SEMINAR PRESENTATION

TITLE: THE COMPLEMENT SYSTEM

BY
JERRY AFRICANUS NEEQUAYE

INSTITUTION
DEPARTMENT OF PHARMACOLOGY,
UNIVERSITY OF GHANA MEDICAL SCHOOL,
KORLE-BU

THE COMPLEMENT SYSTEM

OUTLINE:

Definition and brief historical introduction

Classes of complement pathways

Mechanism of action

Functions of the complement system

DEFINITION: Is a system of interacting proteins in the blood that can be

activated by antigen-antibody reaction or micro-organisms to undergo a
cascade of proteolytic reactions whose end result is the assembly of
membrane attack complexes (MAC). The MAC helps to kill invading
pathogens or cells and as such defend the body against these invaders.

HISTORICAL OVERVIEW: In the late 19th century, blood serum was found to contain a
"factor" or "principle" capable of killing bacteria. In 1896, Jules Bordet, a young Belgian
scientist in Paris at the Pasteur Institute, demonstrated that this principle could be analyzed into
two components: a heat-stable and a heat-labile component. (Heat-labile means that the
component loses its effectiveness if the serum is heated.) The heat-stable component was found
to confer immunity against specific microorganisms, whereas the heat-labile component was
found to be responsible for the non-specific antimicrobial activity conferred by all normal serum.
This heat-labile component is what we now call "complement."

The term "complement" was introduced by Paul Ehrlich in the late 1890s, as part of his larger
theory of the immune system. According to this theory, the immune system consists of cells that
have specific receptors on their surface to recognize antigens. Upon immunization with an
antigen, more of these receptors are formed, and they are then shed from the cells to circulate in
the blood. These receptors, which we now call "antibodies," were called by Ehrlich
"amboceptors" to emphasize their bifunctional binding capacity: They recognize and bind to a
specific antigen, but they also recognize and bind to the heat-labile antimicrobial component of
fresh serum. Ehrlich, therefore, named this heat-labile component "complement," because it is
something in the blood that "complements" the cells of the immune system

The rationale for the inclusion of the complement system under the innate response is based on
the fact that:
 1. It is inherited

2. It is not adaptable, that is, does not change over the course of ones lifetime.

However, it can be recruited and brought into action by the adaptive immune system.

VARIOUS CLASSES OF THE COMPLEMENT PATHWAY:

Three (3) main biochemical pathways activate complement system

1. The classical complement pathway

2. The alternative complement pathway

3. Mannose binding lectin pathway

GENERAL OVERVIEW OF MECHANISM OF ACTION

The complement system has about 20 different proteins circulating as

inactive zymogens. These are produced by different cells including

i. Hepatocytes

ii. Macrophages

iii. Gut epithelial cells

The majority is produced by the hepatocytes.

The reacting components of the complement system are designated C1 to

C9, Factor B and Factor D.

The rest are kind of regulatory proteins. The protein components in the
complement system are all soluble proteins.
The complement proteins can be divided into three main sub groups and
these are based on either their function or the phase of the processes
involved in the pathway.

In terms or function, complement proteins are subdivided into 3. These are:

C1 RECOGNITION

C4, C2, C3 ACTIVATION

C5 to C9 ATTACK

Another way of classification employs the time phase of the whole process.
Hence we have the EARLY PHASE, THE INTERMEDIATE PHASE & LATE PHASE.

COMPLEMENT PHASE
(C1,C4,C2) (FACTOR B AND FACTOR EARLY
D)
C3 INTERMEDIATE
C5 TO C9 LATE
The main role of the complement is to attack the membrane of microbial
cells therefore activation of complement is focused on the microbial cell
membrane where it is triggered either by antibody bound to the
microorganism or by microbial envelope polysaccharide both of which
activate the early complement.

There are 2 sets of the early complements belonging to the 2 distinct

pathways.

C1, C2, C4 Classical Pathway Triggered by antibody

Factor B and Factor Alternative Triggered by microbial

D pathway polysaccharides

The early components act on C3 the most important complement

component. These early components are pro-enzymes (C1, C4, C2) activated
sequentially by limited proteolytic cleavage.

As each pro-enzyme in the sequence is cleaved, it is activated to generate a

serine protease which cleaves the next pro-enzyme in the sequence. Many of
the cleavages liberate

1. A small peptide fragment

2. A large fragment which has an exposed membrane binding site on it.

Larger fragments bind tightly to the target cell membrane by its newly
exposed membrane binding site and helps to carry out the next reaction in
the sequence. In this way complement activation is confined largely to the
cell surface where it begun.

The smaller fragments act independently as a diffusible signal that promotes

an inflammatory response.

C3 activation is the central reaction in the complement activation sequence

and it is here that the classical and alternative pathways converge.

For both pathways, C3 is cleaved by an enzyme complex called C3

convertase though different convertase is produced by each pathway.
Convertase are formed by the spontaneous assembly of 2 of the complement
component activated earlier in the cascade. Both cleave C3 into two
fragments. The larger C3b binds covalently to the target cell membrane and
then binds to C5. Once bound, the C5 protein is cleaved by the C3
convertase now acting as C5 convertase to initiate the spontaneous
assembly of the late component.

THE ALTERNATIVE PATHWAY

Some polysaccharides in the cell envelope of microorganisms can activate

the alternative pathway. This pathway provides the first line of defense
against infection before an immune response can be mounted and it
amplifies the effect of the classical once an immune response has begun.

C3 is spontaneously hydrolysed to C3a and C3b due to the breakdown of the

thio-ester bond through condensation reaction. The C3b binds to the
pathogenic membrane surface if pathogen is near enough. If there is no
pathogen in the blood C3a and C3b protein fragments will be deactivated by
rejoining with each other. When C3b binds to the pathogenic cell membrane,
Factor B binds to the membrane bound C3b to form C3bB.

Factor D which circulates in the blood in an active form cleaves the bound
factor B to generate the active fragment Bb and therefore produce C3bBb
(which is the C3 convertase for the alternative pathway) and therefore
generates more C3b molecules some of which binds C5. The C3 convertase
can also act as a C5 convertase and cleave the membrane bound C5
molecules to initiate the assembly of the Membrane Attack Complex which is
involves the C5b bound to the C3b binding to the C6 to form C56 and then
C7 to form C567. The C567 complex then binds firmly via the C7 to the
membrane. This complex adds one molecule of C8 to form C5678 which then
binds 8 to 18 molecules of C9 which partially unfold and polymerise into a
transmembrane channel.

The Membrane Attack Complexes form aqueous pores through the

membrane this compromise the structure of the lipid bilayer in their vicinity
and they make the membrane leaky. Small molecules leak in and out of the
cell around and through the complexes while macromolecules remain inside.
The cells normal mechanism for controlling water balance is disrupted. Water
is therefore drawn into the cell by osmosis causing it to swell and burst.

The following are the basic functions of the complement

1. Lysis of cells, bacteria and viruses.
2. Opsonization, which promotes phagocytosis of particulate antigens.
3. Binding to specific complement receptors on the cells of the immune system, triggering
specific cell functions, inflammation, and certain immunoregulatory molecules.
4. Immune Clearance, which removes immune complexes from immune system and deposits
them in the spleen and liver.