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Hello, I'm Seppo Meri from the University of Helsinki.
And in this presentation,
I will discuss how pathogenic bacteria can escape complement mediated killing.
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So, the complement system is part of innate immunity;
It is involved in interactions with leukocytes,
cells of the immune system,
and the complement system, with all its recognition molecules,
will recognise microbes or other invaders into the human body.
It's also involved in the clearance of
debris and other material from injured or apoptotic cells.
After binding of complement proteins to the microbes,
they are recognised by complement receptors,
for example, on neutrophils, on macrophages,
and that can lead to phagocytosis of the bacteria.
Complement activation also generates inflammation that
then attracts leukocytes to the area of inflammation.
Complement activation is also involved in the capture of antigens for
the specific adaptive immune response activation.
Antigens will be presented by dendritic cells and macrophages,
and B-cells to T-cells,
and part of the antigen capture is mediated also by complement receptors.
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Complement activation can proceed through different pathways.
If you have a bacterium and bacterial surface,
it can be recognised by antibodies against the bacteria,
different structures on its surface.
Antibodies, when they have bound in a high enough density to the surface,
they can bind the first protein of the complement system,
C1 and its sub-component C1q, and that would activate
the next components, C4 and C2,
in the system, that together make an enzyme which is called C3 convertase.
C3 convertase is cleaving or activating the soluble C3 protein to C3b.
In the so-called alternative pathway,
one doesn't need any specific activator to activate the system.
Spontaneous binding of the C3b is enough to start
the activation and that occurs automatically, by default,
and after binding of C3b covalently to the target,
it binds factor B, which gets activated to Bb by factor D,
and thereby, there will be an activation of new C3 molecules
to generate C3b's that can again bind covalently to the bacterial surface.
Thereby, complement activation is amplified and opsonisation of the target,
the bacterium, occurs very efficiently within a couple of minutes.
And complement activation in general leads also to lysis of the target,
especially if it's a gram-negative bacterium,
it can generate membrane attack complexes to the outer membrane of
the bacterium and thereby cause osmotic lysis.
So, this is how susceptible bacteria are killed by complement,
either by opsonophagocytosis, or by direct membrane attack complex killing.
In order to prevent the complement activation,
there are soluble inhibitors that regulate the C3 convertase enzymes.
Most important of these, is factor H that can
control the activity of the alternative pathway C3 convertase enzyme.
It can prevent its activity towards C3.
Factor H can also promote the inactivation of C3b on the surface.
An equivalent inhibitor in the classical pathway and also in
the lectin pathway, which is the third pathway of complement activation,
is C4b binding protein that can prevent C3 activation by
the classical pathway C3 convertase.
