You’ve heard me talk about complement.
You’ve heard me mention complement.
You may be wondering, what is this?
What is complement?
Well, it’s not a single molecule.
It’s a series of molecules,
it’s a complement system.
And this system of molecules and
regulators of those molecules and receptors for
those molecules are incredibly important
in host defense against infection.
Complement can be activated
by three different pathways.
Firstly, the classical pathway.
It’s called the classical pathway because this was the pathway
of complement activation that was initially discovered.
And at that time, it was thought
there was just one pathway.
Things were simple;
the complement activation pathway.
But subsequently, the other two
pathways were discovered.
So the first pathway was
renamed the classical pathway.
The one everybody knew about.
And this is activated when an
antibody binds to an antigen.
In other words, antibody-antigen
complexes are formed.
There are other ways in which the classical
pathway of complement can be activated.
For example, C-reactive protein, an acute phase
protein that was mentioned in the… a few slides ago.
This C-reactive protein (CRP), can also
activate the classical pathway of complement.
So, antibody binding to antigen
will activate the first component
in the complement system which is
called complement component C1q.
This then helps to recruit two other
components of C1 called C1r and C1s.
These C1 components activate complement component C4,
which then goes on and activates complement component C2.
You’ll notice that the order of these
doesn’t seem to go with the normal order.
Normally we have one, two,
three, four, don’t we?
But these complement components were actually ordered in
the… or named rather in the order they were first discovered.
So scientists discovered complement
component C2 before they discovered C4.
But when the details of the pathways were worked
out, it was found that C4 comes before C2.
So hence the rather confusing numbering
of these complement components.
The next result of activation is that you generate a
enzyme complex that is referred to as a C3 convertase.
And the C3 convertase produced by the
classical pathway of complement activation
consists of a fragment of C4 called C4b,
together with a fragment of C2 called C2a.
So C4b2a is the C3 convertase
of the classical pathway.
What about the two other pathways?
The lectin pathway is
activated by microbial sugars.
Perhaps you already know that a lectin
is a protein that recognizes sugars.
Hence the name of this pathway.
In this pathway, sugars on the surface of microorganisms
are recognized by a molecule called mannose-binding lectin, MBL.
As its name suggests, it recognizes mannose, and
indeed it can recognize some other sugars as well.
But it gets its name from being
able to recognize the sugar mannose.
Mannose-binding lectin, sometimes called
mannose-binding protein as an alternative name.
When mannose-binding lectin recognizes
sugars on the surface of microorganisms, it
recruits two molecules that are very similar
to C1r and C1s of the classical pathway.
And those are called MASP-1 and MASP-2, stands
for Mannose-binding lectin Associated Serine
Protease-1 and Mannose-binding lectin Associated
Serine Protease-2; MASP-1 and MASP-2.
And they are very, very similar to C1r and
C1s, and in fact they do the same thing.
They activate C4, and
then C2 joins the pathway.
So you end up with exactly
the same C3 convertase, C4b2a.
This is in contrast to the alternative pathway
of complement activation, where microbial
sugars are not recognized, but other structures
on the surface of the microbe are recognized.
So various microbial surface structures
are recognized that are not sugars.
And here, complement component C3 binds to the surface
of microorganisms, becomes stabilized on the surface of
microorganisms and then recruits some other molecules
of the complement system called Factor B and Factor D.
And you end up with a C3 convertase
that is a different structure
to the C3 convertases of the classical and lectin pathways.
This particular C3
convertase is called C3bBb.
C3b is a fragment of C3,
and Bb is a fragment of Factor B.
So following activation by, for example a microorganism or by
antibody binding to antigen, you
get splitting of complement C3 by
the C3 convertase; either C4b2a in the case of the classical
or lectin pathways, or C3bBb in the
case of the alternative pathway.
And this complement component C3,
which really lies at the heart of the
complement system gets split into initially
two fragments called C3a and C3b.
And then subsequently, by addition of other molecules
to the C3 convertase, you generate a C5 convertase.
The case of the classical and lectin pathway - C4b2a3b,
the case of the alternative pathway - C3bBb3b.
And that C5 convertase, you won’t be
too surprised to hear, splits C5 into
two fragments, just like the C3
convertase split C3 into two fragments.
C5 convertase split C5 into two fragments,
and of course they’re called C5a and C5b.
So that’s all very well.
A little overview of the biochemistry
if you’d like, of complement.
But from an immunological point of view, perhaps more
interesting is what does complement actually do?
So let’s look at the main functional
components of the complement system.
Complement component C3a is involved in causing
mast cells in the tissues and basophils in
the blood circulation to degranulate, release
granules that contain inflammatory mediators.
Complement component C3b, the other
fragment that is generated when complement
component C3 gets split is involved in
opsonization of microorganisms for phagocytosis.
That term, opsonization,
what does that mean?
Well it means coating a microorganism to
make it more readily detected by a phagocytic cell.
And there are a number of
substances that can do that.
Complement component C3b is really good at doing
that; also the clearance of immune complexes.
Again another sort of slightly strange
term that immunologists tend to use.
Immune complex simply means an
antibody bound to an antigen.
And those complexes of antibody bound to antigen, they can
activate complement via the classical pathway as we’ve heard.
That can lead to the
generation of C3b.
And C3b is involved in linking
immune complexes to erythrocytes,
to red blood cells, which can help in them being cleared.
C5a just like C3a can cause mast
cells and basophils to degranulate,
but additionally is a very potent
chemotactic factor for neutrophils.
Attracting neutrophils out of the blood
circulation and to the site of the infection.
And then complement component C5b,
together with component C6, C7, C8 and
C9 collectively form something called
the Membrane Attack Complex or MAC.
And as its name suggest, the Membrane Attack Complex attacks
the membranes of microorganisms leading to their lysis.
So really, at the heart of activation of the complement
system, which is a key part of inflammation and immune
defense, is splitting complement component C3 into C3a
and C3b, and complement component C5 into C5a and C5b.
Because that leads to the generation
of C3a and C5a involved in mast cell
degranulation, of the C5a which is also
involved in neutrophil chemotaxis.
Of complement component C3b and then a further split fragment
called C3d, which is involved in opsonization of microorganisms.
C5b to C9, as we’ve already heard, generating the
Membrane Attack Complex, lysing microorganisms.
C3b involved in immune clearance of
immune complexes, by red blood cells.
And C3d finally, can also be involved in activating
the B-lymphocytes of the adaptive immune response.