens. The activity of complement components is modulated by a
system of regulatory proteins that prevent tissue damage as a result of inadvertent binding of
activated complement components to host cells or spontaneous activation of complement
components in plasma.