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Complement
activation
We have alluded to complement before and it is described in
detail below. Complement is a group of molecules that will attack
and destroy bacteria and other pathogens. The complement system
has been around in some shape or form for a long time in terms
of evolutionary history, testament to the fact that it is a highly
effective defense mechanism. The complement system can be observed
operating in many invertebrates long before the development of
the adaptive immune system, B cells and antibody production.
Complement can work on its own in invertebrates and still has
that ability under certain circumstances in ourselves and other
vertebrates. However, it has teamed up with the adaptive immune
system and antibodies to be even more potent in its defense activity.
Antibodies can act as a marker for complement molecules. If a
high concentration of antibodies bind to something antigenic (bacteria
etc.) then complement will preferentially bind alongside the antibody.
Once complement is bound to the surface of a cell wall it is activated
into its destructive form (see below).
Complement
The complement system is part of our innate immune defense. The
complement system, like antibodies, can operate independently of
the rest of the immune system to defend against a limited range
of microorganisms but more frequently it works in conjunction with
antibodies and immune cells to remove a pathogenic threat. The complement
system is made up of numerous serum soluble protein molecules each
with particular functions. The system involves a cascade of reactions
between these proteins that must occur in sequence to have an effect.
The complement system is present in some form in most vertebrates
and can be seen to resemble functions observed in many higher invertebrates
too.
The complement system is quite complex and understanding the process
is not helped by the obscure method used to name the different proteins
involved. There are at least 11 different proteins involved and
sometimes more depending on how the process develops with each pathogenic
challenge. A typical complement process would involve (in order)
proteins C1q, C1r, C1s, C4, C2, C3, C5, C6, and lastly C7. The complex
naming is a consequence of the way in which the proteins were discovered.
Different components of the complement system have been discovered
over a time span of 50 years from around 1907 to the mid 1950s.
C2 was discovered before C4 although it works in the system after
C4 has been activated. The potency of the complement system was
first recognized in 1895 when it was known that mixing purified
serum with antibody and applying this to a suspension of bacteria
will result in their rapid destruction. I'm going to avoid discussing
the particular components of the complement system as there are
so many and each can have more than one function.
The complement system has three several roles. 1) We described
antibodies as opsonizers, coating microorganisms and damaged cells
to flag them as suitable for attack and destruction. Some proteins
of the complement system can do the same thing, they are also opsonizers
indicating what particles should be destroyed. 2) Binding of complement
proteins to particles results in small fragments of complement being
broken off. These fragments diffuse away from the site of pathogenic
challenge and act as stimulators of immune cells. Many immune cell
types will migrate towards a high concentration of these complement
fragments. In other words immune cells move up a concentration gradient
of complement fragments towards their source of release, the cells
indulge in chemotaxis. 3) Many immune system cells have receptors
for complement proteins and are able to recognize complement bound
to tissue. Immune cells will attach to the bound complement which
then activates the cells into antigen destroyers. 4) The complement
proteins themselves are capable of destroying microorganisms. The
proteins can come together in such a way as to break up the integrity
of a cell wall and cause lysis (bursting) of the microorganism.
Activation
pathways
To add to the confusion, when we talk about the complement system
we are really talking about two very different mechanisms, the "classic"
pathway and the "alternative" pathway.
The classic pathway is the most common method of complement activation.
It usually involves antibody as the dictator of what happens where.
The complement protein C1q favors binding to both IgM and IgG, but
only if the antibodies are themselves bound to a target. When C1q
is unattached it is inactive and innocuous. When it binds to an
antibody it changes its molecular shape and this exposes a binding
site for another complement protein C1r. This leads to a cascade
of complement proteins binding in sequence to each other and with
binding each protein is activated. C1q can also bind directly to
a minority of pathogens without the help of antibodies. Some types
of retro virus are favorite targets for C1q.
The alternative pathway of complement activation does not involve
the binding of C1 proteins. It starts with a C3 molecule. C3 breaks
into two molecules on binding and becomes active to elicit a cascade
of complement protein interactions similar, but not the same as
the classical pathway.
In the alternative activation pathway the complement system is
capable of acting independently of other parts of the immune system.
Typically antibodies are not involved in the alternative pathway.
For complement to be activated without using bound antibodies as
an initial trigger complement must take on the ability of distinguishing
between self and non self antigens. The protein called "C3"
is the key to distinguishing between different antigens. Self cells
and tissues prohibit binding of C3 to their surface. It's not fully
understood how the mechanism works but self cell membranes promote
binding of two proteins (C3b and factor H). These proteins are entirely
innocuous but they physically block the binding sites for other
complement proteins. Bacterial and viral cell walls cannot bind
C3b or factor H and so are exposed to the alternative pathway of
activation. Any foreign cells that do have a coating of protective
proteins can still be destroyed using antibodies and the classic
pathway of complement activation.
Both the alternative and classic activation pathways ultimately
lead to the formation of a "membrane attack complex".
A group of complement proteins link together to form a cylinder
which is then punched through the cell surface. The mechanism is
very similar to the method used by cytotoxic T cells to destroy
cells. Punching a hole in a cell wall means the cell can no longer
regulate the concentration of water and salts inside, they can flow
freely through the hole. Cells have a high concentration of salts
inside, much higher than in the fluid which bathes tissue. When
a hole is made in a cell membrane water molecules rush in to even
up the salt concentration and make it the same as the external fluid.
The water molecules blow the cell up until it bursts (lysis).
In the classical pathway of complement activation,
complement proteins take their cue from antibodies. Complement
recognizes material to which large amounts of antibody has bound.
Complement proteins preferentially bind to the material alongside
the antibodies. A cascade of events leads to formation of a membrane
attack complex alongside the complement protein. The attack complex
is simply a hollow tube that is pushed into the membrane creating
a hole through which water enters. Water will swell the organism
until it bursts.
I have glossed over much of the complex complement system but
I think this brief overview will be enough to understand how it
acts independently and in conjunction with antibodies and immune
cells to form a potent defense mechanism.
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